Blockade of conditioned avoidance responding by trazodone, etoperidone, and MCPP

Abstract

Phenylpiperazines, such as meta-chlorophenylpiperazine (MCPP) a serotonin agonist, have recently been reported to block conditioned avoidance responding (CAR) in the rat, which is an indication of possible antipsychotic utility. Since MCPP is a major metabolite of both antidepressant drugs trazodone (TZ) and etoperidone (ET), both were examined for activity in blocking CAR in a single-trial lever press task in Fisher 344 rats. Both TZ and ET produced dose-related falls in CAR with ED50 values (95% confidence limits) of 13.3 (9.6, 18.5) and 10.4 (8.5, 13.2) mg/kg IP, respectively. In contrast, MCPP had an ED50 value of 2.5 (1.8, 3.6) mg/kg IP TZ, ET, and MCPP were also examined for the production of catalepsy and the blockade of amphetamine-induced stereotypy to determine whether each was acting to block CAR via a dopaminergic mechanism of action. None, however, was found highly active. On the other hand, the serotonin receptor blocker metergoline (1.0 mg/kg IP) significantly reduced the CAR block produced by each, suggesting a serotonergic mechanism of action. Since TZ and ET are both less potent than MCPP, the data also suggest TZ and ET may block CAR via formation of MCPP.

Effects of the antidepressant trazodone, a 5-HT2A/2C receptor antagonist, on dopamine-dependent behaviors in rats

“…Our study demonstrates that trazodone HCl, at 30, 40 and 50 mg/kg i.p., induces catalepsy and antagonizes apomorphine-and dexamphetamine-induced oral stereotypies in rats. Our findings concur with the observations of Martin et al (1989) that trazodone at 9, 18 and 36 mg/kg i.p. doses (expressed as free base) induced catalepsy and antagonized dexamphetamine-induced oral stereotypy in rats.…”

“…doses (expressed as free base) induced catalepsy and antagonized dexamphetamine-induced oral stereotypy in rats. Furthermore, since Martin et al (1989) have reported that m-chlorophenylpiperazine (mCPP), a metabolite of trazodone, did not induce catalepsy and antagonized amphetamine stereotypy, it indicates that mCPP does not contribute to these actions of trazodone.…”