HT2C Receptors and Dopamine Efflux in Relation to Schizophrenia and Antipsychotic Drug Action

An interesting difference in the effect of haloperidol and clozapine on DA efflux in the nucleus accumbens and striatum was reported by Navailles et al. (2006). Using microdialysis to measure DA efflux, these authors showed differential effects of these two prototypical antipsychotic drugs on DA release in relation to the constitutive effect of 5-HT2C receptors to inhibit DA release in these two regions. The ability of haloperidol 0.01 mg/kg to increase DA efflux in both regions was potentiated by the 5-HT2C inverse agonist SB 206553 (5mg/kg IP) {5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole} but not by the competitive antagonist SB 242084 or the inverse agonist SB 243213 (1 mg/kg IP). However, the effect of clo-zapine at a dose in which it shows 5-HT2C inverse agonist activity (1 mg/kg) was blocked by SB243213 and SB242084. Since haloperidol itself has no activity at the 5-HT2C receptor, the authors suggest that haloperidol promoted the constitutive activity of the 5-HT2C receptor. This is an intriguing suggestion, which, if valid, would suggest an important role of the 5-HT2C receptor in the action of haloperidol and the possible basis for interactions between haloperidol and clozapine. Clozapine, like SB206553, might inhibit the effect of haloperidol on the constitutive activity of the 5-HT2C receptor, thereby altering effects on striatal and accumbal DA efflux. Whether this holds true for the cortex as well remains to be studied.

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