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The inhibitory influence of HPA axis hormones on the 5-HT2A receptor-mediated behavioural effects of risperidone : potential therapeutic implications

University of British Columbia

The present series of experiments was designed to investigate the potential inhibitory influence of stress and stress-related hormones on the 5-HT2A receptor-mediated behavioural effects of risperidone, an atypical antipsychotic. Experiment 1 examined the effects of chronic risperidone treatment; Long-Evans male rats were assigned to a daily regimen of either corticosterone (20 mg/kg) or vehicle for 14 days. Risperidone was administered at a dose of 0.1 mg/kg for 14 days prior to testing. Rats were tested on measures of sexual behaviour and wet dog shakes (WDS), both 5-HT2A receptor-mediated behaviours. Consistent with previous findings, chronic corticosterone treatment induced behavioural changes indicative of an increase in 5-HT2A receptor activity. Results from Experiment 1 demonstrated the efficacy of risperidone in facilitating rat sexual behaviour and inhibiting WDS frequency. Of interest, the behavioural effects of risperidone were significantly attenuated by a chronic corticosterone regimen. In Experiment 2, the behavioural influence of chronic mild stress (CMS) on a chronic risperidone regimen was examined. Rats received daily injections of either risperidone (0.1 mg/kg) or saline and were exposed daily to either CMS or no stress for 21 days. Similar to findings using a chronic corticosterone regimen, CMS significantly attenuated the effects of risperidone on both male rat sexual behaviour and WDS expression. Experiment 3 investigated the possibility that chronic CMS treatment act via elevated corticosterone levels when influencing the behavioural efficacy of risperidone. Rats received risperidone and metyrapone (50 mg/kg), a corticosterone synthesis inhibitor, on a daily basis for a period of 14 days. Results from Experiment 3 indicated the effects of stress on WDS frequency, but not on sexual behaviour, in risperidone-treated rats are likely mediated by corticosterone. Taken together, the data implicate both corticosterone and stress as playing an inhibitory role on the behavioural efficacy of risperidone. The current findings may help to explain the high incidence of psychotic patients who are non-responsive to their medications and demonstrate elevated levels of stress-related hormones.

Thesis/Dissertation

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2009-08-05

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http://hdl.handle.net/2429/11758

Psychology

University of British Columbia

UBCV

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