ro-60-0175 and Disease-Models--Animal

Topics: Animals; Benzazepines; Disease Models, Animal; Ethylamines; Fenfluramine; Indoles; Mice; Piperazines; Pyrazines; Rats; Receptor, Serotonin, 5-HT2C; Seizures; Serotonin 5-HT2 Receptor Agonists; Treatment Outcome

Schizophrenia is a neurodevelopmental disorder in which impaired decision-making and goal-directed behaviors are core features. One of the genes associated with schizophrenia is the Close Homolog of L1 (CHL1); CHL1-deficient mice are considered a model of schizophrenia-like deficits, including sensorimotor gating, interval timing and spatial memory impairments. Here we investigated temporal discounting in CHL1-deficient (KO) mice and their wild-type littermates. Although no discounting differences were found under baseline conditions, CHL1-KO mice showed increased impulsive choice following chronic unpredictable stress (fewer % larger-later choices, and reduced area under the discounting curve). Stressed CHL1-KO mice also showed decreased neuronal activation (number of cFos positive neurons) in the discounting task in the prelimbic cortex and dorsal striatum, areas thought to be part of executive and temporal processing circuits. Impulsive choice alterations were reversed by the 5-HT2C agonist Ro 60-0175. Our results provide evidence for a gene x environment, double-hit model of stress-related decision-making impairments, and identify CHL1-deficient mice as a mouse model for these deficits in regard to schizophrenia-like phenotypes.

Topics: Animals; Cell Adhesion Molecules; Chronic Disease; Corpus Striatum; Delay Discounting; Disease Models, Animal; Ethylamines; Gene-Environment Interaction; Impulsive Behavior; Indoles; Male; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Prefrontal Cortex; Proto-Oncogene Proteins c-fos; Psychotropic Drugs; Receptor, Serotonin, 5-HT2C; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Stress, Psychological

Serotonin (5-HT)2C receptors play a role in psychoaffective disorders and often contribute to the antidepressant and anxiolytic effects of psychotropic drugs. During stress, activation of these receptors exerts a negative feedback on 5-HT release, probably by increasing the activity of GABAergic interneurons. However, to date, the GABA receptor types that mediate the 5-HT2C receptor-induced feedback inhibition are still unknown. To address this question, we assessed the inhibition of 5-HT turnover by a 5-HT2C receptor agonist (RO 60-0175) at the hippocampal level and under conditions of stress, after pharmacological or genetic inactivation of either GABA-A or GABA-B receptors in mice. Neither the GABA-B receptor antagonist phaclofen nor the specific genetic ablation of either GABA-B1a or GABA-B1b subunits altered the inhibitory effect of RO 60-0175, although 5-HT turnover was markedly decreased in GABA-B1a knock-out mice in both basal and stress conditions. In contrast, the 5-HT2C receptor-mediated inhibition of 5-HT turnover was reduced by the GABA-A receptor antagonist bicuculline. However, a significant effect of 5-HT2C receptor activation persisted in mutant mice deficient in the α3 subunit of GABA-A receptors. It can be inferred that non-α3 subunit-containing GABA-A receptors, but not GABA-B receptors, mediate the 5-HT2C -induced inhibition of stress-induced increase in hippocampal 5-HT turnover in mice.

Topics: Animals; Disease Models, Animal; Ethylamines; GABA Agents; Gene Expression Regulation; Hippocampus; Hydroxyindoleacetic Acid; Indoles; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Receptor, Serotonin, 5-HT2C; Receptors, GABA; Serotonin; Stress, Psychological

Lesions of nigrostriatal dopaminergic neurons as seen in Parkinson's disease (PD) increase orofacial responses to serotonergic (5-HT) agonists in rodents. Although this response to 5-HT agonists has been related to aberrant signalling in the basal ganglia, a group a subcortical structures involved in the control of motor behaviours, it deserves additional studies with respect to the specific loci involved. Using measurements of orofacial activity, as well as single-cell recordings in vivo, we have studied the role of the entopeduncular nucleus (EPN; equivalent to the internal globus pallidus of primates), an output structure of basal ganglia, in the hypersensitized responses to a 5-HT agonist in sham- or unilaterally dopamine-depleted rats. Intra-EPN injections of Ro 60-0175 (0.3 and 1 μg/100 nl) promoted robust oral movements in 6-OHDA rats without affecting oral activity in sham-depleted rats. Peripheral administration of Ro 60-0175 (3 mg/kg ip) decreased EPN neuronal firing rate in 6-OHDA rats compared to sham-depleted rats. Such an effect was also observed when the agonist (0.2 μg/20 nl) was locally applied onto EPN neurons. These data demonstrate the contribution of EPN to hypersensitized responses to 5-HT agonists in a rat model of PD.

Topics: Administration, Oral; Animals; Basal Ganglia; Corpus Striatum; Disease Models, Animal; Electrophysiological Phenomena; Entopeduncular Nucleus; Ethylamines; Globus Pallidus; Indoles; Male; Neurons; Parkinson Disease; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin 5-HT2 Receptor Agonists; Substantia Nigra

A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.

Topics: Animals; Anti-Obesity Agents; Disease Models, Animal; Eating; Isoquinolines; Pyrroles; Quinolines; Radioligand Assay; Rats; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists

The behavioural effects of 5-HT(2) receptor agonists, 5-HT(2A) and 5-HT(2C) receptor antagonists were investigated in the mouse four plates test (FPT), light/dark paradigm (L/D) and the elevated plus maze (EPM), in order to elucidate the role of the 5-HT(2) receptor subtypes in these models and to address the inconclusive results previously reported using rat psychopharmacological models. All compounds were administered intraperitoneally 30 min before each test. DOI, a preferential 5-HT(2A) agonist (0.5-8 mg/kg) and BW 723C86, a 5-HT(2B) agonist (8 and 16 mg/kg) provoked an anxiolytic-like response in the FPT. In the EPM, an anxiolytic-like effect was observed for DOI (0.5, 1 and 2 mg/kg), BW 723C86 (0.5, 4, 8 and 16 mg/kg), RO 60-0175 a 5-HT(2C) agonist (4 mg/kg) and the non-selective 5-HT(2) receptor agonist mCPP (0.25 mg/kg.). Ketanserin, a 5-HT(2A/2C) non-selective receptor antagonist (0.015 and 0.03 mg/kg), induced an anxiogenic-like effect in the L/D paradigm. The 5-HT(2C) antagonists (RS 10-2221, SDZ SER082 and SB 206553) were without effect in all three tests. These behavioural results are indicative of an anxiolytic-like action of 5-HT(2) receptor agonists, an anxiogenic-like effect of 5-HT(2A) receptor antagonism, whereas the blockade of 5-HT(2C) receptors are without effect in the mouse models studied.

Topics: Amphetamines; Animals; Anti-Anxiety Agents; Anxiety; Disease Models, Animal; Dose-Response Relationship, Drug; Ethylamines; Indoles; Ketanserin; Male; Maze Learning; Mice; Motor Activity; Naphthyridines; Piperazine; Piperazines; Psychomotor Performance; Pyridines; Reaction Time; Serotonin Antagonists; Serotonin Receptor Agonists; Spiro Compounds; Sulfonamides; Thiophenes

Dose-dependent increases in threshold for operant fear/escape responses of rats submitted to aversive stimulation of the dorsolateral periaqueductal gray (dPAG) were recorded following intraperitoneal injection of three chemically unrelated but selective 5HT2C receptor agonists (Ro 60-0175, Org 12962 and Ro 60-0332) and fluoxetine. The decreased sensitivity of rats to the acute panic-like aversion elicited by stimulation of this limbic periventricular region was detected at dosages devoid of impairing effects on the latencies needed for operant brain stimulation interruption. In this paradigm which has been validated as a simulation of acute anxiety with relevance to panic disorder, the selective activation of 5HT2C receptors by Ro 60-0175, Org 12962 or Ro 60-0332 induces effects analogous to those observed following benzodiazepine receptor activation by antipanic agents such as clonazepam or alprazolam or following non-selective and indirect 5HT receptor activation by fluoxetine. Potency and efficacy of 5HT2C receptor agonists were intermediate between those of clonazepam and fluoxetine, indicating authentic antiaversive properties and suggesting antipanic potential for these 5HT2C receptor agonists. In addition, these data suggest that the 5HT2C receptor subtype may play a major role in the therapeutic properties of selective serotonin reuptake inhibitors. It is also speculated that serotonin/benzodiazepine interactions existing in the brain may functionally involve the 5HT2C receptor subtypes and that the anxiogenic action reported under certain circumstances for 5HT mimetics are not mediated by 5HT2C receptor subtypes.

Topics: Animals; Anxiety; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Escape Reaction; Ethylamines; Fluoxetine; Indoles; Injections, Intraperitoneal; Male; Panic; Periaqueductal Gray; Rats; Rats, Wistar; Selective Serotonin Reuptake Inhibitors; Serotonin Receptor Agonists

Potential antidepressant properties of preferential 5HT2C receptor agonists were investigated in stress-induced anhedonia, a validated simulation of depression. This simulation evaluates the hedonic state of stressed rats by recording variations in self-stimulation threshold measured before, during, and after exposure to intermittent, unpredictable, mild stressors. This stress regimen gradually elevates self-stimulation threshold, suggesting the development of an anhedonic state. In stressed animals, chronic treatment with the preferential 5HT2C receptor agonists Ro 60-0175 and Ro 60-0332 (3 mg/kg i.p. b.i.d.) prevented the loss of sensitivity to reward. Similarly, when stressed anhedonic animals were curatively treated with Ro 60-0175 (3 mg/kg i.p. b.i.d.), the stress-induced anhedonia was gradually reversed. These results suggest a role for 5HT2C receptors in some aspects of depression, and potential antidepressant properties for selective 5HT2C receptor agonists. Such compounds may offer an innovative approach to the treatment of mood disorders.

Topics: Animals; Behavior, Animal; Depressive Disorder; Disease Models, Animal; Ethylamines; Indoles; Male; Rats; Rats, Wistar; Serotonin Receptor Agonists; Stress, Physiological