dizocilpine-maleate and 4-iodo-2-5-dimethoxyphenylisopropylamine

Animal models with predictive and construct validity are necessary for developing novel and efficient therapeutics for psychiatric disorders.. We have carried out a pharmacological characterization of the Roman high- (RHA-I) and low-avoidance (RLA-I) rat strains with different acutely administered propsychotic (DOI, MK-801) and antipsychotic drugs (haloperidol, clozapine), as well as apomorphine, on prepulse inhibition (PPI) of startle and locomotor activity (activity cages).. RHA-I rats display a consistent deficit of PPI compared with RLA-I rats. The typical antipsychotic haloperidol (dopamine D2 receptor antagonist) reversed the PPI deficit characteristic of RHA-I rats (in particular at 65 and 70 dB prepulse intensities) and reduced locomotion in both strains. The atypical antipsychotic clozapine (serotonin/dopamine receptor antagonist) did not affect PPI in either strain, but decreased locomotion in a dose-dependent manner in both rat strains. The mixed dopamine D1/D2 agonist, apomorphine, at the dose of 0.05 mg/kg, decreased PPI in RHA-I, but not RLA-I rats. The hallucinogen drug DOI (5-HT2A agonist; 0.1-1.0 mg/kg) disrupted PPI in RLA-I rats in a dose-dependent manner at the 70 dB prepulse intensity, while in RHA-I rats, only the 0.5 mg/kg dose impaired PPI at the 80 dB prepulse intensity. DOI slightly decreased locomotion in both strains. Finally, clozapine attenuated the PPI impairment induced by the NMDA receptor antagonist MK-801 only in RLA-I rats.. These results add experimental evidence to the view that RHA-I rats represent a model with predictive and construct validity of some dopamine and 5-HT2A receptor-related features of schizophrenia.

Topics: Amphetamines; Animals; Antipsychotic Agents; Apomorphine; Avoidance Learning; Clozapine; Dizocilpine Maleate; Dopamine Agonists; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Haloperidol; Locomotion; Male; Prepulse Inhibition; Rats; Receptor, Serotonin, 5-HT2A; Reflex, Startle; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Serotonin Antagonists

Stereotypy (e.g., repetitive hand waving) is a key phenotype of autism spectrum disorder, Fragile X and Rett syndromes, and other neuropsychiatric disorders, and its severity correlates with cognitive and attention deficits. There are no effective treatments, however, for stereotypy. Perturbation of serotonin (5-HT) neurotransmission contributes to stereotypy, suggesting that distinct 5-HT receptors may be pharmacotherapeutic targets to treat stereotypy and related neuropsychiatric symptoms. For example, preclinical studies indicate that 5-HT7 receptor activation corrects deficits in mouse models of Fragile X and Rett syndromes, and clinical trials for autism are underway with buspirone, a 5-HT1A partial agonist with relevant affinity at 5-HT7 receptors. Herein, we report the synthesis, in vitro molecular pharmacology, behavioral pharmacology, and pharmacokinetic parameters in mice after subcutaneous and oral administration of (+)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine ((+)-5-FPT), a new, dual partial agonist targeting both 5-HT7 (Ki = 5.8 nM, EC50 = 34 nM) and 5-HT1A (Ki = 22 nM, EC50 = 40 nM) receptors. Three unique, heterogeneous mouse models were used to assess the efficacy of (+)-5-FPT to reduce stereotypy: idiopathic jumping in C58/J mice, repetitive body rotations in C57BL/6J mice treated with the NMDA antagonist, MK-801, and repetitive head twitching in C57BL/6J mice treated with the 5-HT2 agonist, DOI. Systemic (+)-5-FPT potently and efficaciously reduced or eliminated stereotypy in each of the mouse models without altering locomotor behavior on its own, and additional tests showed that (+)-5-FPT, at the highest behaviorally active dose tested, enhanced social interaction and did not cause behaviors indicative of serotonin syndrome. These data suggest that (+)-5-FPT is a promising medication for treating stereotypy in psychiatric disorders.

Topics: 2-Naphthylamine; Administration, Oral; Amphetamines; Animals; Blood-Brain Barrier; Brain; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Locomotion; Male; Mice, Inbred C57BL; Molecular Structure; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin; Serotonin Receptor Agonists; Social Behavior; Stereotyped Behavior; Tetrahydronaphthalenes

Both the serotonin and glutamate systems have been implicated in the pathophysiology of schizophrenia, as well as in the mechanism of action of antipsychotic drugs. Psychedelic drugs act through the serotonin 2A receptor (5-HT2AR), and elicit a head-twitch response (HTR) in mice, which directly correlates to 5-HT2AR activation and is absent in 5-HT2AR knockout mice. The precise mechanism of this response remains unclear, but both an intrinsic cortico-cortical pathway and a thalamo-cortical pathway involving glutamate release have been proposed. Here, we used a genetic model of NMDAR hypofunction, the serine racemase knockout (SRKO) mouse, to explore the role of glutamatergic transmission in regulating 5-HT2AR-mediated cellular and behavioral responses. SRKO mice treated with the 5-HT2AR agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) showed a clearly diminished HTR and lower induction of c-fos mRNA. These altered functional responses in SRKO mice were not associated with changes in cortical or hippocampal 5-HT levels or in 5-HT2AR and metabotropic glutamate-2 receptor (mGluR2) mRNA and protein expression. Together, these findings suggest that D-serine-dependent NMDAR activity is involved in mediating the cellular and behavioral effects of 5-HT2AR activation.

Topics: Amphetamines; Animals; Behavior, Animal; Brain; Dizocilpine Maleate; Dose-Response Relationship, Drug; Gene Expression Regulation; Head Movements; Hydroxyindoleacetic Acid; Mice; Mice, Knockout; Proto-Oncogene Proteins c-fos; Racemases and Epimerases; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Serotonin; Serotonin Receptor Agonists

Schizophrenic patients have been shown to exhibit abnormal cortical gamma band oscillation (GBO), which is thought to be related to the symptoms of schizophrenia, including cognitive impairment. Recently, non-competitive NMDA receptor (NMDAr) antagonists such as MK-801 and ketamine have been reported to increase the basal GBO power in rat cortical electroencephalograms. However, the mechanisms underlying the increase in basal GBO power induced by non-competitive NMDAr antagonists remain unclear. In the present study, we characterized the non-competitive NMDAr antagonists-increased GBO (30-80 Hz) power. MK-801 (0.05-0.2 mg/kg) increased the GBO power, exhibiting an inverted U-shape dose-response curve; at higher doses (0.3-1 mg/kg), the increase in GBO was reversed. The GBO power was closely correlated with the high-frequency oscillation (130-180 Hz) power following MK-801 administration, while the GBO power was inversely correlated with the increase in delta oscillation (0.5-4 Hz) power at higher doses. PCP (1.25-10 mg/kg) and ketamine (2.5-30 mg/kg) also exhibited the inverted U-shape dose-responses for the basal GBO power similar to MK-801. Interestingly, memantine (10-30 mg/kg) dose-dependently and potently increased the GBO power without remarkably affecting the other frequency band. In contrast, other psychotomimetics, such as methamphetamine (1-10 mg/kg) and DOI (0.5-2 mg/kg), did not induce noticeable changes in the basal GBO power even at doses that induce abnormal behaviors, indicating that the increase in GBO power induced by NMDAr antagonists is not necessarily attributed to psychotomimetic effects. In conclusion, the basal GBO power increase in response to non-competitive NMDAr antagonists may reflect the cortical hyperglutamatergic state through GABAergic disinhibition.

Topics: Amphetamines; Animals; Brain; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electrodes, Implanted; Electroencephalography; Excitatory Amino Acid Antagonists; Gamma Rhythm; Ketamine; Male; Memantine; Methamphetamine; Phencyclidine; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Several studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new way to achieve antipsychotic-like activity. LSP1-2111, the group III mGlu receptor orthosteric agonist, with a high affinity towards mGlu4 receptors, was previously shown to exhibit antipsychotic-like action in animal models displaying positive symptoms of schizophrenia.. Here, we decided to investigate the possible role of LSP1-2111 in models of negative (social interaction) and cognitive (NOR) symptoms of psychosis. We also investigated the involvement of 5-HT1A receptors in the LSP1-2111-induced antipsychotic effects. Apart from the above-mentioned models of negative and cognitive symptoms, MK-801 and amphetamine-induced hyperactivity tests, plus the DOI-induced head twitches in mice as models for positive symptoms of psychosis, were used in this part of the investigations.. LSP1-2111 (0.5, 2, and 5 mg/ kg) dose-dependently inhibited MK-801-induced deficits in social interaction and NOR tests. The effects of the drug were antagonized by 5-HT1A antagonist, WAY100635 (0.1 mg/kg). A similar inhibition of LSP1-2111-induced effects was observed in models of positive symptoms of schizophrenia. Moreover, the concomitant administration of subeffective doses of LSP1-2111 (0.3-0.5 mg/kg) with a subeffective dose of 5-HT1A agonist, (R)-(+)-8-Hydroxy-DPAT (0.01 mg/kg), induced a clear antipsychotic-like effect in all of the procedures used.. Altogether, we propose that the activation of group III mGlu receptors may be a promising target for the development of novel antipsychotic drugs, towards not only positive but also negative and cognitive symptoms. The action of the compound is 5-HT1A-dependent.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aminobutyrates; Amphetamines; Animals; Antipsychotic Agents; Cyclohexanes; Dextroamphetamine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Mice; Phosphinic Acids; Piperazines; Psychotic Disorders; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A; Receptors, Metabotropic Glutamate; Signal Transduction

Several clinical reports have suggested that the mirtazapine-induced augmentation of risperidone activity may effectively improve the positive, negative and some cognitive symptoms of schizophrenia.. The present study was aimed at examining the effect of mirtazapine and risperidone, given separately or jointly in mice, on the locomotor hyperactivity induced by D-amphetamine or MK-801 as well as a 5-HT(2A) receptor agonist DOI-induced head twitches as models for positive symptoms of psychosis.. The obtained results showed that co-treatment with mirtazapine (2.5 or 5 mg/kg) and risperidone (0.01 mg/kg) inhibited the locomotor hyperactivity induced by D-amphetamine or MK-801. Moreover, co-administration of mirtazapine (1.25 or 2.5 mg/kg) and risperidone (0.01 mg/kg) reduced the number of head twitches induced by DOI, whereas those drugs given separately changed neither the locomotor hyperactivity induced by D-amphetamine or MK-801 nor the syndrome induced by DOI.. The obtained results indicated that lower doses of mirtazapine enhanced the antipsychotic-like effect of risperidone in animal tests of positive symptoms of schizophrenia. Further studies are necessary to elucidate its mechanism of action.

Topics: Amphetamines; Animals; Antipsychotic Agents; Behavior, Animal; Dextroamphetamine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hyperkinesis; Male; Mianserin; Mice; Mirtazapine; Motor Activity; Risperidone; Schizophrenia; Schizophrenic Psychology

Several studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new and efficient way to achieve antipsychotic-like activity.. Here, we decided to investigate the possible role of the group III mGlu receptor ligands, LSP1-2111, the group III mGlu receptor orthosteric agonist, preferentially stimulating mGlu4 receptors especially in low doses, and AMN082, the mGlu7 receptor positive modulator. We used MK-801- and amphetamine-induced hyperactivity tests, as well as DOI-induced head twitches in mice as models for positive symptoms of psychosis. The C57Bl/6J mGlu7 receptor knockout mice were used to confirm that AMN082-induced effect was receptor specific. A non-selective antagonist of the group II/III mGlu receptors, LY341495, was used to block LSP1-2111-induced effects.. LSP1-2111 (1, 2, and 5 mg kg(-1)) dose dependently inhibited both MK-801- and amphetamine-induced hyperactivities. Moreover, the drug antagonized DOI-induced head twitches. The effects of the drug were antagonized by LY341495 administration (1.5 mg kg(-1), i.p.). In contrast, AMN082 (3 and 6 mg kg(-1)) had no effect on amphetamine-induced hyperactivity but induced an enhancement of MK-801-induced hyperactivity and DOI-induced head twitches in mice. In C57Bl/6J mGlu7 receptor knockout animals (KO), those effects of AMN082 were not observed. Moreover, mGlu7 KO animals were less sensitive for DOI-induced effect than their wild type littermates.. Altogether, we propose that among group III mGlu receptors, mGlu4 receptor may be a promising target for the development of novel antipsychotic drugs.

Topics: Aminobutyrates; Amphetamines; Animals; Antipsychotic Agents; Benzhydryl Compounds; Dextroamphetamine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Delivery Systems; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphinic Acids; Receptors, Metabotropic Glutamate; Schizophrenia

In the absence of overt cellular pathology but profound perceptual disorganization and cognitive deficits, schizophrenia is increasingly considered a disorder of neural coordination. Thus, different causal factors can similarly interrupt the dynamic function of neuronal ensembles and networks, in particular in the prefrontal cortex (PFC), leading to behavioral disorganization. The importance of establishing preclinical biomarkers for this aberrant function has prompted investigations into the nature of psychotomimetic drug effects on PFC neuronal activity. The drugs used in this context include serotonergic hallucinogens, amphetamine, and NMDA receptor antagonists. A prominent line of thinking is that these drugs create psychotomimetic states by similarly disinhibiting the activity of PFC pyramidal neurons. In the present study we did not find evidence in support of this mechanism in PFC subregions of freely moving rats. Whereas the NMDA receptor antagonist MK801 increased PFC population activity, the serotonergic hallucinogen DOI dose-dependently decreased population activity. Amphetamine did not strongly affect this measure. Despite different effects on the direction of change in activity, all three drugs caused similar net disruptions of population activity and modulated gamma oscillations. We also observed reduced correlations between spike-rate and local field potential power selectively in the gamma band suggesting that these drugs disconnect spike-discharge from PFC gamma oscillators. Gamma band oscillations support cognitive functions affected in schizophrenia. These findings provide insight into mechanisms that may lead to cortical processing deficits in schizophrenia and provide a novel electrophysiological approach for phenotypic characterization of animal models of this disease.

Topics: Action Potentials; Amphetamines; Animals; Dizocilpine Maleate; Hallucinogens; Male; Neurons; Prefrontal Cortex; Random Allocation; Rats; Rats, Sprague-Dawley

Working memory impairment is a core symptom of schizophrenia, but no existing treatment remediates this deficit. Inconsistent conceptualizations and few reliable translational measures are major hindrances to understanding the neurobiology of this aspect of cognition. Using comparable task designs may help bridge clinical and preclinical research efforts.. A novel rodent procedure was designed to translate the n-back working memory task used in schizophrenic patients.. Rats were trained in five-lever operant chambers to recall either the last (one-back) or penultimate (two-back) lever from random sequences of lever presentations of variable lengths. Psychotomimetic doses of amphetamine, dizocilpine maleate (MK801), and (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) were tested for disruption of accuracy, and cognitive-enhancing doses of amphetamine, nicotine, and (+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF38393 hydrochloride) were examined for improvements in performance.. High doses of amphetamine (0.8 and 1.6 mg/kg) significantly reduced accuracy while increasing total trials; 0.1 mg/kg MK801 and 2.0 mg/kg DOI also reduced accuracy, but the latter concurrently impaired responding. At the lowest dose (0.2 mg/kg), amphetamine increased total trials and rewards without affecting accuracy; 1.0 mg/kg nicotine reduced accuracy without affecting total trials, whereas 10.0 mg/kg SKF38393 had the opposite effect.. Although the possibility for mediating behaviors may exist, the rodent n-back task provides a clinically relevant model of working memory. Amphetamine and MK801 produced selective impairments without disrupting responding. The cognitive enhancers did not improve working memory, but low doses of amphetamine improved response efficiency. This novel procedure may be useful for examining cognitive deficits and their potential reversal in animal models of schizophrenia.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Amphetamines; Animals; Arousal; Attention; Central Nervous System Stimulants; Cognition; Conditioning, Operant; Dextroamphetamine; Dizocilpine Maleate; Dopamine Agonists; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Hallucinogens; Male; Memory, Short-Term; Nicotine; Nicotinic Agonists; Psychomotor Performance; Psychotropic Drugs; Rats; Rats, Long-Evans; Reaction Time

Several lines of evidence implicate dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. Previous behavioral studies have indicated that metabotropic glutamate (mGlu) receptors may be useful targets for the treatment of psychosis. It has been shown that agonists and positive allosteric modulators of group II mGlu receptors produce potential antipsychotic effects in behavioral models of schizophrenia in rodents. Group III mGlu receptors seem to be also promising targets for a variety of neuropsychiatric and neurodegenerative disorders. However, despite encouraging data in animal models, most ligands of group III mGlu receptors still suffer from weak affinities, incapacity to cross the blood-brain barrier or absence of full pharmacological characterization. These limitations slow down the validation process of group III mGlu receptors as therapeutic targets. In this work, we choose to study an agonist of group III mGlu receptors (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) using intraperitoneal administration in three animal behavioral models predictive of psychosis or hallucinations. The results of the present study show that ACPT-I, given at doses of 10 or 30mg/kg, decreased MK-801-induced hyperlocomotion and at a dose of 100mg/kg decreased amphetamine-induced hyperlocomotion in rats. Furthermore, ACPT-I dose-dependently decreased DOI-induced head twitches in mice and suppresses DOI-induced frequency and amplitude of spontaneous EPSPs in slices from mouse brain frontal cortices. These data demonstrate that ACPT-I is a brain-penetrating compound and illustrates its promising therapeutic role for the treatment of schizophrenia.

Topics: Amphetamine; Amphetamines; Animals; Antipsychotic Agents; Behavior, Animal; Cyclopentanes; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Administration Routes; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Frontal Lobe; Hyperkinesis; In Vitro Techniques; Male; Mice; Motor Activity; Psychotic Disorders; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Metabotropic Glutamate; Tricarboxylic Acids

Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists, like phencyclidine (PCP), elicit schizophrenia-like symptoms in humans and behavioral abnormalities in animals, such as hyperactivity. We investigated the effect of the atypical antipsychotic risperidone on hyperlocomotion produced in mice by 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801), an NMDA receptor antagonist. MK-801 (0.125, 0.25, 0.50 mg/kg) dose-dependently increased the total distance traveled in an open field during a 90 min period in mice. The increase in MK-801 (0.25 mg/kg)-induced total distance traveled was attenuated by pretreatment with risperidone at doses that alone had no effect on spontaneous locomotor activity. Furthermore, (+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), a serotonin 5-HT(2A/2C) receptor agonist, at the doses that failed to change spontaneous locomotor activity or hyperlocomotion induced by MK-801, reversed the attenuation by risperidone. The serotonin 5-HT(2A/2C) receptor antagonist, ritanserin, enhanced the inhibitory effect of risperidone. These findings indicate that risperidone attenuates MK-801-induced hyperlocomotion in mice by blocking serotonin 5-HT(2A/2C) receptors.

Topics: Amphetamines; Animals; Antipsychotic Agents; Behavior, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Mice; Motor Activity; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Risperidone; Ritanserin; Serotonin Antagonists; Serotonin Receptor Agonists

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

Characterization of anxiolytic drugs often employs conflict paradigms in which the drug effects on punished and unpunished responding can be compared. In this study, a fixed interval schedule generating a range of baseline response rates allowed comparison of the effects of anxiolytic drugs with those of psychotomimetic drugs on equivalent and differing rates of punished and unpunished responding. The first response made by the rat after a 40-s fixed interval elapsed resulted in food pellet delivery. In punished intervals, signalled by the illumination of stimulus lamps above each lever, a 0.6-mA shock was delivered after every 20th response, resulting in a lower rate of responding than that in the unpunished intervals. Three psychotomimetic agents, D-amphetamine, MK801 and DOI were compared with the anxiolytics chlordiazepoxide, NS2710 and pregabalin. The three psychotomimetics preferentially increased rates of unpunished responding compared with those of punished responding. Chlordiazepoxide, NS2710 and, to a lesser extent, pregabalin increased rates of both unpunished and punished responding. In comparison studies, yohimbine also increased rates of both unpunished and punished responding whereas the antidepressant citalopram had no effect. In conclusion, stable baseline performance over many months allowed the direct comparison of several different drugs in the same subjects with no need to adjust shock levels or equate baseline response rates. The drugs had systematic and replicable effects in this procedure, which, in the case of amphetamine and chlordiazepoxide, were similar to those in other species, and psychotomimetic drugs could clearly be distinguished from anxiolytic drugs. The procedure, however, has limited value for characterizing novel anxiolytic agents as the examples used here increased punished and unpunished responding to the same extent, and were indistinguishable in that regard from the clinically anxiogenic agent, yohimbine.

Topics: Amphetamines; Animals; Anti-Anxiety Agents; Appetitive Behavior; Association Learning; Benzimidazoles; Chlordiazepoxide; Conditioning, Operant; Dextroamphetamine; Dizocilpine Maleate; Electroshock; gamma-Aminobutyric Acid; Hallucinogens; Oximes; Pregabalin; Punishment; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Reinforcement Schedule; Yohimbine

Prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating, is a time-linked phenomenon which depends on prepulse duration (PD) and prepulse-pulse interval (PP). Rats treated with dopaminergic agonists, serotoninergic agonists or glutamatergic antagonists are commonly used as models for the deficit in PPI observed in schizophrenic patients. An important question was whether there is a parametric specificity for the effects of such pharmacological agents.. We investigated the contribution of PD, PP, and then of ratio R (PD:PP) to the expression of PPI and we looked for a modification of the temporal dependency of PPI by either apomorphine, DOI, ketamine and/or MK-801.. Male Sprague-Dawley rats were used. The values used to test PD varied from 5 to 1280 ms, with PP being fixed at 20 ms and vice versa to test PP. Different ratios were used to test R. The effect of either apomorphine (0.5 mg/kg), DOI (1 mg/kg), ketamine (1.5-6 mg/kg) or MK-801 (0.1-0.5 mg/kg) was compared to their vehicle.. PPI was a non-monotonic function of each parameter tested. The functions of PD and PP differed. All drugs reduced PPI in each parameter. The shape of the function obtained by varying PD was modified by ketamine and MK-801, but not by apomorphine or DOI.. The specific effect of ketamine and MK-801 was discussed in relation to the hypotheses about the mechanism underlying the modulation of PPI by temporal parameters. These findings stress the importance of non-competitive NMDA antagonist-induced disruption of PPI as a model of the sensorimotor gating deficit observed in schizophrenic patients.

Topics: Acoustic Stimulation; Amphetamines; Animals; Apomorphine; Dizocilpine Maleate; Dopamine Agonists; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Ketamine; Male; Rats; Rats, Sprague-Dawley; Reflex, Startle; Serotonin Receptor Agonists; Time Factors

The administration of dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist acting at the associated ion channel, increased the grooming time induced in rats by the D1 dopamine receptor agonist SKF 38393 and the stereotyped behaviour elicited by the D1/D2 dopamine receptor agonist apomorphine, and reduced the locomotor response to the D2 dopamine receptor agonist quinpirole. This supports the view that glutamate deficiency plays an important role in the pathogenesis of schizophrenia by altering the balance between glutamatergic and dopaminergic systems. Blockade of serotonin receptors counteracted the effect of dizocilpine on dopaminergic responses. Both the non-selective 5HT1/5HT2 antagonist methysergide, and ketanserin, which more specifically blocks 5HT2 receptors, given at doses inhibiting serotonin-mediated behaviours but which did not affect spontaneous motility and dopaminergic behaviours, hampered the dizocilpine-induced potentiation of responses elicited by the stimulation of D1 or D1/D2 dopamine receptors and counteracted the dizocilpine-induced reduction of hyperactivity observed following quinpirole administration. The results suggest that the functional integrity of the serotonergic system is fundamental for the occurrence of dopaminergic changes resulting from non-competitive NMDA blockade.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; 8-Hydroxy-2-(di-n-propylamino)tetralin; Amphetamines; Animals; Behavior, Animal; Dizocilpine Maleate; Dopamine; Dopamine Agonists; Excitatory Amino Acid Antagonists; Grooming; Ketanserin; Male; Methysergide; Motor Activity; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Antagonists; Serotonin Receptor Agonists; Stereotyped Behavior

We examined the effects of neonatal treatment with MK-801 on 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head shaking as well as [(3)H]ketanserin binding in adult rats. Neonatal rats were injected with MK-801 (0.25 mg/kg, s.c., twice daily) or with saline from postnatal days (PND) 7-18. At PND 60, a statistically significant increase in the frequency of head shaking induced by DOI (1.0 mg/kg, s.c.) was observed in the rats neonatally treated with MK-801, compared to saline-treated rats, without any change in the specific [(3)H]ketanserin binding in the frontal cortex. These results suggest that repeated NMDA receptor blockades during the critical period of brain development produce a long lasting hyper-responsiveness in the 5-HT(2A) receptor-mediated behavior, interfering with the development of neural circuits related to the behavior.

Topics: Amphetamines; Animals; Animals, Newborn; Dizocilpine Maleate; Drug Synergism; Dyskinesia, Drug-Induced; Excitatory Amino Acid Antagonists; Head; Ketanserin; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Serotonin Antagonists; Serotonin Receptor Agonists

Forepaw treading induced in rats by the 5HT1A agonist 8-OH-DPAT, and head shakes caused by the administration of the 5HT2A receptor against DOI, and by the 5HT precursor (-)5HTP, were significantly increased by pretreatment with the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine. Dizocilpine administration also significantly increased the locomotor activity induced by the serotonin agonists. The competitive NMDA receptor antagonist CGP 43487 increased only the head shakes induced by DOI, but did not alter the behavior elicited by 8-OH-DPAT, or (-)5HTP, and did not modify locomotor responses to any of the agonists used. The dizocilpine-induced potentiation of head shakes elicited by DOI and (-)5HTP was inhibited by the 5HT2 agonist ketanserin, but was not modified by the selective dopamine D1 and D2 receptor blockers SCH 23390 and (-)sulpiride. The dopamine receptor antagonists did, however, counteract the dizocilpine facilitation of both forepaw treading induced by 8-OH-DPAT, and the locomotor response to all the serotonergic agonists. The results indicate that, unlike competitive NMDA receptor antagonists, the non-competitive antagonists enhanced the expression of serotonergic stimulation, and suggest that a glutamate deficiency could contribute to the pathogenesis of schizophrenia, not only through dopaminergic, but also through serotonergic, hyperactivity.

Topics: 2-Amino-5-phosphonovalerate; 8-Hydroxy-2-(di-n-propylamino)tetralin; Amphetamines; Animals; Benzazepines; Dizocilpine Maleate; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Ketanserin; Male; Motor Activity; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D1; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin; Serotonin Receptor Agonists; Sulpiride

Phencyclidine, ketamine, and other agents that block NMDA glutamate receptors trigger a schizophrenia-like psychosis in humans and induce pathomorphological changes in cerebrocortical neurons in rat brain. Accumulating evidence suggests that a complex network disturbance involving multiple transmitter receptor systems is responsible for the neuronal injury, and it is proposed that a similar network disturbance is responsible for the psychotomimetic effects of NMDA antagonists, and might also be involved in the pathophysiology of schizophrenia. In the present study we present evidence that serotonergic agents possessing 5HT2A agonist activity prevent NMDA antagonist neurotoxicity in rat brain. It is proposed that 5HT2A agonists may also prevent the psychotomimetic effects of NMDA antagonists. Among the 5HT2A agonists examined and found to be neuroprotective are LSD and related hallucinogens. The apparent contradiction in proposing that these agents might have antipsychotic properties is resolved by evidence linking their hallucinogenic activity to agonist action at 5HT2C receptors, whereas antipsychotic activity would be attributable to agonist action at 5HT2A receptors.

Topics: Amphetamines; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Ritanserin; Serotonin Antagonists; Serotonin Receptor Agonists