Effects of 5HT2C Inverse Agonists in Animal Models of Psychosis

There are three commonly used models for antipsychotic activity: blockade of conditioned avoidance response, antagonism of locomotor activity produced by amphetamine or the N-methyl-d-asparate (NMDA)-receptor antagonists, phencyclidine

(PCP) or MK-801, and blockade of the disruption of prepulse inhibition by indirect or direct DA agonists or NMDA receptor antagonists. Atypical and typical antipsy-chotic drugs are active in all these models, with atypical antipsychotic drugs, apparently because of their 5-HT2A antagonist properties, preferentially effective in blocking NMDA-receptor blockade-mediated hyperlocomotion. Pretreatment of rats with the 5-HT2C/2B receptor antagonist SB 221284 (0.1-1 mg/kg, intraperitoneal (IP)]) or with the selective 5-HT2C receptor antagonist SB 242084 (1 mg/kg, IP), at doses shown to block mCPP-\induced hypolocomotion, significantly enhanced the hyperactivity induced by PCP or MK-801. Neither compound altered locomotor activity when administered alone. Both 5-HT2C antagonists enhanced the ability of PCP to increase the efflux of DA from the nucleus accumbens while having no effect on their own in that regard (Hutson et al. 2000). These results demonstrate that blockade of 5-HT2C receptors enhance the activation of mesolimbic DA neuronal function in hypoglutamatergic rodents, a state consistent with a deficit thought to be important to the pathophysiology of schizophrenia.

SB 243213 {5-methyl-1-[[-2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline hydrochloride} is a highly selective 5-HT2C receptor inverse agonist (Wood et al. 2001; Berg et al. 2006). In vivo studies indicated anxiolytic-like activity in both the social interaction and Geller-Seifter conflict tests, and it attenuated haloperidol-induced catalepsy. However, it did not affect amphetamine-, MK-801-, or PCP-induced hyperactivity, suggesting it would not be useful as an antipsychotic drug. However, it or other 5-HT2C inverse agonists might be of benefit in reducing anxiety or extrapyramidal symptoms (EPS) in some patients. There are no studies of the effect of 5-HT2C antagonists on prepulse inhibition in rodents. 5-HT2C null mice have some deficits in prepulse inhibition (Sun and Meltzer, in preparation). There have been, to our knowledge, no clinical trials of specific 5-HT2C inverse agonists as monotherapy for schizophrenia or as adjunctive agents for those antipsychotic drugs that lack affinity for 5-HT2C receptors. These agents might be useful to reduce anxiety or EPS, but it appears unlikely that they will improve the ability of antipsychotic agents to reduce psychotic symptoms. Indeed, the results reported by Hutson et al. (2000) suggest the possibility of exacerbating psychotic symptoms following selective blockade of 5-HT2C receptors.

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