title: Sedative effect of Clozapine is a function of 5-HT2Aand environmental novelty.
abstract: Antipsychotic drugs are the mainstay in the treatment of schizophrenia and bipolar disorder. However, antipsychotics often exhibit sedation or activity suppression among many other side effects, and the factors that influence them remain poorly understood. We now show, using a 5-HT2Aknockout (Htr2a-/-) mouse, that environmental circumstances can affect suppression of activity induced by the atypical antipsychotic- Clozapine. We observed that Htr2a-/-mice were more resistant to Clozapine-induced suppression of activity (CISA) and this behaviour was dependent on the environment being 'novel'. In their 'home' environment, at identical doses the mice exhibited CISA. Interestingly, the effect of genotype and environmental novelty on CISA could not be extended to the other antipsychotics that were tested, i.e. Haloperidol and Risperidone. Haloperidol-induced activity suppression was independent of context and genotype. Whereas context affected Risperidone-induced activity suppression only in the Htr2a+/+mice. Furthermore, we observed that caffeine, a stimulant, elicited resistance to CISA similar to that seen in the 'novel' context. Our study establishes a previously unknown interaction between the environmental context, 5-HT2Aand CISA and emphasises the role of non-pharmacological factors such as environment on the effects of the drug, which seem antipsychotic-specific. Our findings should advance the understanding of the side effects of individual antipsychotics and the role of environment to overcome side effects such as sedation.
authors.affiliation: National Centre for Biological Sciences, (TIFR), GKVK Campus, Bellary Road, Bengaluru 560065, India. Electronic address: radhikasj@ncbs.res.in.
authors.forename: Radhika S
authors.initials: RS
authors.lastname: Joshi
authors.affiliation: National Centre for Biological Sciences, (TIFR), GKVK Campus, Bellary Road, Bengaluru 560065, India.
authors.forename: Rolen
authors.initials: R
authors.lastname: Quadros
authors.affiliation: National Centre for Biological Sciences, (TIFR), GKVK Campus, Bellary Road, Bengaluru 560065, India; Massachusetts General Hospital, Department of Radiation Oncology, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Drumm
authors.affiliation: National Centre for Biological Sciences, (TIFR), GKVK Campus, Bellary Road, Bengaluru 560065, India.
authors.forename: Rupasri
authors.initials: R
authors.lastname: Ain
authors.affiliation: National Centre for Biological Sciences, (TIFR), GKVK Campus, Bellary Road, Bengaluru 560065, India. Electronic address: panic@ncbs.res.in.
authors.forename: Mitradas M
authors.initials: MM
authors.lastname: Panicker
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004777:Environment; D005106:Exploratory Behavior / Q000187:drug effects*; D005838:Genotype; D006220:Haloperidol / Q000494:pharmacology; D007266:Inhibition, Psychological; D051379:Mice; D018345:Mice, Knockout; D044402:Receptor, Serotonin, 5-HT2A / Q000172:deficiency* / Q000235:genetics; D018967:Risperidone / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D002110:Caffeine; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone
keywords: 5-HT(2A); Clozapine; Environmental novelty; Knockout