piperidines and 4-iodo-2-5-dimethoxyphenylisopropylamine

Psychedelic drugs acting as 5-hydroxyptryptamine 2A receptor (5-HT

Topics: Aminopyridines; Amphetamines; Animals; Behavior, Animal; Citalopram; Compulsive Behavior; Disease Models, Animal; Female; Fluorobenzenes; Indoles; Mice; Piperidines; Psilocybin; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Agonists; Serotonin Antagonists

It has been recognized that serotonin 2A receptor (5-HT

Topics: Acetophenones; Amphetamines; Animals; Behavior, Animal; Benzopyrans; Ginsenosides; Hypothalamus; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Oxidative Stress; Piperidines; Protein Kinase C-delta; Protein Kinase Inhibitors; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Serotonin Syndrome

Atypical antipsychotic drugs (APDs) used to treat positive and negative symptoms in schizophrenia block serotonin receptors 5-HT

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amphetamines; Animals; Antipsychotic Agents; Brain Waves; Cortical Synchronization; Dopamine Agonists; Dopamine Antagonists; Electroencephalography; Fluorobenzenes; Gamma Rhythm; Haloperidol; Hippocampus; Locomotion; Mice; Neural Pathways; Piperazines; Piperidines; Prefrontal Cortex; Pyridines; Quinpirole; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Risperidone; Serotonin Antagonists; Serotonin Receptor Agonists

There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT

Topics: Adrenergic Antagonists; Amphetamines; Animals; Behavior, Animal; Binding Sites; Carvedilol; Computational Chemistry; Drug Discovery; Fluorobenzenes; HEK293 Cells; Humans; Lysergic Acid Diethylamide; Male; Mice; Models, Animal; Models, Molecular; Piperidines; Protein Binding; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists; Transfection

Serotonin

Topics: Amino Acids; Amphetamines; Animals; Bridged Bicyclo Compounds, Heterocyclic; Compulsive Behavior; Drinking Behavior; Excitatory Amino Acid Agonists; Fluorobenzenes; Glutamic Acid; Male; Piperidines; Prefrontal Cortex; Random Allocation; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Receptors, Metabotropic Glutamate; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists

Endocannabinoids and their receptors not only contribute to the control of natural processes of appetite regulation and energy balance but also have an important role in the pathogenesis of obesity. CB1 receptors (CB1R) are expressed in several hypothalamic nuclei, including the paraventricular nucleus (PVN), where induce potent orexigenic responses. Activation of CB1R in the PVN induces hyperphagia by modulating directly or indirectly orexigenic and anorexigenic signals; however, interaction among these mediators has not been clearly defined. CB1R mRNA is expressed in serotonergic neurons that innervate the PVN, and activation of 5-HT receptors in the PVN constitutes an important satiety signal. Some GABAergic terminals are negatively influenced by 5-HT, suggesting that the hyperphagic effect of CB1R activation could involve changes in serotonergic and GABAergic signaling in the PVN. Accordingly, the present study was aimed to characterize the neurochemical mechanisms related to the hyperphagic effects induced by activation of CB1R in the PVN, studying in vitro and in vivo changes induced by direct activation these receptors. Here, we have found that the neurochemical mechanisms activated by stimulation of CB1 receptors in the PVN involve inhibition of 5-HT release, resulting in a decrease of serotonergic activity mediated by 5-HT

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amphetamines; Animals; Arachidonic Acids; Cyproheptadine; Drug Interactions; Eating; gamma-Aminobutyric Acid; Male; Microinjections; Paraventricular Hypothalamic Nucleus; Piperazines; Piperidines; Piperidones; Pyrazoles; Pyridines; Pyrroles; Rats; Receptor, Cannabinoid, CB1; Receptors, Serotonin, 5-HT1; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Spiro Compounds; Tritium

These experiments examined the effects of selective 5-HT. Water-restricted rats learned to associate a conditioned stimulus (CS) with water in operant chambers. Subsequently, two response levers were made available; responding on one lever delivered the CS (now a CRf), while responding on the second lever had no consequences. The effects of agonist and antagonists of 5-HT. Responding for a CRf was reduced by the agonists 8-OH-DPAT, DOI and Ro60-0175. 8-OH-DPAT also reduced responding for water and seemed to impair responding in a non-specific fashion. None of the receptor antagonists affected responding. Methylphenidate dose-dependently enhanced responding for a CRf, and this was attenuated by DOI and Ro60-0175. Conversely, the 5-HT. No evidence was found for a behaviourally selective effect of 5-HT

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aminopyridines; Amphetamines; Animals; Conditioning, Operant; Fluorobenzenes; Indoles; Male; Methylphenidate; Piperazines; Piperidines; Pyridines; Rats; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Reinforcement, Psychology; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists

Several receptor mediated pathways have been shown to modulate the murine head twitch response (HTR). However, the role of sigma receptors in the murine (±)-2,5-dimethoxy-4-iodoamphetamine (DOI)-induced HTR has not been previously investigated. We examined the ability of LS-1-137, a novel sigma-1 vs. sigma-2 receptor selective phenylacetamide, to modulate the DOI-induced HTR in DBA/2J mice. We also assessed the in vivo efficacy of reference sigma-1 receptor antagonists and agonists PRE-084 and PPCC. The effect of the sigma-2 receptor selective antagonist RHM-1-86 was also examined. Rotarod analysis was performed to monitor motor coordination after LS-1-137 administration. Radioligand binding techniques were used to determine the affinity of LS-1-137 at 5-HT2A and 5-HT2C receptors. LS-1-137 and the sigma-1 receptor antagonists haloperidol and BD 1047 were able to attenuate a DOI-induced HTR, indicating that LS-1-137 was acting in vivo as a sigma-1 receptor antagonist. LS-1-137 did not compromise rotarod performance within a dose range capable of attenuating the effects of DOI. Radioligand binding studies indicate that LS-1-137 exhibits low affinity binding at both 5-HT2A and 5-HT2C receptors. Based upon the results from these and our previous studies, LS-1-137 is a neuroprotective agent that attenuates the murine DOI-induced HTR independent of activity at 5-HT2 receptor subtypes, D2-like dopamine receptors, sigma-2 receptors and NMDA receptors. LS-1-137 appears to act as a sigma-1 receptor antagonist to inhibit the DOI-induced HTR. Therefore, the DOI-induced HTR can be used to assess the in vivo efficacy of sigma-1 receptor selective compounds.

Topics: Acetanilides; Amphetamines; Animals; Head Movements; Male; Mice; Mice, Inbred DBA; Morpholines; Piperidines; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Receptors, sigma; Sigma-1 Receptor

Blonanserin differs from currently used serotonin 5-HT₂A/dopamine-D₂ receptor antagonists in that it exhibits higher affinity for dopamine-D₂/₃ receptors than for serotonin 5-HT₂A receptors. We investigated the involvement of dopamine-D₃ receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT₂A receptor agonist) and 7-OH-DPAT (a dopamine-D₃ receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D₁ receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr(197) and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser(897) by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser(896) by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D₁-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D₃ and serotonin 5-HT₂A receptors in the mPFC.

Topics: Amphetamines; Animals; Benzazepines; Benzodiazepines; Dopamine; Dopamine Agonists; Isoquinolines; Male; Mice; Olanzapine; Phencyclidine; Phosphorylation; Piperazines; Piperidines; Prefrontal Cortex; Protein Kinase Inhibitors; Receptors, Dopamine D1; Receptors, Dopamine D3; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology; Serotonin Receptor Agonists; Sulfonamides; Tetrahydronaphthalenes

Disturbances of serotonergic signaling, including the serotonin 2A (5-HT2A) receptor, have been implicated in neuropsychiatric and neurodegenerative disorders. The aim of the present study was to characterize the effect of a 5-HT2A receptor agonist on cytotoxicity in a neuronal cell line and address the involved mechanism. HTR2A mRNA and protein expression in human neuroblastoma SK-N-SH cells was confirmed. Cells were subjected to serum deprivation and cell viability was monitored continuously with xCELLigence. In a dose-response study the 5-HT2A agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) (25 nM to 5 μM) protected against serum deprivation cytotoxicity. The selective 5-HT2A receptor antagonist MDL 11,939, the general protein tyrosine kinase inhibitor genistein, and the extracellular signal-regulated kinase (ERK) pathway MEK inhibitor U0126, all attenuated DOI's protective effect. An antibody array suggested that 1 μM DOI affected phosphorylation of several tyrosine kinases. Western blot further confirmed that DOI transiently increased ERK phosphorylation, indicating its activation. Finally, protective concentrations of DOI increased cellular mitochondrial mass, an effect prevented by pretreatment with U0126. In conclusion, our results suggest that DOI protects SK-N-SH cells against serum deprivation through ERK pathway activation. They imply 5-HT2A receptor modulation as a potential target for neuroprotection.

Topics: Amphetamines; Cell Line, Tumor; Cell Proliferation; Culture Media, Serum-Free; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Humans; MAP Kinase Signaling System; Neuroblastoma; Organic Chemicals; Piperidines; Receptor, EphB3; Receptor, Serotonin, 5-HT2A; RNA, Messenger; Serotonin Antagonists; Serotonin Receptor Agonists; Time Factors

The psychotropic drug asenapine is approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. Asenapine exhibits higher affinity for several 5-HT receptors and α(2)-adrenoceptors than for D(2) receptors. Noteworthy, blockage of both the 5-HT(2A) and α(2)-adrenergic receptors has been shown to enhance prefrontal dopamine release induced by D(2) receptor antagonists. Previous results show that asenapine, both systemically and locally, increases dopamine, noradrenaline, and serotonin release in the medial prefrontal cortex (mPFC), and that the increased dopamine release largely depends on an intracortical action. Using reverse microdialysis in freely moving rats, we here assessed the potency of low concentrations of asenapine to cause a pharmacologically significant blockage in vivo of 5-HT(2A) receptors and α(2)-adrenoceptors within the mPFC, and thus its ability to affect cortical monoamine release by these receptors. Intracortical administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), a 5-HT(2A/2C) receptor agonist, increased cortical monoamine release, effects that were antagonized both by asenapine and the selective 5-HT(2A) antagonist M100907. Application of clonidine, an α(2)-adrenoceptor agonist, significantly reduced monoamine release in the mPFC. The selective α(2)-adrenoceptor antagonist idazoxan blocked, whereas asenapine partially blocked clonidine-induced cortical dopamine and noradrenaline decrease. The effects of asenapine and idazoxan on clonidine-induced serotonin decrease were less pronounced. Our results propose that low concentrations of asenapine in the mPFC exhibit a pharmacologically significant 5-HT(2A) and α(2) receptor antagonistic activity, which may contribute to enhance prefrontal monoamine release in vivo and, secondarily, its clinical effects in schizophrenia and bipolar disorder.

Topics: Adrenergic alpha-2 Receptor Antagonists; Amphetamines; Animals; Antipsychotic Agents; Biogenic Monoamines; Dibenzocycloheptenes; Fluorobenzenes; Heterocyclic Compounds, 4 or More Rings; Male; Microdialysis; Norepinephrine; Piperidines; Prefrontal Cortex; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptors, Adrenergic, alpha-2; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Up-Regulation

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration in cognitive functioning. Overall, 25-50% of patients with AD also show symptoms of psychosis including hallucinations and delusions. As all available antipsychotic drugs have a 'black-box' warning for use in these patients because of increased mortality, no appropriate treatment for psychotic symptoms in AD currently exists. In the present study, we examined whether selective antagonism of 5-HT(2A) serotonin receptors has antipsychotic-like activity in an animal model of AD. Mice receiving an intracerebroventricular infusion of the amyloid β(25-35) peptide fragment showed AD-like histopathology and a psychosis-related behavioral phenotype with enhanced responses to the psychostimulants 2,5-dimethoxy-4-iodoamphetamine hydrochloride and amphetamine as well as disrupted prepulse inhibition. Treatment with pimavanserin, a selective serotonin 5-HT(2A) receptor inverse agonist, prevented 2,5-dimethoxy-4-iodoamphetamine hydrochloride-induced head twitches, reversed the augmented locomotor response to amphetamine, and normalized prepulse inhibition in mice with amyloid pathology. These data suggest that an infusion of amyloid β might induce alterations in serotonergic function that underlie a psychosis-like phenotype that can be normalized by treatment with a 5-HT(2A) inverse agonist. This in turn suggests that 5-HT(2A) inverse agonists, such as pimavanserin, might have therapeutic benefits in the treatment of psychosis in AD patients.

Topics: Alzheimer Disease; Amphetamine; Amphetamines; Animals; Antipsychotic Agents; Behavior, Animal; Disease Models, Animal; Drug Inverse Agonism; Male; Mice; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Antagonists; Urea

The serotonin (5-HT) 2A receptor is implicated in numerous psychiatric disorders, making it an important, clinically relevant target. Despite the availability of transgenic mouse lines, the native mouse 5-HT(2A) receptor is not well-characterized.. The goals of the current study were to determine 5-HT(2A) and 5-HT(2C) receptor densities in mouse cortex, establish a pharmacological profile of the mouse 5-HT(2A) receptor, and determine the effects of chronic drug treatment on 5-HT(2A) receptor density and 5-HT(2A) receptor-mediated behavior.. Receptor densities were determined in cortex and frontal cortex via saturation binding assays using [(3)H]ketanserin or [(3)H]mesulergine. A pharmacological profile was established by displacing [(3)H]ketanserin binding with several ligands. Chronic treatment with 5-HT(2A/2C) receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), 5-HT(2A) receptor antagonist, MDL 11939, or vehicle was followed by 5-HT(2A) receptor density determination. Head twitch responses (HTRs) were counted on select days.. Mice had high 5-HT(2A), but low 5-HT(2C) receptor densities. Ligand binding affinities for mouse 5-HT(2A) receptors correlated with rat, but not rabbit or human, affinities. Chronically DOI-treated mice displayed reduced HTRs and 5-HT(2A) receptor density compared to saline-treated mice. Receptor density was unchanged following chronic treatment with MDL 11939.. The current study provides some basic information about mouse 5-HT(2A) and 5-HT(2C) receptors and provides comparisons to rats, rabbits, and humans. The current chronic agonist treatment study demonstrated an important similarity between the 5-HT(2A) receptor in mice, rats, and rabbits, while antagonist treatment revealed an interesting difference from previous studies in rabbits.

Topics: Amphetamines; Animals; Cerebral Cortex; Humans; Ligands; Male; Mice; Mice, Inbred C57BL; Piperidines; Protein Binding; Rabbits; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin Antagonists; Serotonin Receptor Agonists; Species Specificity

Parkinson's disease psychosis (PDP) is a condition for which a safe, tolerated, and effective therapy is lacking. Treatment with typical or atypical antipsychotics may be contraindicated in patients with PDP because of the potential for aggravating motor symptoms. This study used a novel animal model with features of both Parkinson's disease (PD) and psychosis to examine a potential mechanism for reversing PDP. Animals with bilateral 6-hydroxydopamine lesions of the substantia nigra displayed motoric impairments characteristic of humans with PD. In addition, they displayed augmented head twitches, augmented amphetamine-induced locomotor activity, and disrupted prepulse inhibition compared with sham controls, behavioral indices frequently used to assess antipsychotic activity in animal models. Pimavanserin, a selective 5-HT2A antagonist/inverse agonist, reversed the psychotic-like behavioral deficits, suggesting that nigrostriatal (6-hydroxydopamine) lesions induced alterations in 5-HT2A-mediated signaling. The selective 5-HT2A inverse agonist M100907, but not the selective 5-HT2C inverse agonist SB 252084 paralleled the effects of pimavanserin. Of note, the reversal of psychotic-like behaviors produced by 5-HT2A inverse agonists occurred without disrupting motor behaviors in lesioned subjects, suggesting that 5HT2A antagonism/inverse agonism may be beneficial in the treatment of PDP.

Topics: Amphetamine; Amphetamines; Animals; Antipsychotic Agents; Behavior, Animal; Central Nervous System Stimulants; Disease Models, Animal; Dyskinesias; Fenfluramine; Fluorobenzenes; Hyperkinesis; Male; Motor Activity; Oxidopamine; Parkinson Disease; Piperidines; Psychotic Disorders; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Sensory Gating; Serotonin 5-HT2 Receptor Antagonists; Serotonin Agents; Serotonin Receptor Agonists; Substantia Nigra; Tyrosine 3-Monooxygenase; Urea

We verified the hypothesis that serotonin (5-HT)(2) receptors control the locomotor effects of nicotine (0.4 mg kg(-1)) in rats by using the 5-HT(2A) receptor antagonist M100907, the preferential 5-HT(2A) receptor agonist DOI, the 5-HT(2C) receptor antagonist SB 242084, and the 5-HT(2C) receptor agonists Ro 60-0175 and WAY 163909. Repeated pairings of a test environment with nicotine for 5 days, on Day 10 significantly augmented the locomotor activity following nicotine administration. Of the investigated 5-HT(2) receptor ligands, M100907 (2 mg kg(-1)) or DOI (1 mg kg(-1)) administered during the first 5 days in combination with nicotine attenuated or enhanced, respectively, the development of nicotine sensitization. Given acutely on Day 10, M100907 (2 mg kg(-1)), Ro 60-0175 (1 mg kg(-1)), and WAY 163909 (1.5 mg kg(-1)) decreased the expression of nicotine sensitization. In another set of experiments, where the nicotine challenge test was performed on Day 15 in animals treated repeatedly (Days: 1-5, 10) with nicotine, none of 5-HT(2) receptor ligands administered during the second withdrawal period (Days: 11-14) to nicotine-treated rats altered the sensitizing effect of nicotine given on Day 15. Our data indicate that 5-HT(2A) receptors (but not 5-HT(2C) receptors) play a permissive role in the sensitizing effects of nicotine, while stimulation of 5-HT(2A) receptors enhances the development of nicotine sensitization and activation of 5-HT(2C) receptors is essential for the expression of nicotine sensitization. Repeated treatment with the 5-HT(2) receptor ligands within the second nicotine withdrawal does not inhibit previously established sensitization.

Topics: Aminopyridines; Amphetamines; Animals; Azepines; Ethylamines; Fluorobenzenes; Indoles; Male; Motor Activity; Nicotine; Nicotinic Agonists; Piperidines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Time Factors

Stress and anxiety disorders are risk factors for depression and these behaviors are modulated by corticotrophin-releasing factor receptor 1 (CRFR1) and serotonin receptor (5-HT(2)R). However, the potential behavioral and cellular interaction between these two receptors is unclear. We found that pre-administration of corticotrophin-releasing factor (CRF) into the prefrontal cortex of mice enhanced 5-HT(2)R-mediated anxiety behaviors in response to 2,5-dimethoxy-4-iodoamphetamine. In both heterologous cell cultures and mouse cortical neurons, activation of CRFR1 also enhanced 5-HT(2) receptor-mediated inositol phosphate formation. CRFR1-mediated increases in 5-HT(2)R signaling were dependent on receptor internalization and receptor recycling via rapid recycling endosomes, resulting in increased expression of 5-HT(2)R on the cell surface. Sensitization of 5-HT(2)R signaling by CRFR1 required intact PDZ domain-binding motifs at the end of the C-terminal tails of both receptor types. These data suggest a mechanism by which CRF, a peptide known to be released by stress, enhances anxiety-related behavior via sensitization of 5-HT(2)R signaling.

Topics: Amphetamines; Animals; Anxiety; Behavior, Animal; Biotinylation; Cells, Cultured; Corticotropin-Releasing Hormone; Cyclic AMP; Disease Models, Animal; Dose-Response Relationship, Drug; Embryo, Mammalian; Fluorobenzenes; Hormones; Humans; Inositol Phosphates; Ionophores; Male; Maze Learning; Mice; Monensin; Mutation; Neurons; Piperidines; Prefrontal Cortex; Rats; Reaction Time; Receptors, Corticotropin-Releasing Hormone; Receptors, Serotonin, 5-HT2; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Agents; Signal Transduction; Transfection

Intrahippocampal injections of aggregated amyloid-beta (Abeta)1-42 in rats result in memory impairment and in reduction of hippocampal 5-HT2A receptor levels. In order to investigate how changes in 5-HT2A levels and functionality relate to the progressive accumulation of Abeta protein, we studied 5-HT2A receptor regulation in double transgenic AbetaPPswe/PS1dE9 mice which display excess production of Abeta and age-dependent increase in amyloid plaques. Three different age-groups, 4-month-old, 8- month-old, and 11-month-old were included in the study. [3H]-MDL100907, [3H]-escitalopram, and [11C]-PIB autoradiography was performed for measuring 5-HT2A receptor, serotonin transporter (SERT), and Abeta plaque levels in medial prefrontal cortex (mPFC), prefrontal cortex (PFC), frontoparietal cortex (FPC), dorsal and ventral hippocampus, and somatosensory cortex. To investigate 5-HT2A receptor functionality, animals were treated with the 5-HT2A receptor agonist DOI and head-twitch response (HTR) subsequently recorded. Expression level of the immediate early gene c-fos was measured by in situ hybridization. We found that the age-related increase in Abeta plaque burden was accompanied by a significant decrease in 5-HT2A receptor binding in mPFC in the 11-month-old group. The changes in 5-HT2A receptor binding correlated negatively with [11C]-PIB binding and were not accompanied by decreases in SERT binding. Correspondingly, 11-month-old transgenic mice showed diminished DOI-induced HTR and reduced increase in expression of c-fos mRNA in mPFC and FPC. These observations point towards a direct association between Abeta accumulation and changes in 5-HT2A receptor expression that is independent of upstream changes in the serotonergic system.

Topics: Aging; Amphetamines; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Autoradiography; Citalopram; Data Interpretation, Statistical; Fluorobenzenes; Genes, fos; Head Movements; Humans; In Situ Hybridization; Indicators and Reagents; Male; Mice; Mice, Transgenic; Piperidines; Plaque, Amyloid; Receptor, Serotonin, 5-HT2A; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Serotonin Receptor Agonists; Thiazoles

Drug-elicited head-twitch behavior is a useful model for studying hallucinogen activity at 5-HT(2A) receptors in the mouse. Chemically diverse compounds active in this assay yield biphasic dose-effect curves, but there is no compelling explanation for the "descending" portion of these functions. A set of experiments was designed to test the hypothesis that the induction of head-twitch behavior is mediated by agonist actions at 5-HT(2A) receptors, whereas the inhibition of head-twitch behavior observed at higher doses results from competing agonist activity at 5-HT(2C) receptors. The effects of the phenethylamine hallucinogen R(-)-2,5-dimethoxy-4-iodoamphetamine (DOI) on head-twitch behavior were studied over a range of doses in the mouse, generating a characteristic biphasic dose-response curve. Pretreatment with the selective 5-HT(2A) antagonist (+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907) shifted only the ascending limb of the DOI dose-effect function, whereas pretreatment with the nonselective 5-HT(2A/2C) antagonist 3-{2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl}quinazoline-2,4(1H,3H)-dione (ketanserin) produced a parallel shift to the right in the DOI dose-response curve. Administration of the 5-HT(2C) agonist S-2-(chloro-5-fluoro-indol-l-yl)-1-methylethylamine (Ro 60-0175) noncompetitively inhibited DOI-elicited head-twitch behavior across the entire dose-effect function. Finally, pretreatment with the selective 5-HT(2C) antagonists 6-chloro-5-methyl-1-[(2-[2-methylpyrid-3-yloxy]pyrid-5yl)carbamoyl]indoline (SB242084) or 8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulfonamido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4,5]decane-2,4-dione hydrochloride (RS 102221) did not alter DOI-elicited head-twitch behavior on the ascending limb of the dose-response curve but shifted the descending limb of the DOI dose-response function to the right. The results of these experiments provide strong evidence that DOI-elicited head-twitch behavior is a 5-HT(2A) agonist-mediated effect, with subsequent inhibition of head-twitch behavior being driven by competing 5-HT(2C) agonist activity.

Topics: Aminopyridines; Amphetamines; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Ethylamines; Fluorobenzenes; Hallucinogens; Head; Indoles; Ketanserin; Male; Mice; Mice, Inbred Strains; Movement; Piperidines; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Spiro Compounds; Sulfonamides

The mechanisms underlying individual differences in the response to serotonergic drugs are poorly understood. Rat studies may contribute to our knowledge of the neuronal substrates that underlie these individual differences.. A pharmacobehavioural study was performed to assess individual differences in the sensitivity to serotonergic drugs in rats that were selected based on their response to a novel environment.. Low responders (LR) and high responders (HR) to novelty rats were tested on the elevated T-maze following systemic injections of increasing doses of various serotonergic agents. The duration of avoidance of the open arms was scored for five trials.. The duration of avoidance behaviour was larger in saline-treated LR rats compared to saline-treated HR rats. The 5-HT1A agonist 8-OH-DPAT and the 5-HT2 agonists mCPP and DOI decreased the duration of avoidance behaviour in LR rats, but increased it in HR rats. The 5-HT3 agonist SR57227A and the 5-HT releaser/reuptake inhibitor d-fenfluramine increased the duration of avoidance behaviour in both types of rat. However, higher doses of SR57227A were required to alter avoidance behaviour in HR than in LR rats. The onset of the effects of SR57227A, d-fenfluramine and WAY100635 was faster in LR than in HR rats. The described effects were receptor specific. A model explaining the data is presented.. These data demonstrate that LR and HR rats differ in their sensitivity to serotonergic drugs that act at 5-HT3, 5-HT2 and 5-HT1A receptors. The implications of these individual differences for individual-specific treatment of substance abuse are briefly discussed.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amphetamines; Animals; Avoidance Learning; Dose-Response Relationship, Drug; Exploratory Behavior; Fenfluramine; Individuality; Male; Maze Learning; Piperazines; Piperidines; Pyridines; Rats; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Serotonin Receptor Agonists

Variability in expression of the 5-HT transporter (5-HTT) gene in the human population has been associated with a range of behavioural phenotypes. The underlying mechanisms are unclear but may involve changes in 5-HT receptor levels and/or signalling. The present study used a novel 5-HTT overexpressing transgenic mouse to test the hypothesis that variability in 5-HTT expression may alter 5-HT(2A) receptor function. In wildtype mice, the 5-HT(2) receptor agonist DOI increased regional brain mRNA expression of two immediate early genes (c-fos and Arc), and induced head twitches, and both effects were abolished by pre-treatment with the 5-HT(2A) receptor antagonist MDL 100907. In 5-HTT overexpressing mice, DOI induced a greater increase in both c-fos and Arc mRNA expression in cortical brain regions, and more head twitches, compared to wildtype mice. Autoradiographic and in situ hybridisation experiments showed that 5-HT(2A) receptor binding sites and 5-HT(2A) receptor mRNA did not differ between transgenic and wildtype mice. Finally, the transgenic mice had lower regional brain 5-HT levels compared to wildtype mice. This depletion of 5-HT may underpin the increase in 5-HT(2A) receptor function because in wildtype mice 5-HT depletion using the 5-HT synthesis inhibitor, p-chlorophenylalanine, enhanced the head twitch response to DOI. These data demonstrate that elevated 5-HTT expression is accompanied by increased 5-HT(2A) receptor function, an effect possibly mediated by decreased availability of synaptic 5-HT. Variation in levels of 5-HTT expression may therefore be a source of variability in 5-HT(2A) receptor function, which may be an important modifier of 5-HTT-linked phenotypes.

Topics: Amphetamines; Analysis of Variance; Animals; Brain; Cytoskeletal Proteins; Dose-Response Relationship, Drug; Fluorobenzenes; Gene Expression; Genetic Variation; Head Movements; Ketanserin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Piperidines; Protein Binding; Proto-Oncogene Proteins c-fos; Receptor, Serotonin, 5-HT2A; Serotonin; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Serotonin Receptor Agonists

Serotonin 5-HT2A and 5-HT2C receptors have been implicated in the pathophysiology of obsessive-compulsive disorder (OCD) and in the mechanism mediating the anti-compulsive effects of serotonin reuptake inhibitors. Yet it is currently unclear whether activation or blockade of these receptors would have an anti-compulsive effect. The present study tested the effects of 5-HT2A and 5-HT2C activation and blockade in the signal attenuation rat model of OCD. In this model, 'compulsive' behaviour is induced by attenuating a signal indicating that a lever-press response was effective in producing food. Experiments1-4 revealed that systemic administration of the 5-HT2C antagonist RS 102221 (2 mg/kg) selectively decreases compulsive lever-pressing, whereas systemic administration of the 5-HT2A antagonist MDL11,939(0.2-5 mg/kg) or of the 5-HT2A/2C agonist DOI (0.05-5 mg/kg) did not have a selective effect on this behaviour. Experiments 5 and 6 found that systemic co-administration of DOI (0.5 mg/kg) withMDL11,939 (1 mg/kg) or with RS 102221 (2 mg/kg) had a non-selective effect on lever-press responding,with the former manipulation increasing and the latter manipulation decreasing lever-pressing. Finally,experiment 7 demonstrated that administration of RS 102221 directly into the orbitofrontal cortex also exerts an anti-compulsive effect. The results of these experiments suggest that blockade of 5-HT2Creceptors may have an anti-compulsive effect in OCD patients, and that this effect may be mediated by5-HT2C receptors within the orbitofrontal cortex.

Topics: Amphetamines; Analysis of Variance; Animals; Behavior, Animal; Compulsive Behavior; Conditioning, Operant; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Extinction, Psychological; Male; Obsessive-Compulsive Disorder; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Antagonists; Spiro Compounds; Sulfonamides

Perceptual and psychic alterations and thought disorder are fundamental elements of schizophrenia symptoms, a pathology associated with an abnormal macro- and microcircuitry of several brain areas including the prefrontal cortex (PFC). Alterations in information processing in PFC may partly underlie schizophrenia symptoms.. The 5-HT(2A/2C) agonist DOI and antipsychotic drugs were administered to anesthetized rats. Single unit and local field potential (LFP) extracellular recordings were made in medial PFC (mPFC). Electrolytic lesions were performed in the thalamic nuclei.. DOI markedly disrupts cellular and network activity in rat PFC. DOI altered pyramidal discharge in mPFC (39% excited, 27% inhibited, 34% unaffected; n = 51). In all instances, DOI concurrently reduced low-frequency oscillations (.3-4 Hz; power spectrum: .25 +/- .02 and .14 +/- .01 microV(2) in basal conditions and after 50-300 microg/kg intravenous (i.v.) DOI, respectively; n = 51). Moreover, DOI disrupted the temporal association between the active phase of LFP and pyramidal discharge. Both effects were reversed by M100907 (5-HT(2A) receptor antagonist) and were not attenuated by thalamic lesions, supporting an intracortical origin of the effects of DOI. The reduction in low-frequency oscillations induced by DOI was significantly reversed by the antipsychotic drugs haloperidol (.1-.2 mg/kg i.v.) and clozapine (1 mg/kg i.v.).. DOI disorganizes network activity in PFC, reducing low-frequency oscillations and desynchronizing pyramidal discharge from active phases of LFP. These effects may underlie DOI's psychotomimetic action. The reversal by clozapine and haloperidol indicates that antipsychotic drugs may reduce psychotic symptoms by normalizing an altered PFC function.

Topics: Action Potentials; Amphetamines; Analysis of Variance; Animals; Antipsychotic Agents; Biological Clocks; Clozapine; Dose-Response Relationship, Drug; Electroencephalography; Electrolysis; Evoked Potentials; Fluorobenzenes; Fourier Analysis; Hallucinogens; Male; Neurons; Piperidines; Prefrontal Cortex; Rats; Rats, Wistar; Serotonin Antagonists; Thalamus

Dopamine D(2) receptor antagonism contributes to the therapeutic action of antipsychotic drugs (APDs) but also produces undesirable side effects, including extrapyramidal motor deficits, cognitive dulling, and prolactinemia. The introduction of atypical APDs was a significant advancement in the treatment of schizophrenia. Whereas these agents are D(2) receptor antagonists, they are also potent 5-hydroxytryptamine (5-HT)(2A) receptor inverse agonists, a feature that may explain their improved efficacy and tolerability. Recently, we reported that N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel selective 5-HT(2A) receptor inverse agonist that fails to bind D(2) receptors, is active in several models predictive of antipsychotic activity. Using ACP-103, we tested the hypothesis that combining high levels of 5-HT(2A) inverse agonism with low levels of D(2) antagonism would result in a favorable interaction, such that antipsychotic efficacy could be achieved with reduced D(2) receptor-related adverse effects. Here we show that ACP-103 1) potently inhibited head-twitching produced by the 5-HT(2A/2C) receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine, 2) increased the potency of haloperidol against amphetamine-induced hyperactivity, 3) interacted synergistically with haloperidol or risperidone to suppress hyperactivity induced by the N-methyl-d-aspartate receptor antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), and, by contrast, 4) attenuated haloperido-l- or risperidone-induced prolactinemia. ACP-103 also attenuated catalepsy produced by haloperidol or risperidone. However, the doses that were required for this effect were higher than would be expected for a 5-HT(2A) receptor-mediated mechanism. These data indicate that utilizing ACP-103 as an adjunctive therapy to currently used APDs may result in enhanced antipsychotic efficacy while reducing adverse effects including those attributable to D(2) receptor antagonism.

Topics: Amphetamine; Amphetamines; Animals; Antipsychotic Agents; Behavior, Animal; Brain Chemistry; Catalepsy; Dizocilpine Maleate; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Haloperidol; Head Movements; Male; Mice; Mice, Inbred Strains; Motor Activity; Piperidines; Prolactin; Rats; Rats, Sprague-Dawley; Risperidone; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists; Urea

The present study tested the hypothesis that serotonergic (5-HT) 5-HT2A or 5-HT2C receptors or their pharmacological stimulation modulated the discriminative stimulus effects of nicotine in male Wistar rats. To this end the selective 5-HT2A receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (M100,907; 0.5-1 mg/kg, i.p.), the functional 5-HT2A receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI; 0.1-1 mg/kg, s.c.), the selective 5-HT2C receptor antagonist 6-chloro-5-methyl-1-{[2-(2-methylpyrid-3-yloxy)pyrid-5-yl]carbamoyl}indoline (SB 242,084; 0.25-1 mg/kg, i.p.) and the 5-HT2C receptor agonists (S)-2-chloro-5-fluoro-indol-1-yl)-1-methylethylamine fumarate (Ro 60-0175; 0.3-1 mg/kg, s.c.) and (7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole (WAY 163,909; 0.75-1.5 mg/kg, i.p.) were used. Additionally, the effects of the selective alpha4beta2 nicotinic acetylcholine receptor subtype agonist 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-IA; 0.01 mg/kg, s.c.) were investigated. In rats trained to discriminate (-)-nicotine (0.4 mg/kg, s.c.) from saline in a two-lever, water-reinforced fixed ratio 10 task, substitutions were not observed with 5-HT2 receptor ligands (<32% nicotine-lever responding), conversely 5-IA induced a full substitution (100% nicotine-lever responding). In combination studies, fixed doses of M100,907 (0.5-1 mg/kg) or SB 242,084 (0.25-1 mg/kg) did not alter the dose-response curve of nicotine, while DOI (0.3 mg/kg), Ro 60-0175 (1 mg/kg) and WAY 163,909 (1 and 1.5 mg/kg) attenuated the discriminative stimulus effects of nicotine. The decrease in the expression of the discriminative stimulus effects of nicotine produced by DOI was blocked by M100,907 (1 mg/kg), but not by SB 242,084 (1 mg/kg), while that evoked by Ro 60-0175 or WAY 163,909 was blocked by SB 242,084 (1 mg/kg), but not by M100,907 (1 mg/kg). Further studies showed that DOI (0.3 mg/kg) and Ro 60-0175 (1 mg/kg), but not WAY 163,909 (1.5 mg/kg) blocked full substitution of 5-IA (0.01 mg/kg) for nicotine. Our pharmacological analyses indicate that tonic activation of 5-HT2A or 5-HT2C receptors is not required for subjective effects of nicotine, however these receptors appear to have inhibitory influence on nicotine cue, since pharmacological stimulation of either receptor attenuates the discriminative stimulus effects of nicotine.

Topics: Aminopyridines; Amphetamines; Animals; Azepines; Azetidines; Behavior, Animal; Brain; Discrimination, Psychological; Dose-Response Relationship, Drug; Ethylamines; Fluorobenzenes; Indoles; Ligands; Male; Nicotine; Nicotinic Agonists; Piperidines; Pyridines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Receptors, Nicotinic; Serotonin 5-HT2 Receptor Agonists; Serotonin Antagonists; Serotonin Receptor Agonists

5-Hydroxytryptamine (serotonin; 5-HT)2 receptor agonists such as (+/-)-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) injected systemically or directly into frontal cortex, elicit stereotyped head movements that are mediated by 5-HT2A receptors. Chronic administration of 5-HT2A receptor antagonists can produce either a down-regulation, e.g., d-2-bromolysergic acid diethylamide (BOL) or an up-regulation, e.g., alpha-phenyl-10(2-phenylethyl)-4-piperidinemethanol (MDL11,939) of cortical 5-HT2A receptors in the rabbit with no change in the density of the 5-HT2C receptor. We examined the degree to which the time course for the onset and offset of changes in cortical 5-HT2A receptor density was correlated with functional changes as measured by the magnitude of DOI elicited, 5-HT2A receptor-mediated head movements (head bobs). First, the magnitude of DOI-elicited head bobs was measured over 1 to 8 days after chronic BOL (5.8 micromol/kg), MDL11,939 (10 micromol/kg), or vehicle administration. Second, rabbits were injected with BOL, MDL11,939, or vehicle once daily for 8 days, and then, 1 to 8 days after the cessation of drug or vehicle, DOI-elicited head bobs were determined. Samples of frontal cortex were obtained for each animal immediately following behavioral testing, and 5-HT2A receptor density was measured using [3H]ketanserin. Thus, each animal provided a value for receptor density and number of head bobs, and these two measures showed a high degree of correlation between 0.94 for BOL and 0.95 for MDL11,939. This study establishes that the density of 5-HT2A receptors in cortex reflects their functional status.

Topics: Amphetamines; Animals; Behavior, Animal; Cerebral Cortex; Down-Regulation; Injections, Intraventricular; Male; Piperidines; Rabbits; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists; Up-Regulation

Serotonin (5-HT) has been linked to impulsivity with recent data suggesting that different receptor sub-types exert opposing influences on this behaviour.. This work characterised the effects of 5-HT(2A) (ketanserin, (+/-)2,3-dimethoxyphenyl-1-[2-4-(piperidine)-methanol] [M100907]), 5-HT(2B) (6-chloro-5-methyl-1-(5-quinolylcarbamoyl) indoline [SB215505]) and 5-HT(2C) (6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbomyl] indoline [SB242084]) receptor antagonists on impulsive behaviour, measured in the five-choice serial reaction time test (5CSRTT), in rats and mice. The effects of (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4 (Ro60-0175), two compounds that have been used extensively as agonists for the 5-HT(2A) and 5-HT(2C) receptor, were also measured.. Rats and mice were trained on the 5CSRTT in which reinforcement is earned for detecting and correctly responding to brief presentations of a stimulus light. Impulsivity in this task is measured as premature responding, before stimulus presentation. Several variants of the task were used in which the inter-trial interval (ITI) length was manipulated to alter basal levels of premature responding.. In the rat, ketanserin and M100907 reduced and SB242084 enhanced premature responding. SB215505 had no effect. DOI generally disrupted responding, while Ro60-0175 reduced premature responding when a long ITI was used. In mice, M100907 reduced and SB242084 increased premature responding when the ITI was lengthened. The effects of these drugs on other aspects of performance were less robust. M100907 and ketanserin did not affect response accuracy but tended to slow speed of responding; SB242084 occasionally increased speed of responding and slightly reduced accuracy.. Serotonin exerts both excitatory and inhibitory influences on motor impulsivity via 5-HT(2A) and 5-HT(2C) receptors in both rats and mice.

Topics: Aminopyridines; Amphetamines; Animals; Conditioning, Operant; Ethylamines; Fluorobenzenes; Impulsive Behavior; Indoles; Ketanserin; Male; Mice; Mice, Inbred C57BL; Piperidines; Quinolines; Rats; Reaction Time; Serial Learning; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Species Specificity

We recently found that rats' ability to discriminate durations of exteroceptive stimuli is disrupted by the non-selective 5-HT receptor agonist quipazine. Ketanserin reversed this effect, suggesting that the effect may be mediated by 5-HT2A receptors. Here, we report that the 5-HT2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) also disrupts temporal discrimination, and that this effect can be reversed by ketanserin and the highly selective 5-HT2A receptor antagonist (+/-)2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol] (MDL-100907). Twenty rats were trained to discriminate durations in a discrete-trials psychophysical procedure. In each 50-s trial, a light was presented for t seconds, following which two levers (A and B) were presented. A response on A was reinforced if t < 25 s, and a response on B if t > 25 s. Logistic psychometric curves were fitted to the proportional choice of B (%B) for derivation of timing indices [T50: time corresponding to %B = 50; Weber fraction: (T75-T25)/2T50, where T75 and T25 are times corresponding to %B = 75 and 25, respectively]. DOI 0.25 mg kg (subcutaneous) significantly increased the Weber fraction and tended to increase T50. Ketanserin 2 mg kg (subcutaneous) did not alter either parameter, but completely antagonized the effects of DOI. Similarly, MDL-100907 0.5 and 1 mg kg (intraperitoneal) did not affect performance, but completely antagonized the effects of DOI. The results indicate that the mixed 5-HT2A/2C receptor agonist DOI disrupts temporal discrimination via stimulation of 5-HT2A receptors.

Topics: Amphetamines; Animals; Association Learning; Brain; Discrimination Learning; Female; Fluorobenzenes; Injections, Intraperitoneal; Injections, Subcutaneous; Ketanserin; Piperidines; Psychophysics; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin Antagonists; Serotonin Receptor Agonists; Time Perception

The dopamine-releasing agent d-amphetamine and the 5-HT(2) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) have similar effects on free-operant timing behavior. The selective D(1) dopamine receptor antagonist 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SKF-83566), but not the D(2) dopamine receptor antagonist haloperidol, can antagonize the effect of d-amphetamine, and the selective 5-HT(2A) receptor antagonist (+/-)2,3-dimethoxyphenyl-1-(2-(4-piperidine)-methanol (MDL-100907) can antagonize the effect of DOI. However, it is not known whether the effect of d-amphetamine can be reversed by MDL-100907 and the effect of DOI by dopamine receptor antagonists.. The objective of this work is to examine the interactions of d-amphetamine and DOI with MDL-100907, SKF-83566, and haloperidol on timing performance.. Rats (n = 12-15 per experiment) were trained under the free-operant psychophysical procedure to press two levers (A and B) in 50-s trials in which reinforcement was provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic functions were fitted to the data from each rat for the derivation of timing indices [T (50) (time corresponding to %B = 50); Weber fraction]. Rats were treated systemically with d-amphetamine or DOI, alone and in combination with haloperidol, SKF-83566, or MDL-100907.. d-Amphetamine (0.4 mg kg(-1)) reduced T (50) compared to vehicle; this effect was antagonized by SKF-83566 (0.03 mg kg(-1)) and MDL-100907 (0.5 mg kg(-1)), but not by haloperidol (0.05, 0.1 mg kg(-1)). DOI (0.25 mg kg(-1)) also reduced T (50); this effect was reversed by MDL-100907 (0.5 mg kg(-1)), but not by SKF-83566 (0.03 mg kg(-1)) or haloperidol (0.05 mg kg(-1)).. The results suggest that both 5-HT(2A) and D(1) receptors, but not D(2) receptors, are involved in d-amphetamine's effect on timing behavior in the free-operant psychophysical procedure. DOI's effect on timing is mediated by 5-HT(2A) receptors, but neither D(1) nor D(2) receptors are involved in this effect.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Amphetamine; Amphetamines; Animals; Conditioning, Operant; Drug Interactions; Female; Fluorobenzenes; Piperidines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Serotonin Antagonists; Serotonin Receptor Agonists; Time Perception

The effect of LSD in humans has been described as occurring in two temporal phases. The behavioral effects in rats also occur in two temporal phases: an initial suppression of exploration followed by increased locomotor activity.. We decided to investigate this phenomenon from the perspective that the pharmacology might have relevance to the neurochemical mechanisms underlying psychosis.. Twenty-five male Sprague-Dawley rats were trained to discriminate LSD (186 nmol/kg, 0.08 mg/kg, i.p.) with a 30-min preinjection time (LSD-30, N=12) and LSD (372 nmol/kg, 0.16 mg/kg, i.p.) with a 90-min preinjection time (LSD-90, N=13) from saline, using a two-lever, food-reinforced operant conditioning task.. LSD (186 or 372 nmol/kg, 0.08 or 0.16 mg/kg) given 30 min prior to training produced a cue that was completely antagonized by 5-HT2A antagonists and lasted no longer than 1 h. LSD (372 nmol/kg, 0.16 mg/kg) injected 90 min before training produced a cue that was not fully blocked by 5-HT2A antagonists, but instead was significantly inhibited by haloperidol. In these rats, substitution no longer occurred with the 5-HT2 agonists DOI or LSD (30 min preinjection), but full substitution was obtained with the D2 agonists apomorphine, N-propyldihydrexidine, and quinelorane.. The discriminative stimulus effect of LSD in rats occurs in two phases, and these studies provide evidence that the later temporal phase is mediated by D2 dopamine receptor stimulation. A second temporal phase that involves dopaminergic pathways would be consistent with the widespread belief that excessive dopaminergic activity may be an underlying cause of paranoid psychosis.

Topics: Amphetamine; Amphetamines; Animals; Apomorphine; Behavior, Animal; Cues; Discrimination Learning; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Fluorobenzenes; Hallucinogens; Haloperidol; Indans; Injections, Intraperitoneal; Lysergic Acid Diethylamide; Male; Piperidines; Psychotic Disorders; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Serotonin Antagonists; Serotonin Receptor Agonists; Time Factors

Tolerance is defined as a decrease in responsiveness to a drug after repeated administration. Tolerance to the behavioral effects of hallucinogens occurs in humans and animals. In this study, we used drug discrimination to establish a behavioral model of lysergic acid diethylamide (LSD) tolerance and examined whether tolerance to the stimulus properties of LSD is related to altered serotonin receptor signaling. Rats were trained to discriminate 60 microg/kg LSD from saline in a two-lever drug discrimination paradigm. Two groups of animals were assigned to either chronic saline treatment or chronic LSD treatment. For chronic treatment, rats from each group were injected once per day with either 130 microg/kg LSD or saline for 5 days. Rats were tested for their ability to discriminate either saline or 60 microg/kg LSD, 24 h after the last chronic injection. Rats receiving chronic LSD showed a 44% reduction in LSD lever selection, while rats receiving chronic vehicle showed no change in percent choice on the LSD lever. In another group of rats receiving the identical chronic LSD treatment, LSD-stimulated [35S]GTPgammaS binding, an index of G-protein coupling, was measured in the rat brain by autoradiography. After chronic LSD, a significant reduction in LSD-stimulated [35S]GTPgammaS binding was observed in the medial prefrontal cortex and anterior cingulate cortex. Furthermore, chronic LSD produced a significant reduction in 2,5-dimethoxy-4-iodoamphetamine-stimulated [35S]GTPgammaS binding in medial prefrontal cortex and anterior cingulate cortex, which was blocked by MDL 100907, a selective 5-HT2A receptor antagonist, but not SB206553, a 5-HT2C receptor antagonist, indicating a reduction in 5-HT2A receptor signaling. 125I-LSD binding to 5-HT2A receptors was reduced in cortical regions, demonstrating a reduction in 5-HT2A receptor density. Taken together, these results indicate that adaptive changes in LSD-stimulated serotonin receptor signaling may mediate tolerance to the discriminative stimulus effects of LSD.

Topics: Amphetamines; Analysis of Variance; Animals; Autoradiography; Behavior, Animal; Cerebral Cortex; Diagnostic Imaging; Drug Interactions; Drug Tolerance; Fluorobenzenes; Guanosine 5'-O-(3-Thiotriphosphate); Hallucinogens; Indoles; Iodine Isotopes; Lysergic Acid Diethylamide; Male; Piperidines; Protein Binding; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Serotonin Antagonists; Signal Transduction; Sulfur Isotopes; Time Factors

These experiments sought to determine the influence of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors and the endocannabinoid system in the functional expression of the serotonin (5-HT) type 2A receptor-mediated wet dog shake response. Male Long-Evans rats were pretreated with either 1 mg/kg i.p. of the 5-HT(2A/2C) receptor antagonist ketanserin; 1, 10 or 30 mg/kg i.p. of the AMPA/kainate antagonist 6,7-dinitroquinnoxaline-2,3-dione (DNQX); 1, 5 or 10 mg/kg i.p. of the endocannabinoid uptake inhibitor AM404; or 1, 5 or 10 mg/kg i.p. of the cannabinoid CB(1) receptor antagonist AM 251 prior to injection of the 5-HT(2A/2C) receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI, 1 mg/kg i.p.). Results demonstrated that 10 mg/kg of AM404 significantly reduced the expression of DOI-induced wet dog shakes, but lower doses were ineffective. Administration of AM251 did not induce wet dog shakes behavior when administered alone, but significantly potentiated DOI-induced wet dog shaking behavior at a dose of 10 mg/kg. Pretreatment with DNQX significantly reduced the expression of DOI-induced wet dog shakes at all doses tested. These data suggest that AMPA/kainate receptors play a role in the mediation of 5-HT(2A) receptor activity, whereas the endocannabinoid system may act as a regulatory buffer system during periods of elevated activity, but not under basal conditions.

Topics: Amphetamines; Animals; Arachidonic Acids; Behavior, Animal; Cannabinoid Receptor Modulators; Dose-Response Relationship, Drug; Endocannabinoids; Excitatory Amino Acid Antagonists; Injections, Intraperitoneal; Ketanserin; Male; Piperidines; Pyrazoles; Quinoxalines; Rats; Rats, Long-Evans; Receptor, Serotonin, 5-HT2A; Receptors, AMPA; Receptors, Kainic Acid; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists

New data show that 5-hydroxytryptamine (5-HT) neurons of the dorsal raphe nucleus (DRN) are subject to feedback control from 5-HT2 receptors, but the circuitry involved is uncertain. This study investigated whether 5-HT2 receptor agonism activates DRN gamma-aminobutyric acid (GABA) neurons, which are known to inhibit neighbouring 5-HT neurons. Systemic administration of the 5-HT2 receptor agonist, DOI, caused a striking increase in Fos-immunoreactivity in the DRN. This effect was abolished by the 5-HT2 antagonists ritanserin and MDL 100907, but not SB 206553, indicating the involvement of 5-HT2A receptors. Importantly, DOI-induced Fos-immunoreactivity in the DRN was extensively colocalized in GAD67-immunoreactive neurons. These findings suggest that activated local GABA neurons may play an important role in 5-HT2 receptor-mediated feedback control of DRN 5-HT neurons.

Topics: Amphetamines; Analysis of Variance; Animals; Cell Count; Feedback; Fluorobenzenes; gamma-Aminobutyric Acid; Gene Expression Regulation; Glutamate Decarboxylase; Immunohistochemistry; Isoenzymes; Male; Neurons; Oncogene Proteins v-fos; Piperidines; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

The aim of the present study was to investigate the modulation of locus coeruleus neurons by the selective serotonin (5-HT) reuptake inhibitor citalopram using single-unit extracellular recordings in rat brain slices. Citalopram inhibited the activity of a subpopulation of locus coeruleus neurons; thus 10 microM citalopram inhibited neurons by 53+/-17% (5 out of 15 cells), whereas the inhibition due to 100 microM was 64+/-4% (32 out of 42 cells). This effect was partially reversed (47+/-11%) by the alpha(2)-adrenoceptor antagonist idazoxan (10 microM), whereas it was unaffected by antagonists for 5-HT(1A), 5-HT(2,) and 5-HT(3) receptors, and mu opioid receptors. 5-HT (50 or 200 microM), the 5-HT(1A) receptor agonist 8-OH-DPAT (+/-)-8-hydroxy-2-(DI-n-propyl-amino) tetralin hydrobromide, 10 microM) and the 5-HT(2) receptor agonist DOI ([+/-]-2,5-dimetoxy-4-iodoamphetamine) hydrochloride, 10 or 30 microM) also inhibited a subpopulation of locus coeruleus cells. In addition, citalopram but not 5-HT, enhanced by 1.7 fold the inhibitory effect of noradrenaline. Long-term treatment with citalopram (20 mg/kg/day) did not modify the effect of noradrenaline and bromoxidine. Taken together, our results indicate that citalopram exerts an inhibitory effect on locus coeruleus noradrenergic neurons. alpha(2)-adrenoceptor activation may underlie this effect as a result of elevated levels of noradrenaline in the synaptic cleft.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Action Potentials; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Amphetamines; Animals; Bridged Bicyclo Compounds, Heterocyclic; Brimonidine Tartrate; Citalopram; Dose-Response Relationship, Drug; Duloxetine Hydrochloride; Idazoxan; In Vitro Techniques; Locus Coeruleus; Male; Methiothepin; Naloxone; Narcotic Antagonists; Neurons; Norepinephrine; Oxazines; Piperazines; Piperidines; Pyridines; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2; Receptors, Opioid, mu; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Thiophenes

We have previously reported that acute and chronic donepezil and nicotine administration significantly attenuate DOI-induced head twitch response (HTR) in mice. This behavior, primarily mediated by stimulation of 5-HT2A receptors, has been proposed to model tic symptoms seen in Tourette's syndrome (TS). Haloperidol, a drug widely used to treat symptoms of TS, has also been reported to reduce DOI-induced head shakes in rodents when administered acutely. These findings suggest an inhibitory interaction of these drugs with 5-HT2A receptors. To test this hypothesis, we evaluated the effects of chronic donepezil, nicotine and haloperidol on expression levels of 5-HT2A mRNA and 5-HT2A receptor density in select brain regions. Initially, we established a dose-response relationship for the acute and chronic haloperidol and DOI-induced HTR. Male ICR mice were treated twice daily with donepezil (0.1 mg/kg), nicotine (0.5 mg/kg), and once daily with haloperidol (0.4 mg/kg) for 14 days and were sacrificed 16-18 h after the last injection. These drug regimens were chosen because of their significant effects on DOI-induced HTR. Donepezil significantly increased 5-HT2A mRNA level, but not the receptor density in the striatum. In the midbrain, donepezil significantly decreased the receptor density without affecting the 5-HT2A mRNA level. In the frontal cortex, only haloperidol significantly reduced the 5-HT2A receptor density. The cortex was the only area where donepezil, nicotine and haloperidol significantly reduced the 5-HT2A receptor density. The results suggest that the anti-tic properties of donepezil, nicotine and haloperidol in this paradigm might be due to antagonism of cortical 5-HT2A receptors. Thus, further investigation of involvement of cortical 5-HT2A receptors in TS as well as evaluation of selective 5-HT2A receptor antagonists in this disorder is warranted.

Topics: Amphetamines; Animals; Behavior, Animal; Binding, Competitive; Cerebral Cortex; Corpus Striatum; Donepezil; Dose-Response Relationship, Drug; Frontal Lobe; Gene Expression; Haloperidol; Humans; Indans; Ketanserin; Male; Mesencephalon; Mice; Mice, Inbred ICR; Nicotine; Piperidines; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Serotonin Antagonists; Tourette Syndrome

Previous studies have outlined an important role for serotonin (5-HT) in the development of synaptic connectivity and function in the cerebral cortex. In this study, we have examined the effects of 5-HT on synaptic function in prefrontal cortex at a time of intense synapse formation and remodelling. Whole-cell recordings in slices derived from animals aged postnatal (P) days 16-20 showed that administration of 5-HT induced a robust increase in synaptic activity that was blocked by CNQX but not by bicuculline. This 5-HT-induced increase in glutamate-mediated synaptic activity was pharmacologically heterogeneous as it was differentially inhibited by the receptor subtype-selective antagonists SB-269970, MDL 100907 and GR 113808 and thus involved 5-HT(7), 5-HT(2A) and 5-HT(4) receptors. These results, obtained in juvenile cortex, contrast with those seen in adults where the increase in spontaneous excitatory postsynaptic currents (sEPSCs) was mediated solely by 5-HT(2A) receptors. In developing cortex, activation of 5-HT(7), but not 5-HT(2A) or 5-HT(4) receptors, elicited a robust inward current. However, the facilitation of synaptic activity mediated by all three of these receptors involved increases in both the amplitude and frequency of sEPSCs and was blocked by TTX. These results are best interpreted as indicating that all three receptor subtypes increase synaptic activity by exciting neuronal elements within the slice. No evidence was found for a postsynaptic facilitation of synaptic currents by 5-HT. Together, these results show that the repertoire of electrophysiologically active 5-HT receptors in prefrontal cortex is developmentally regulated, and that 5-HT(7) and 5-HT(4) receptors play a previously unsuspected role in regulating synaptic activity in this region.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Amphetamines; Animals; Bicuculline; Fluorobenzenes; GABA-A Receptor Antagonists; Glutamic Acid; Indoles; Lidocaine; Male; Patch-Clamp Techniques; Phenols; Pindolol; Piperidines; Prefrontal Cortex; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, AMPA; Receptors, Metabotropic Glutamate; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin 5-HT4 Receptor Antagonists; Serotonin Antagonists; Sodium Channel Blockers; Sulfonamides; Synapses; Tetrodotoxin; Time Factors

An imbalance between serotonin-2A (5-HT2A) and 5-HT1A receptors may underlie several mood disorders. The present studies determined whether 5-HT2A receptors interact with 5-HT1A receptors in the rat hypothalamic paraventricular nucleus (PVN). The sensitivity of the hypothalamic 5-HT1A receptors was measured as oxytocin and adrenocorticotropic hormone (ACTH) responses to the 5-HT1A receptor agonist (+)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide [(+)8-OH-DPAT] (40 microg/kg s.c.). The 5-HT(2A/2C) receptor agonist (-)DOI [(-)-1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane HCl] (1 mg/kg s.c.) injected 2 h prior to (+)8-OH-DPAT significantly reduced the oxytocin and ACTH responses to (+)8-OH-DPAT, producing a heterologous desensitization of the 5-HT1A receptors. Microinjection of the 5-HT2A receptor antagonist MDL100,907 [(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol; 0, 10, or 20 nmol, 15 min prior to (-)DOI] into the PVN dose-dependently prevented the desensitization of 5-HT1A receptors induced by the 5-HT2A receptor agonist (-)DOI. Double-label immunocytochemistry revealed a high degree of colocalization of 5-HT1A and 5-HT2A receptors in the oxytocin and corticotropin-releasing factor neurons of the PVN. Thus, activation of 5-HT2A receptors in the PVN may directly induce a heterologous desensitization of 5-HT1A receptors within individual neuroendocrine cells. These findings may provide insight into the long-term adaptation of 5-HT1A receptor signaling after changes in function of 5-HT2A receptors; for example, during pharmacotherapy of mood disorders.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Adrenocorticotropic Hormone; Amphetamines; Animals; Antibody Specificity; Corticotropin-Releasing Hormone; Fluorobenzenes; Microinjections; Neurons; Neurosecretory Systems; Oxytocin; Paraventricular Hypothalamic Nucleus; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Serotonin Antagonists; Serotonin Receptor Agonists

Motor movements (head bobs) in the rabbit have been shown to be elicited by LSD-like hallucinogenic drugs through actions at central serotonin 5-HT(2A) receptors, though their central locus remains unknown. Serotonergic innervation of the hippocampus has been suggested to play an important role in motor programming including movements of the head.. We examined whether intrahippocampal injections of a 5-HT(2A) receptor agonist would elicit head bobs and whether elicitation of head bobs would be modified by increases in hippocampal 5-HT(2A) receptor density.. Animals received bilateral injections of DOI or its vehicle into the dorsal hippocampus either before or after chronic administration of MDL 11,939 or its vehicle. The number of head bobs was counted continuously for 60 min and reported in blocks of 10 min and this was compared with the density of 5-HT(2A) receptors in dorsal hippocampus.. Infusion of DOI into the CA1 region of the dorsal hippocampus elicited head bobs that were blocked by prior intrahippocampal injection of the 5-HT(2A) receptor antagonist ketanserin. Receptor autoradiography revealed that chronic administration of MDL 11,939 produced a 2.5-fold up-regulation of 5-HT(2A) receptors in the CA1 field and dentate gyrus of the hippocampus. This 5-HT(2A) receptor up-regulation was associated with a nearly 2-fold increase in head bobs elicited by infusion of DOI into the CA1 field.. These results indicate that 5-HT(2A) receptors located in the CA1 field of the hippocampus mediate a motor movement, head bobs, and that this mediation is functionally related to receptor density.

Topics: Amphetamines; Animals; Autoradiography; Diffusion; Dose-Response Relationship, Drug; Head Movements; Hippocampus; Immunohistochemistry; Injections; Male; Piperidines; Pyramidal Tracts; Rabbits; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin Receptor Agonists

Menopause-associated thermoregulatory dysfunction, including hot flushes and night sweats, is effectively treated by hormonal therapies that include estrogens. Evidence suggests that estrogen regulates serotonin 2A (5-HT(2A)) receptor expression and that 5-HT(2A) receptors are involved in thermoregulation. Therefore, the role of 5-HT(2A) receptors in thermoregulation was assessed in two rat models of ovariectomy-induced thermoregulatory dysfunction. The first model is based on measurement of the tail-skin temperature (TST) increase following naloxone-induced withdrawal in morphine-dependent ovariectomized (OVX) rats (MD model), while the second model relies on telemetric assessment of diurnal TST changes in ovariectomized rats (telemetry model). Treatment with a 5-HT(2A/2C) receptor agonist, (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), prevented the naloxone-induced TST increase in the MD model and restored normal active-phase TST in the telemetry model. The selective 5-HT(2A) receptor antagonist, MDL-100907, had no effect on the naloxone-induced flush when administered alone in the MD model, but it decreased DOI's ability to abate the flush. In the telemetry model, MDL-100907 attenuated the DOI-induced decrease in active-phase TST. Interestingly, MDL-100907 increased TST in both models when given alone, with the TST increase occurring prior to the naloxone-induced flush in the MD model. To evaluate the role of central nervous system (CNS) 5-HT(2A) receptors in TST regulation, DOI was administered in combination with a known peripheral 5-HT(2A/2C) receptor antagonist, xylamidine, in the MD model. Xylamidine had no effect on DOI's ability to abate the naloxone-induced flush. These results indicate that activation of central 5-HT(2A) receptors restores temperature regulation in two rodent models of ovariectomy-induced thermoregulatory dysfunction.

Topics: Amidines; Amphetamines; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Endocrine System Diseases; Estradiol; Estrogens; Female; Fluorobenzenes; Naloxone; Ovariectomy; Piperidines; Rats; Reaction Time; Receptor, Serotonin, 5-HT2A; Serotonin Antagonists; Serotonin Receptor Agonists; Skin Temperature; Substance Withdrawal Syndrome; Telemetry; Time Factors

Activation of the cerebral cortex is seen during hallucinations. The 5-HT(2A/C) agonist 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) is a potent hallucinogen that has been proposed to act by targeting 5-HT(2A) heteroceptors on thalamocortical neurons and eliciting release of glutamate from these cells, which in turn drives cortical neurons. We used in vivo microdialysis to determine if DOI increases extracellular glutamate levels. Systemic administration of DOI significantly increased extracellular glutamate levels in the somatosensory cortex of the freely-moving rat. Similarly, intracortical administration of DOI by reverse dialysis increased cortical extracellular glutamate levels. No consistent changes in either extracellular GABA or glycine levels were observed in response to DOI. The increase in glutamate levels elicited by intracortical DOI was blocked by treatment with the selective 5-HT(2A) antagonist MDL 100,907. These data are consistent with the hypothesis that 5-HT(2A) receptor-mediated regulation of glutamate release is the mechanism through which hallucinogens activate the cerebral cortex.

Topics: Amphetamines; Animals; Extracellular Space; Fluorobenzenes; Glutamic Acid; Hallucinogens; Microdialysis; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Somatosensory Cortex

Tourette syndrome (TS) is a neurological disorder characterized by persistent motor and phonic tics. Administration of the selective 5-HT(2A/2C) agonist 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induces head twitches in mice that have been proposed to model tics seen in TS. Previous studies have demonstrated that nicotine markedly attenuates DOI-induced head twitch response (HTR). This and the reports that nicotine may have clinical efficacy in reducing symptoms of TS suggest possible involvement of the nicotinic cholinergic system in this disorder. Donepezil is an acetylcholinesterase inhibitor approved for use in mild to moderate Alzheimer's disease. The purpose of this study was to investigate whether donepezil might also reduce DOI-induced HTR, and whether its combination with nicotine might result in an additive or synergistic effect. Moreover, to elucidate the possible role of nicotinic receptors in this paradigm, the effects of mecamylamine, a nicotinic antagonist, was also evaluated. Acute and chronic administration of donepezil (0.1 mg/kg) or nicotine (0.5 mg/kg base), significantly reduced DOI-induced HTR. No additive or synergistic effects of donepezil and nicotine were observed. Acute mecamylamine administration (0.5-5.0 mg/kg) dose-dependently inhibited DOI-induced HTR. None of the mecamylamine doses blocked the inhibitory effects of donepezil or nicotine on DOI-induced HTR. These results suggest that donepezil may have therapeutic potential in treating motor tic symptoms of TS. Moreover, the action of donepezil and nicotine may be mediated through the same mechanism.

Topics: Amphetamines; Animals; Donepezil; Drug Synergism; Head Movements; Indans; Male; Mecamylamine; Mice; Mice, Inbred ICR; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Nootropic Agents; Piperidines; Serotonin Receptor Agonists; Tics; Time Factors; Tourette Syndrome

The present study determined whether the serotonin2A (5-HT2A) receptors in the hypothalamic paraventricular nucleus mediate the neuroendocrine responses to a peripheral injection of the 5-HT2A/2C receptor agonist (-)DOI [(-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]. The 5-HT2A receptor antagonist MDL100,907 ((+/-)-alpha(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol), the 5-HT2C receptor antagonist SB-242084 (6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline), or vehicle were microinjected bilaterally through a chronically implanted double-barreled cannula into the hypothalamic paraventricular nucleus 15 min before a peripheral injection of (-)DOI in conscious rats. (-)DOI significantly elevated plasma levels of oxytocin, prolactin, ACTH, corticosterone, and renin. Neither the 5-HT2A receptor antagonist nor the 5-HT2C receptor antagonist, injected alone, altered the basal levels of these hormones. MDL100,907 (0.748, 7.48, and 18.7 nmol) dose dependently inhibited the (-)DOI-induced increase in all of the hormones except corticosterone. In contrast, SB-242084 (10 nmol) did not inhibit (-)DOI-increased hormone levels. To confirm the presence of 5-HT2A receptors in the hypothalamic paraventricular nucleus, 5-HT2A receptors were mapped using immunohistochemistry. Densely labeled magnocellular neurons were observed throughout the anterior and posterior magnocellular subdivisions of the hypothalamic paraventricular nucleus. Moderately to densely labeled cells were also observed in parvicellular regions. Thus, it is likely that 5-HT2A receptors are present on neuroendocrine cells in the hypothalamic paraventricular nucleus. These data provide the first direct evidence that neuroendocrine responses to a peripheral injection of (-)DOI are predominantly mediated by activation of 5-HT2A receptors in the hypothalamic paraventricular nucleus.

Topics: Adrenocorticotropic Hormone; Amphetamines; Animals; Corticosterone; Dose-Response Relationship, Drug; Fluorobenzenes; Immunohistochemistry; Male; Microinjections; Neurosecretory Systems; Oxytocin; Paraventricular Hypothalamic Nucleus; Piperidines; Prolactin; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Renin; Serotonin Antagonists; Serotonin Receptor Agonists

Direct-acting serotonin (5-HT) receptor agonists increase serum corticosterone in rats by activating receptors of the 5-HT(1A) or the 5-HT(2A/2C) subtypes. While involvement of 5-HT(1A) receptors in activation of the hypothalamic-pituitary-adrenocortical (HPA) axis is clear, the 5-HT(2) receptor subtype--5-HT(2A) or 5-HT(2C)--responsible for activation of the HPA axis by direct-acting 5-HT(2) receptor agonists has been difficult to determine due to the lack of selective pharmacologic agents. Recently, however, 5-HT(2) receptor antagonists with high selectivity for 5-HT(2A) and 5-HT(2C) receptor subtypes have been discovered. The selective 5-HT(2A) receptor antagonist MDL 100,907 and the selective 5-HT(2C) receptor antagonist SB 242084 were used to block the increases in rat serum corticosterone elicited by 5-HT(2) receptor agonists with varying degrees of affinity for 5-HT(2A) and 5-HT(2C) receptors. MDL 100,907 was fully effective in blocking the increases in corticosterone concentrations produced by quipazine, DOI, m-CPP and Ro 60-0175, whereas SB 242084 was ineffective or was only marginally effective. Our findings implicate 5-HT(2A) receptors rather than 5-HT(2C) receptors in mediating increases in rat serum corticosterone produced by direct-acting 5-HT(2) receptor agonists in vivo.

Topics: Aminopyridines; Amphetamines; Animals; Corticosterone; Dose-Response Relationship, Drug; Ethylamines; Fluorobenzenes; Hypothalamo-Hypophyseal System; Indoles; Male; Piperazines; Piperidines; Quipazine; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

Previous research has suggested that serotonin 5-HT(2A) receptors modulate the functioning of the mesocortical dopamine (DA) pathway. However, the specific role of 5-HT(2A) receptors localized within the medial prefrontal cortex (mPFC) is not known. The present study employed in vivo microdialysis to examine the role of this receptor in the modulation of basal and K(+)-stimulated (Ca(2+)-dependent) DA release. The selective 5-HT(2A) antagonist M100,907 was infused directly into the mPFC of conscious rats. This resulted in a concentration-dependent blockade of K(+)-stimulated DA release. Intracortical application of M100,907 also blocked increases in DA release produced by the systemic administration of the 5-HT(2A/2C) agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). These findings demonstrate that local 5-HT(2A) antagonism has an inhibitory effect on stimulated, Ca(2+)-dependent DA release. They suggest that cortical 5-HT(2A) receptors potentiate the phasic release of mesocortical DA.

Topics: Amphetamines; Animals; Brain Chemistry; Dopamine; Fluorobenzenes; Male; Microdialysis; Piperidines; Potassium; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists; Serotonin Receptor Agonists

Desensitization of 5-HT(1A) receptors could be involved in the long-term therapeutic effect of anxiolytic and antidepressant drugs. Pretreatment of rats with the 5-HT(2A/2C) agonist DOI induces an attenuation of hypothalamic 5-HT(1A) receptor-G(z)-protein signaling, measured as the ACTH and oxytocin responses to an injection of the 5-HT(1A) agonist 8-OH-DPAT. We characterized this functional heterologous desensitization of 5-HT(1A) receptors in rats and examined some of the mechanisms that are involved. A time course experiment revealed that DOI produces a delayed and reversible reduction of the ACTH and oxytocin responses to an 8-OH-DPAT challenge. The maximal desensitization occurred at 2 hr, and it disappeared 24 hr after DOI injection. The desensitization was dose-dependent, and it shifted the oxytocin and ACTH dose-response curves of 8-OH-DPAT to the right (increased ED(50)) with no change in their maximal responses (E(max)). The 5-HT(2A) receptor antagonist MDL 100,907 prevented the DOI-induced desensitization, indicating that 5-HT(2A) receptors mediate the effect of DOI. Analysis of the components of the 5-HT(1A) receptor-G(z)-protein signaling system showed that DOI did not alter the level of membrane-associated G(z)-proteins in the hypothalamus. Additionally, DOI did not alter the binding of [(3)H]8-OH-DPAT or the inhibition by GTPgammaS of [(3)H]8-OH-DPAT binding in the hypothalamus. In conclusion, the activation of 5-HT(2A) receptors induces a transient functional desensitization of 5-HT(1A) receptor signaling in the hypothalamus, which may occur distal to the 5-HT(1A) receptor-G(z)-protein interface.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Adrenocorticotropic Hormone; Amphetamines; Animals; Binding, Competitive; Dose-Response Relationship, Drug; Fluorobenzenes; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Hypothalamus; Male; Membrane Proteins; Oxytocin; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Antagonists; Serotonin Receptor Agonists

Previous studies, using in vivo extracellular unitary recordings in anaesthetized rats, have shown that the selective 5-HT(1A) receptor antagonist WAY 100,635 suppressed the firing rate of locus coeruleus (LC) norepinephrine (NE) neurons and that this effect was abolished by lesioning 5-HT neurons. In the present experiments, the selective 5-HT(2A) receptor antagonist MDL 100,907, while having no effect on the spontaneous firing activity of LC neurons in controls, was able to restore NE neuronal discharges following the injection of WAY 100,635. The 5-HT(1A) receptor agonist 8-OH-DPAT enhanced the firing activity of NE neurons and this action was entirely dependent on intact 5-HT neurons, unlike the inhibitory effect of the 5-HT(2) receptor agonist DOI. Taken together, these data indicate that 5-HT(2A) but not 5-HT(1A) receptors controlling LC firing activity are postsynaptic to 5-HT neurons. Prolonged, but not subacute, administration of selective 5-HT reuptake inhibitors (SSRIs) produces a decrease in the spontaneous firing activity of LC NE neurons. MDL 100,907 partially reversed this suppressed firing activity of LC neurons in paroxetine-treated rats. Although the alpha(2)-adrenoceptor antagonist idazoxan also enhanced the firing activity of NE neurons in paroxetine-treated rats, this increase was similar to that obtained in controls. In conclusion, prolonged SSRI treatment enhances a tonic inhibitory influence by 5-HT on LC neurons through postsynaptic 5-HT(2A) receptors that are not located on NE neurons. A speculative neuronal circuitry accounting for these phenomena on LC NE activity is proposed.

Topics: 5,7-Dihydroxytryptamine; 8-Hydroxy-2-(di-n-propylamino)tetralin; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Amphetamines; Animals; Electric Stimulation; Electrophysiology; Fluorobenzenes; Idazoxan; Locus Coeruleus; Male; Neurons; Norepinephrine; Paroxetine; Patch-Clamp Techniques; Piperazines; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Antagonists

We examined the in vivo effects of the hallucinogen 4-iodo-2,5-dimethoxyamphetamine (DOI). DOI suppressed the firing rate of 7 of 12 dorsal raphe (DR) serotonergic (5-HT) neurons and partially inhibited the rest (ED(50) = 20 microg/kg, i.v.), an effect reversed by M100907 (5-HT(2A) antagonist) and picrotoxinin (GABA(A) antagonist). DOI (1 mg/kg, s.c.) reduced the 5-HT release in medial prefrontal cortex (mPFC) to 33 +/- 8% of baseline, an effect also antagonized by M100907. However, the local application of DOI in the mPFC increased 5-HT release (164 +/- 6% at 100 microm), an effect antagonized by tetrodotoxin, M100907, and BAY x 3702 (5-HT(1A) agonist) but not by SB 242084 (5-HT(2C) antagonist). The 5-HT increase was also reversed by NBQX (AMPA-KA antagonist) and 1S,3S-ACPD (mGluR 2/3 agonist) but not by MK-801 (NMDA antagonist). AMPA mimicked the 5-HT elevation produced by DOI. Likewise, the electrical-chemical stimulation of thalamocortical afferents and the local inhibition of glutamate uptake increased the 5-HT release through AMPA receptors. DOI application in mPFC increased the firing rate of a subgroup of 5-HT neurons (5 of 10), indicating an enhanced output of pyramidal neurons. Dual-label fluorescence confocal microscopic studies demonstrated colocalization of 5-HT(1A) and 5-HT(2A) receptors on individual cortical pyramidal neurons. Thus, DOI reduces the activity of ascending 5-HT neurons through a DR-based action and enhances serotonergic and glutamatergic transmission in mPFC through 5-HT(2A) and AMPA receptors. Because pyramidal neurons coexpress 5-HT(1A) and 5-HT(2A) receptors, DOI disrupts the balance between excitatory and inhibitory inputs and leads to an increased activity that may mediate its hallucinogenic action.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Amphetamines; Animals; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Fluorobenzenes; GABA Antagonists; Glutamic Acid; Hallucinogens; Male; Mice; Mice, Inbred BALB C; Microdialysis; Neurons; Picrotoxin; Piperidines; Prefrontal Cortex; Raphe Nuclei; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sesterterpenes; Tetrodotoxin

The ability of m-CPP [1-(m-chlorophenyl)piperazine] to produce hypolocomotion is well documented. This effect has been postulated to be due to activation of the 5-HT(2C) receptor. It is only recently that the tools necessary to clearly delineate which serotonin receptors are involved in the mediation of m-CPP hypolocomotion have become available. We investigated the effects of the selective 5-HT(2A) antagonists, MDL 100,907 and ketanserin, the selective 5-HT(2B) antagonists, LY 202146 and LY 266097, the 5-HT(2B/2C) antagonist, SB 206553, and the selective 5-HT(2C) antagonist, SB 242084 on m-CPP-induced hypolocomotion and spontaneous locomotor activity in mice. Furthermore, we investigated the effects of the non-selective serotonin antagonists, ritanserin, LY 53857, mianserin and cyproheptadine on m-CPP hypolocomotion. Additionally, receptor-binding studies were employed as an in vitro assessment of relative affinities at the 5-HT(2A), 5-HT92B) and 5-HT(2C) receptors. Antagonists tested alone were without effect on spontaneous activity, with the sole exception of ketanserin, which decreased spontaneous activity at the high dose of 1 mg/kg. m-CPP-induced hypolocomotion was not significantly attenuated by various doses of MDL 100,907, ketanserin, LY 202146, LY 266097, ritanserin or cyproheptadine. In contrast, SB 206553, SB 242084, LY 53857 and mianserin were capable of reversing m-CPP-induced hypolocomotion. Consistent with previous suggestions, a detailed pharmacological evaluation with selective antagonists for the 5-HT2 family of receptors supports a primary role for the 5-HT(2C) receptor, and not 5-HT(2A) or 5-HT(2B) receptors, in mediating the hypolocomotion produced by m-CPP.

Topics: Amphetamines; Animals; Binding, Competitive; Cell Line; Cricetinae; Fluorobenzenes; Humans; Kinetics; Male; Mice; Mice, Inbred Strains; Motor Activity; Piperazines; Piperidines; Radioligand Assay; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Serotonin Agents; Serotonin Antagonists

We have reported previously prenatal cocaine-induced functional deficits in serotonergic terminals, and gender-specific supersensitivity of postsynaptic 5-HT(1A) receptor-mediated hormone responses in offspring. This study investigates the effects of prenatal exposure to cocaine on postsynaptic 5-HT(2A) receptor-mediated responses in prepubescent male and female offspring. Pregnant rats were administered saline or (-)cocaine (15 mg/kg, s.c., b.i.d) from gestational day 13 through 20. Changes in 5-HT(2A) receptor function in offspring were assessed by differences in the ability of DOI [4-iodo, 2,5-dimethoxyphenyl-isopropylamine; 2. 0 mg/kg, s.c.] to elevate plasma levels of the hormones ACTH, corticosterone and renin. Basal hormone levels in male and female progeny were unaffected by prenatal cocaine exposure. However, prenatal exposure to cocaine significantly potentiated the magnitude of the ACTH response to DOI in both male (+19%) and female (+43%) progeny. Similarly, the DOI-induced elevation of plasma renin was markedly potentiated in male (+51%) and female (+83%) cocaine-exposed offspring. Although DOI significantly elevated corticosterone levels in both male and female offspring, the magnitude of corticosterone responses was not altered by prenatal exposure to cocaine. Densities of agonist ((125)I-DOI)-labeled receptors in hypothalamus and cortex were unaltered by prenatal exposure to cocaine. These data indicate prenatal cocaine-induced supersensitivity of postsynaptic 5-HT(2A) receptor function in male and female offspring without changes in receptor density. Synapse: 35:163-172, 2000.

Topics: Adrenocorticotropic Hormone; Amphetamines; Animals; Cerebral Cortex; Cocaine; Corticosterone; Female; Fluorobenzenes; Male; Piperidines; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Renin; Serotonin Antagonists; Serotonin Receptor Agonists; Vasoconstrictor Agents

Agonist activation of G protein-coupled receptors induces an increase in the binding of guanosine 5'-(gamma-[(35)S]thio)triphosphate ([(35)S]GTPgammaS); this increase in binding has been used as a tool to investigate receptor interaction with the heterotrimer guanine nucleotide-binding regulatory protein (G protein). The present study uses agonist-stimulated [(35)S]GTPgammaS binding to characterize serotonin 5-HT(2A/2C) receptors in rat brain membrane fractions and demonstrate the anatomical localization of the receptors by in vitro autoradiography on slide-mounted sections. The stimulatory effect of the agonist [1-(2,5-dimethoxy-4-iodophenyl)]-2 aminopropane (DOI) is compared to that of serotonin (5-HT). Autoradiography revealed a similar localization of DOI- and 5-HT-stimulated binding of [(35)S]GTPgammaS in distinct areas of prefrontal and parietal cortex, consistent with previously reported 5-HT(2A) receptor distribution. Specific binding was demonstrated in the frontal and parietal cortex, medial prefrontal, and cingular and orbital-insular areas as well as in the hippocampal formation, septal areas, the nucleus accumbens, and the choroid plexus. MDL 100105, a specific 5-HT(2A) antagonist, and ketanserin, an antagonist of 5-HT(2A/2C) receptors, blocked DOI stimulation in all labeled areas, whereas 5-HT stimulation was only partially blocked (70-80%). A small but significant inhibition was observed with the specific antagonist of 5-HT(2C/2B), SB 206553. This autoradiographic technique provides a useful tool for measuring in situ changes in specific receptor-Gq protein coupling in anatomically discrete brain regions, under physiological and pathological conditions.

Topics: Amphetamines; Animals; Autoradiography; Brain Chemistry; Dose-Response Relationship, Drug; Fluorobenzenes; GTP-Binding Protein alpha Subunits, Gq-G11; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Diphosphate; Image Processing, Computer-Assisted; Indoles; Ketanserin; Male; Membrane Proteins; Piperidines; Pyridines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Subcellular Fractions; Sulfur Radioisotopes

The 5-HT2 receptor agonist, DOI, dose-dependently (0.16-10.0 mg/kg, s.c.) increased dialysate levels of dopamine (DA) and noradrenaline (NA), but not 5-HT, in the frontal cortex (FCX) of freely-moving rats. This action was abolished by the selective 5-HT2A antagonist, MDL100,907 (0.04), which did not, itself, modify levels of DA and NA. In contrast, the selective 5-HT2B/2C antagonist, SB206,553 (0.63), increased levels of DA and NA additively with DOI. Thus, in contrast to a tonic, inhibitory influence of 5-HT2C receptors (see Millan, M.J., Dekeyne, A., Gobert, A., 1998. Serotonin (5-HT)2C receptors tonically inhibit dopamine (DA) and noradrenaline (NAD), but not 5-HT, release in the FCX in vivo. Neuropharmacology 37, 953-955), 5-HT2A receptors exert a phasic, facilitatory influence upon FCX levels of DA and NA.

Topics: Amphetamines; Animals; Dopamine; Fluorobenzenes; Frontal Lobe; Indoles; Male; Microdialysis; Norepinephrine; Piperidines; Pyridines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

The 5-HT2A and 5-HT2C antagonists MDL 100,907 and SER-082 were tested with the 5-HT2A/C agonist DOI and the 5-HT1A/2A/2C agonist LSD in the Behavioral Pattern Monitor, which provides multiple measures of locomotor and investigatory activity. Previous investigations have shown that these measures load onto three independent behavioral factors: amount of activity, exploratory behavior, and behavioral organization. Rats pretreated with saline, MDL 100,907 (0.25-2.0 mg/kg), or SER-082 (0.5-1.0 mg/kg) were treated with saline, 0.25 mg/kg DOI, or 60 micrograms/kg LSD. All effects of DOI were blocked by all doses of MDL 100,907, but only by the highest dose of SER-082. While the effects of LSD on activity and exploratory behavior were largely unaffected, either pretreatment antagonized the effects of LSD on behavioral organization. Thus, all of these effects of DOI were attributable to 5-HT2A receptors, whereas the effect of LSD on behavioral organization was influenced by both 5-HT2A and 5-HT2C receptors.

Topics: Amphetamines; Animals; Exploratory Behavior; Fluorobenzenes; Hallucinogens; Lysergic Acid Diethylamide; Male; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

In this study, we assessed the effects of the acute administration of various 5-HT receptor agonists on hippocampal partial seizures generated by low-frequency electrical stimulation in male Wistar rats. The seizure threshold and severity were determined by measuring the pulse number threshold and primary and secondary afterdischarges and the latency of secondary discharge was also determined. The administration (0.1-1 mg/kg, i.p.) of either the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-aminopropyl)tetralin (8-OH-DPAT), or the selective 5-HT3 receptor agonist, 4-amino-(6-chloro-2-pyridyl)-1-piperidine (SR 57227A, 0.3-3 mg/kg, i.p.), did not alter any of the seizure parameters compared to those in vehicle-treated animals. Similarly, the administration of 0.3 and 1 mg/kg, i.p., of the 5-HT2A,C receptor agonist, (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), did not alter any of the seizure parameters, whereas 3 mg/kg significantly decreased the latency of the secondary afterdischarge compared to that in vehicle-treated animals. The selective serotonin reuptake inhibitor, (+/-)-fluoxetine (2 mg/kg, i.p.), significantly increased the pulse number threshold and decreased the primary afterdischarge duration compared to those in vehicle-treated animals. In contrast, higher doses (6 or 20 mg/kg, i.p.) of fluoxetine did not significantly alter any of the seizure parameters measured. These results suggest that, in this model, stimulation of 5-HT1A, 5-HT2A,C and 5-HT3 receptors does not alter seizure threshold or severity and that the blockade of 5-HT uptake produced by a low dose of fluoxetine appears to increase seizure threshold and decrease seizure severity.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amphetamines; Animals; Behavior, Animal; Electric Stimulation; Electrodes, Implanted; Electroencephalography; Epilepsy, Complex Partial; Fluoxetine; Hippocampus; Kindling, Neurologic; Male; Piperidines; Rats; Rats, Wistar; Selective Serotonin Reuptake Inhibitors; Serotonin Receptor Agonists

Topics: Amphetamines; Animals; Cerebral Cortex; Fluorobenzenes; Guanylyl Imidodiphosphate; Ketanserin; Magnesium; Methysergide; Piperidines; Prazosin; Rabbits; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Spiperone

Serotonin (5-HT)2A receptors are known to be involved in prepulse inhibition of the startle response (PPI), a measure of sensorimotor inhibition that is deficient in schizophrenia, Huntington's disease, and obsessive compulsive disorder. In the present studies, the localization of the 5-HT2A receptors responsible for modulating PPI was investigated using central injections of the hallucinogenic 5-HT2 agonist DOI and the novel 5-HT2A antagonist MDL 100,907. 5-HT2A receptors are densely localized in the nucleus accumbens (NAC) and the ventral pallidum (VP), areas known to be important components of neural circuitry that mediates the ventral forebrain modulation of PPI. In the present studies, it was found that the infusion of DOI (0.0-5.0 microg/0.5 microl) into the VP disrupted PPI without having effects on startle reactivity. In contrast, similar infusions into the NAC had no effect on PPI or startle reactivity. The infusion of MDL 100,907 into the VP was found to increase PPI by itself and to attenuate the PPI-disruptive effects of systemically administered DOI. It is concluded that 5-HT2A receptors within the VP are important for the modulation of PPI, presumably through interactions at intrinsic GABAergic or cholinergic interneurons.

Topics: Amphetamines; Animals; Fluorobenzenes; Globus Pallidus; Hallucinogens; Male; Microinjections; Neural Inhibition; Nucleus Accumbens; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Reflex, Startle; Serotonin Antagonists

To characterize their in vivo 5-hydroxytryptamine (5-HT)2A antagonist properties, the ability of the putative mixed 5-HT1A agonists/5-HT(2A,2C) antagonists (N-(29(4-(2-pyrimidinyl)-1-piperazinyl)ethyl)tricyclo(3.3.1.1(3,7) ) decane-1-carboxamide (WY-50,324), (2-(4-(4,4-bis(4-fluorophenyl)butyl)-1-piperazinyl)-3-pyridinecarboxy lic acid hydrochloride (FG5974), 9,10-didehydro-N-(2-propynyl)-6-methylergoline-8b-carboxamid e (LEK-8804) and trans-1,3,4,a5,10b-hexahydro10-methoxy-4-propyl-2H-(1)benzopyra nol[3,4-b]pyridine (CGS 18102A) to antagonize both head twitches and discriminative stimulus (DS) effects produced by (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) in rats were compared with those of the 5-HT2 antagonists ketanserin and ritanserin, and the 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone. All of these compounds produced dose-related decreases in DOI-induced head twitches; however pretreatment with the 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide (WAY-100635) failed to alter the ability of ritanserin, ketanserin or CGS 18102A to attenuate DOI-induced head twitches. In contrast, WAY-100635 completely blocked the effects of 8-OH-DPAT, buspirone and WY-50,324, and partially blocked the effects of LEK-8804, demonstrating that 5-HT1A agonist properties are involved in the effects of all of the mixed compounds except CGS 18102A. In rats trained to discriminate DOI (0.63 mg/kg) from saline in a two-lever, FR10 drug discrimination paradigm, ketanserin, ritanserin and CGS 18102A blocked the DS effects of the training dose by more than 50%. In contrast, WY-50,324, FG5974, LEK-8804, buspirone and 8-OH-DPAT, up to doses that completely suppressed responding, failed to produce more than a 33% blockade of the DS effects of DOI. In vivo 5-HT1A agonist effects were demonstrated by the finding that relatively selective- and mixed-5-HT1A agonists produced one or more elements of the "serotonin syndrome," i.e., flat-body posture, forepaw treading, or lower-lip retraction, and produced high levels of drug-lever selection in rats trained to discriminate 8-OH-DPAT (0.16 mg/kg) from saline. Because DOI-induced head twitches and DS effects are thought to be mediated by 5-HT2A receptors, the results demonstrate that the putative mixed compound, CGS 18102A has prominent 5-HT2A antagonist properties in vivo, whereas 5-HT2A antagonist effects of WY-50,324, FG5974 and LEK-8804 could not

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amphetamines; Animals; Anti-Anxiety Agents; Behavior, Animal; Benzopyrans; Discrimination, Psychological; Ketanserin; Lysergic Acid Diethylamide; Male; Nicotinic Acids; Piperazines; Piperidines; Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Ritanserin; Serotonin Antagonists; Serotonin Receptor Agonists

Latent inhibition (LI), a measure of the ability to learn to ignore irrelevant stimuli, is disrupted in acute schizophrenics and in rats treated with amphetamine; antipsychotics prevent amphetamine disruption of LI in rats. The 5-HT2A/C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) has hallucinogenic properties in humans, and evidence suggests that 5-HT2 antagonism is an important component of atypical antipsychotic activity. Therefore, the ability of DOI to disrupt LI in rats was tested, and the ability of clinically-used and putative antipsychotics to reverse DOI disruption of LI was assessed. The method consisted of four phases. After habituation to the apparatus, thirsty rats underwent preexposure to a tone stimulus 24 h prior to two tone-shock conditioning trials. LI was demonstrated at testing (an additional 24 h later) by reduced lick suppression during tone presentation. When administered at the preexposure phase only, DOI disrupted LI. However, when administered at both preexposure and conditioning phases, DOI did not disrupt LI except at the highest dose, where lick suppression itself was also disrupted. Therefore, disruptive effects of DOI on LI are not easily dissociated from state-dependent learning effects. Additional experiments demonstrated that haloperidol, clozapine, risperidone, and the selective 5-HT2A antagonist MDL 100,907 prevented the disruptive effects of DOI on LI when administered at preexposure only. These results agree with findings that these compounds can also prevent other behavioral effects of DOI. Further experiments will be required to explore the possible involvement of state-dependent learning effects in the present results. However, if the disruptive effects of DOI on LI are due to an influence on attentional processes rather than state-dependent learning, this procedure may have potential as a method for detection of antipsychotic activity.

Topics: Amphetamines; Animals; Antipsychotic Agents; Clozapine; Conditioning, Operant; Fluorobenzenes; Haloperidol; Male; Piperidines; Rats; Rats, Sprague-Dawley; Reflex, Startle; Reinforcement, Psychology; Risperidone; Serotonin Antagonists; Serotonin Receptor Agonists

Described and evaluated here is a newly designed apparatus for the assessment of conditioned avoidance response (CAR) performance in rats. The system is computer-assisted using a design and system control development package based on the virtual instrument concept (LabView). The program, which allows for significant flexibility, greatly facilitated and simplified the process of timing and data acquisition. The apparatus was found effective and appropriately designed for CAR performance training, as well as for a reliable assessment of the effects of antipsychotic and potentially antipsychotic compounds on CAR in rats. The design presents a new, effective, and inexpensive option for laboratories involved in animal behavioral research.

Topics: Amphetamines; Animals; Antipsychotic Agents; Avoidance Learning; Benzazepines; Clozapine; Computers; Cross-Over Studies; Dopamine Antagonists; Fluorobenzenes; Haloperidol; Male; Physical Conditioning, Animal; Piperidines; Raclopride; Rats; Rats, Sprague-Dawley; Salicylamides; Serotonin Antagonists; Serotonin Receptor Agonists

Correlations between 5-hydroxytryptamine (5-HT) receptor binding affinities and human hallucinogenic potency have suggested that 5-HT2 receptors mediate the hallucinogenic effects of lysergic acid diethylamide (LSD) and phenethylamine hallucinogens. Electrophysiological studies have suggested that a subpopulation of gamma-aminobutyric acid (GABA)ergic interneurons in layer III of the rat piriform cortex are excited by serotonin (5-HT) via 5-HT2A receptors. These interneurons have inhibitory inputs on pyramidal cells in layer II. In the present study, we tested low concentrations of both LSD (3-100 nM) and the phenethylamine hallucinogen 1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI; 0.3-10 microM) on rat piriform cortical interneurons that were excited by 5-HT. Both LSD (3-100 nM) and DOI (0.3-10 microM) excited almost every cell excited by 5-HT. The maximal excitation achieved with LSD and DOI was 39% and 55% of the effect of a near-maximal 5-HT concentration (100 microM). Consistent with a partial agonist action, LSD and DOI blocked the 5-HT excitation of piriform cortical interneurons only at the higher hallucinogen concentrations tested. A specific 5-HT2A receptor antagonist, MDL 100,907, blocked excitation of these interneurons by 5-HT, LSD and DOI, but not by norepinephrine or alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate. Again, consistent with a partial agonist action of the hallucinogens, intracellular experiments showed that a maximal concentration of DOI (10 microM) induced fewer postsynaptic inhibitory currents than did 5-HT (100 microM) in pyramidal neurons in layer II of the piriform cortex. Based on the present electrophysiological studies, we conclude that LSD and DOI, a phenethylamine hallucinogen, act as highly potent partial agonists at cortical 5-HT2A receptors.

Topics: Action Potentials; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Amphetamines; Animals; Cerebral Cortex; Dose-Response Relationship, Drug; Fluorobenzenes; Hallucinogens; In Vitro Techniques; Interneurons; Lysergic Acid Diethylamide; Male; Norepinephrine; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

Increasing evidence suggests an important role of 5-HT, and 5-HT2A receptors in particular, in the etiology and treatment of schizophrenia. The prepulse inhibition paradigm is used as a model for sensorimotor gating processes that are disrupted in schizophrenia. The present study used the selective serotonin2A (5-HT2A) antagonist and putative antipsychotic agent MDL 100,907 to evaluate the contribution of 5-HT2A receptors to the disruptions of prepulse inhibition produced by several 5-HT agonists. The D2 antagonist haloperidol was used to evaluate a possible interaction with dopamine neurons. Sound or light prepulses were used to measure the generality of these drug effects on cross-modal prepulse inhibition. In the first study, MDL 100,907 antagonized the disruptions of auditory prepulse inhibition produced by the 5-HT releasing agents fenfluramine and 3,4-methylenedioxymethamphetamine (MDMA). These effects on prepulse inhibition were modality-specific in that MDL 100,907 did not reverse the effects of the 5-HT releasers on visual prepulse inhibition. Haloperidol did not alter the disruptive effects of MDMA or fenfluramine on either auditory or visual prepulse inhibition. In the second study, the direct acting 5-HT2A/2C receptor agonist/hallucinogen (+)1-4-iodo-2,5-dimethoxyphenyl-2-aminopropane (DOI) consistently disrupted auditory prepulse inhibition, and this effect was blocked by MDL 100,907 but not by haloperidol. A dose-response analysis demonstrated that MDL 100,907 potently antagonized DOI disrupted auditory prepulse inhibition, with an ED50 of 0.04 mg/kg, IP. DOI did not consistently disrupt visual prepulse inhibition. In summary, these data indicate that, at least under the conditions of the present studies, the disruptions of auditory prepulse inhibition produced by fenfluramine, MDMA, and DOI result from stimulation of 5-HT2A receptors. Furthermore, these disruptions do not involve direct or indirect stimulation of D2 receptors. The identity of the 5-HT receptor(s) underlying the disruptive effects of fenfluramine or MDMA on visual prepulse inhibition has not yet been identified. MDL 100,907 may be generally useful in CNS disorders in which excessive 5-HT2A receptor tone disrupts sensory gating processes.

Topics: Amphetamines; Animals; Antipsychotic Agents; Dose-Response Relationship, Drug; Fenfluramine; Fluorobenzenes; Haloperidol; Male; Piperidines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Reflex, Startle; Serotonin Receptor Agonists

Action potential duration (APD) lengthening is believed to underlie the cardiac arrhythmogenicity of ketanserin, a serotonin (5-HT)2A/2C receptor antagonist. We wished to determine (a) whether this activity involves blockade of 5-HT2A/2C receptors and (b) the precise mechanism of ketanserin-induced APD prolongation. APs were recorded in guinea pig isolated papillary muscles by conventional "floating" microelectrodes, and potassium currents in guinea pig isolated myocytes were recorded in the whole-cell configuration. Ketanserin (1-10 microM) increased APD (EC50 value for enhancing APD at 90% repolarization (APD90) 3.1 +/- 2.7 microM, n = 24), without affecting resting potential, maximum upstroke velocity (Vmax) or AP amplitude (APA). Pirenperone (10 microM), a ketanserin congener, similarly increased APD90 from 204 +/- 3 to 241 +/- 7 ms (p < 0.001, n = 6). No increase in APD was observed, however, with ritanserin or ICI 170809, even at high concentrations (10 microM, n = 6, respectively), two 5-HT2A/2C receptor antagonists chemically distinct from ketanserin, thereby excluding the involvement of 5-HT2A/2C receptors in mediating APD lengthening. That APD prolongation was mediated specifically by the benzolyl-piperidine moiety of ketanserin and pirenperone was confirmed by 1-propyl-4(4-fluorobenzoyl)piperidine (PFBP), which evoked APD lengthening effects remarkably similar to those produced by ketanserin and pirenperone (EC50 3.73 +/- 2.6 microM, n = 12). In isolated cardiomyocytes, ketanserin (1-32 microM) selectively and concentration-dependently reduced the IKr component of the delayed outward current (IK) without affecting the inward rectifier current, IK1. Thus, ketanserin (32 microM) significantly reduced IK at a potential value of -20 mV from 813 +/- 65 to 569 +/- 55 pA (p < 0.001, n = 6), whereas at a potential value of -110 mV, IK1 was not significantly affected (730 +/- 103 vs. 603 +/- 143 pA, respectively; n=6). The results demonstrate that APD is prolonged by ketanserin and congeners but not be chemically different 5-HT2A/2C receptor antagonists. The benzoyl-piperidine moiety appears to mediate the APD-prolonging effects of ketanserin and pirenperone specifically. Furthermore, ketanserin-induced APD lengthening does not appear to involve 5-HT2A/2C receptors but is consecutive to direct blockade of myocardial potassium channels.

Topics: Action Potentials; Amphetamines; Animals; Guinea Pigs; Heart; Ketanserin; Male; Piperidines; Potassium Channels; Serotonin Antagonists

In a drug discrimination paradigm, the 5-HT2A/2C receptor antagonists, ritanserin, ICI 169,369 (2-(2-dimethylaminoethylthio-3-phenylquinoline hydrochloride) and mianserin, and the preferential 5-HT2A receptor antagonist, ketanserin, antagonised the discriminative stimulus effects of the 5-HT2A/2C receptor agonist, DOI ((2,5-dimethoxy-4-iodohenyl)-2-aminopropan) (0.63 mg/kg i.p.). Effective dose50 (ED50) values were: 0.32, 0.39, 0.15 and 0.03 mg/kg s.c., respectively. While the novel, selective 5-HT2C receptor antagonist, SB 200,646 (N-(1-methyl-5-iodolyl)-N'-(3-pyridyl) urea hydrochloride) was inactive (10 mg/kg s.c. and 20 mg/kg p.o.), the highly selective 5-HT2A receptor antagonist, MDL 100,907 (R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl]-4- piperidine-methanol) very potently (ED50 = 0.0006) abolished the action of DOI. MDL 100,907 may display antipsychotic properties and the 'atypical' antipsychotics, clozapine, risperidone and sertindole, each of which possesses marked affinity at 5-HT2A receptors, abolished the discriminative stimulus effects of DOI (ED50 values of 0.07, 0.03 and 0.33 mg/kg, respectively). In contrast, haloperidol (0.16) was ineffective. These data demonstrate that 5-HT2A receptors mediate the discriminative stimulus effects of DOI and support the hypothesis that an antagonistic action at 5-HT2A receptors contributes to the in vivo actions of 'atypical' antipsychotics.

Topics: Amphetamines; Animals; Antipsychotic Agents; Behavior, Animal; Clozapine; Fluorobenzenes; Isoxazoles; Male; Motor Activity; Piperidines; Rats; Rats, Wistar; Receptors, Serotonin; Risperidone; Serotonin Antagonists

In this study, we examined the interaction of 5-HT1A and 5-HT2A receptors in the rat medial prefrontal cortex (mPFc) using the techniques of extracellular single unit recording and microiontophoresis. The iontophoresis of the selective 5-HT1A receptor agonist (+-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) produced a current-dependent suppression (2.5-20 nA) of the basal firing rate of spontaneously active mPFc cells. The iontophoretic (5-10 nA) and systemic administration (0.1-0.5 mg/kg, i.v.) of the 5-HT2A/5-HT2C receptor antagonist ritanserin and the selective 5-HT2A receptor antagonist MDL 28727 significantly potentiated and prolonged 8-OHDPAT's suppressant action. In addition, the systemic administration of another selective 5-HT2A antagonist MDL 100907, but not its less active enantiomer MDL 100009, also potentiated and prolonged 8-OHDPAT's action. The potentiating effect of the 5-HT2A receptor antagonists on the action of 8-OHDPAT is specific in that neither the iontophoresis of ritanserin nor MDL 28727 altered the suppressant action produced by the iontophoresis of the 5-HT3 receptor agonist 2-methylserotonin onto mPFc cells. Moreover, the suppressant action of 8-OHDPAT was not altered by the systemic administration of the selective 5-HT3 receptor antagonist granisetron (0.1-0.5 mg/kg, i.v.). On the other hand, the iontophoresis of a low current (0.5 nA) of the 5-HT2A,2C receptor agonist (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) potentiated the excitation induced by the iontophoresis of l-glutamate on quiescent mPFc cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amphetamines; Animals; Electrophysiology; Fluorobenzenes; Glutamic Acid; Injections, Intravenous; Iontophoresis; Male; Organic Chemicals; Piperidines; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

Relatively little is known regarding the role of 5-HT2 receptor activity in male rat sexual behavior. Previous work has yielded equivocal results, and both facilitation and inhibition of copulation have been reported to follow administration of selective 5-HT2 antagonists. In the present series of experiments, the ability of a variety of 5-HT2 antagonists to block inhibition induced by the 5-HT2/5-HT1C agonist DOI was examined. Systemic ritanserin, pirenperone and ketanserin all potently blocked DOI-induced (1.0 mg/kg SC) inhibition of mounts, intromissions and ejaculations. None of these drugs influenced the sexual behavior of the male rats when given alone in doses that effectively blocked DOI-induced inhibition. In addition, unlike ritanserin and ketanserin, pirenperone produced a biphasic effect on DOI-induced inhibition, exhibiting a diminished blockade at higher doses. This may be due to activity at receptors other than 5-HT2. Overall, the present data suggest that activity at 5-HT2 receptors mediates an inhibition of male rat sexual behavior.

Topics: Amphetamines; Animals; Copulation; Ejaculation; Female; Ketanserin; Male; Piperidines; Rats; Rats, Inbred Strains; Ritanserin; Serotonin Antagonists; Tranquilizing Agents

The functional role of brain 5-HT and 5-HT receptor subtypes in periaqueductal gray (PAG) induced aversion has been investigated in rats. Antiaversive effects were found with the serotonin agonists TFMPP, mCPP and DOI but not with RU 24969 which was found to facilitate PAG aversion. The first three serotonin agonists share potent 5-HT1C activity while RU 24969 differs with a high 5-HT1A activity. Proaversive effects were found with the mixed 5-HT1C/5-HT2 antagonists cyproheptadine and ritanserin; this effect was already reported for the mixed 5-HT1C/5-HT2 antagonists metergoline and mianserin and is opposite to the effects of the selective 5-HT2 antagonists ketanserin, pirenperone, trazodone and spiperone. The antiaversive effects of mCPP (1 mg/kg) could be prevented by pretreatment of the animals with mianserin (1 and 10 mg/kg). These results suggest that 5-HT1C receptors play an important role in the serotonergic control of PAG aversion. 5-HT1C receptor activation seems to mediate antiaversive effects whereas acute 5-HT1C receptor blockade appears to facilitate PAG aversion. Functional interactions take place between several receptor types in the in vivo control of PAG aversion, where 5-HT1C receptors appear to play a predominant function.

Topics: Amphetamines; Animals; Cyproheptadine; Indoles; Ketanserin; Male; Periaqueductal Gray; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Reinforcement, Psychology; Ritanserin; Serotonin; Serotonin Antagonists

Administration of the 5-HT1C/5-HT2 receptor agonist 1-(2,5-dimethoxy-4- iodophenyl)-2-aminopropane (DOI, 0.125-2.0 mg/kg i.v.) triggered dose-dependent increases in plasma glucose; plasma insulin levels remained unchanged. Pretreatment with the 5-HT1C/5-HT2 receptor antagonists LY 53857, ritanserin, or the mixed 5-HT2/alpha 1-adrenoceptor antagonist ketanserin either diminished or prevented the hyperglycemic effect of DOI (0.5 mg/kg). Administration of the mixed 5-HT1C receptor agonists/5-HT2 receptor antagonists 1-(3-chlorophenyl)-piperazine (mCPP) or 1-(3-trifluoromethyl)phenyl)piperazine level (TFMPP) did not affect plasma glucose levels. However, pretreatment with mCPP or TFMPP decreased DOI-induced hyperglycemia in a dose-dependent manner. The alpha 2-adrenoceptor antagonist idazoxan and the ganglionic blocker hexamethonium both decreased DOI-induced hyperglycemia, Whilst the alpha 1-adrenoceptor antagonist prazosin amplified the rise in plasma glucose elicited by DOI. The peripherally acting 5-HT1C/5-HT2 receptor agonist alpha-methyl-5-HT (0.5-1.0 mg/kg i.v.) triggered a rise in plasma glucose levels that was associated with an increase in plasma insulin levels. Pretreatment with LY 53857 diminished alpha-methyl-5-HT-induced hyperglycemia. These data indicate that 5-HT2 receptors, but not 5-HT1C receptors, and catecholaminergic systems, mediate DOI-induced hyperglycemia. Moreover, it is suggested that the inhibition of insulin release by DOI is centrally mediated, and that activation of peripheral 5-HT2 receptors may affect glycemia.

Topics: Amphetamines; Animals; Blood Glucose; Catecholamines; Ergolines; Hyperglycemia; Insulin; Male; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Ritanserin; Serotonin

An intrarenal infusion of (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a selective 5-HT2 agonist, at a rate of 5 micrograms/min in anesthetized dogs resulted in an increase in renal blood flow (RBF) without any transient decrease as usually observed during the infusion of 5-HT. During the infusion, urine flow (UF) and urinary sodium excretion rates (UNaV) increased along with RBF while the mean arterial pressure and glomerular filtration rate did not change. After pretreatment with ritanserin, a selective 5-HT2 antagonist, DOI failed to increase RBF, UF and UNa V. It is concluded that DOI produces renal vasodilatation mediated via 5-HT2 receptors and has a diuretic action.

Topics: Amphetamines; Animals; Blood Pressure; Creatinine; Dogs; Female; Glomerular Filtration Rate; Male; Piperidines; Receptors, Serotonin; Renal Circulation; Ritanserin; Urodynamics; Vasodilation

In rats tested during their first exposure to a Behavioral Pattern Monitor chamber, acute injections of the 5HT-2 agonists mescaline, quipazine, 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM), or 2,5-dimethoxy-4-ethylamphetamine (DOET) produced an inhibition of locomotor and investigatory behavior during the first 30 min of the test session. This suppression of exploratory behavior was attenuated when rats were familiarized with the testing chamber prior to the administration of DOI. Hence, as previously observed with both LSD and DOM, 5HT-2 agonists appear to potentiate the normal neophobic reaction to a novel environment. The mixed 5HT-1 and 5HT-2 agonist 5-methoxy-N,N-dimethyltryptamine (5MeODMT) also produced a decrease in activity when animals were tested in the novel environment. However, as previously found with 5HT-1A agonists, this effect was unchanged when animals were tested in the familiar environment and may therefore reflect a generalized sedation. The receptor specificity of these differential effects of 5HT-1 and 5HT-2 agonists in this paradigm was tested by assessing the ability of selective 5HT-2 antagonists to block the effects of the agonists. A dose of the 5HT-2 antagonist ketanserin which had no effect by itself significantly reduced the behavioral effects of mescaline, DOM, and quipazine. Similarly, the selective 5HT-2 antagonist ritanserin blocked the effect of quipazine. In contrast, ketanserin had no significant effect on the suppression of activity produced by the 5HT-1A agonist 8-hydroxy-2(di-n-propylamino)tetralin (8OHDPAT).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amphetamines; Animals; Behavior, Animal; DOM 2,5-Dimethoxy-4-Methylamphetamine; Dose-Response Relationship, Drug; Hallucinogens; Ketanserin; Male; Mescaline; Piperidines; Quipazine; Rats; Rats, Inbred Strains; Ritanserin; Serotonin; Tetrahydronaphthalenes

Serotonin receptor ligands, with differential affinity for subtypes of serotonin (5-HT) receptors, were administered intravenously or iontophoretically to urethane-anesthetized rats and the effects of these compounds on glutamate-evoked firing of spinal motoneurons were tested. The excitability of spinal motoneurons was markedly enhanced after intravenous administration of the selective 5-HT1A ligand 8-hydroxy-2-(di-n-propylamino) tetralin (DPAT) in rats with acute spinal transections at C1. However, local application of DPAT, directly into the ventral horn by microiontophoresis, inhibited the glutamate-evoked firing of motoneurons in direct contrast to the facilitatory effects of iontophoretically applied 5-HT. The DPAT-induced inhibition may have been nonspecific, since it was not antagonized by methysergide. Other 5-HT agonists, with relatively selective affinity for 5-HT1B, 5-HT1C and 5-HT2 receptors, increased the excitability of spinal motoneurons when applied iontophoretically or intravenously. The excitatory effect of iontophoretically applied 5-HT was antagonized by the nonselective 5-HT antagonist, methysergide and by ketanserin and ritanserin, which have relatively selective affinity for 5-HT1C and 5-HT2 receptors. These results indicate that 5-HT1A receptors do not mediate facilitation of excitability of motoneurons produced by local application of 5-HT directly into the vicinity of the motoneurons. However, the marked increase in firing of motoneurons that was caused by intravenous administration of DPAT in spinal transected rats, suggests that 5-HT1A receptors in the spinal cord may participate in 5-HT-induced enhancement of somatomotor outflow, at sites presynaptic to the motoneurons. The iontophoretic results suggest that 5-HT1B, 5-HT1C and 5-HT2 receptors may all play a role in facilitation of the excitability of spinal motoneurons by locally applied 5-HT. Differentiation between these subtypes of receptor awaits the development of more completely selective agonists and antagonists.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amphetamines; Animals; In Vitro Techniques; Injections, Intravenous; Iontophoresis; Ketanserin; Male; Methysergide; Microelectrodes; Motor Neurons; Piperidines; Prazosin; Quipazine; Rats; Rats, Inbred Strains; Receptors, Serotonin; Ritanserin; Serotonin; Serotonin Antagonists; Spinal Cord; Tetrahydronaphthalenes

The potency of the serotonin 1A (5-HT1A) agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT), to induce forepaw treading was increased 20-fold after co-treatment with the 5-HT2 agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). DOI induced head twitches which were inhibited by 8-OHDPAT. The putative 5-HT1B agonist, 1-(3-trifluoromethylphenyl)piperazine (TFMPP), had a weak effect on the responses to DOI or 8-OHDPAT. The forepaw treading induced by 8-OHDPAT plus DOI was inhibited by high doses of (-)-alprenolol, ketanserin or ritanserin, but was not influenced by the beta-adrenoceptor antagonist, ICI 118.551, or the 5-HT3 antagonist, ICS 205-930. A non-effective dose of (-)-alprenolol increased the inhibitory effect of ketanserin and ritanserin. These results indicate a complex and different interaction between 5-HT1A and 5-HT2 receptors in the expression of two behavioural responses mediated by 5-HT.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Alprenolol; Amphetamines; Animals; Behavior, Animal; Cerebral Cortex; Injections, Subcutaneous; Ketanserin; Male; Naphthalenes; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Ritanserin; Tetrahydronaphthalenes

The present studies have attempted to evaluate the role of 5-HT2 receptors in the regulation of sexual behavior of male rats by determining the effects of 5-HT2 receptor antagonists, pirenperone, LY53857 and LY281067, and a 5-HT2 receptor agonist, DOI. The administration of 1 mg/kg s.c. pirenperone produced a total suppression of ejaculatory response and lower doses had no effect. However, the administration 0.1 mg/kg s.c. of either LY53857 or LY281067 restored ejaculatory capacity to rats that were unable to ejaculate and produced significant decreases in ejaculatory latency in rats with full sexual capacity. Although all of these agents are 5-HT2 antagonists, LY53857 and LY281067 lack the additional monoaminergic activity of pirenperone. Since the effects of pirenperone were opposite from the effects of the selective 5-HT2 antagonists, the suppressive effects of this agent were probably related to its other monoaminergic activity e.g. alpha 1 antagonist activity. This proposal was supported by the observation that the administration of prazosin, an alpha 1 antagonist, significantly increased ejaculatory latency and suppressed the stimulatory effects of LY53857. In contrast to the stimulatory effects of the selective 5-HT2 antagonists, the administration of DOI, resulted in a suppression of sexual performance, which was blocked by pretreatment with LY53857.

Topics: Amphetamines; Animals; Copulation; Ejaculation; Ergolines; Female; Lysergic Acid; Male; Piperidines; Prazosin; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin Antagonists; Sexual Behavior, Animal