Antidepressant-like effects of trazodone on a behavioral screen are mediated by trazodone, not the metabolite m-chlorophenylpiperazine.
Trazodone is an atypical antidepressant drug (i.e. blocks neither monoamine uptake nor monoamine oxidase) which tests as an antidepressant drug on the differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule of reinforcement by increasing the reinforcement rate and decreasing the response rate. m-Chlorophenylpiperazine (m-CPP) is a 5-HT1B and 5-HT1C agonist, weak 5-HT2 antagonist, and trazodone metabolite. It has been suggested that formation of m-CPP is responsible for the antidepressant action of trazodone. Administration of m-CPP (1-10 mg/kg i.p.) 60, 30 or 10 min before the behavioral session did not mimic the reinforcement rate-increasing effects of trazodone (10-20 mg/kg i.p.) on rats performing under the DRL 72-s schedule of water reinforcement. Pretreatment with proadifen (50 mg/kg i.p.), an inhibitor of trazodone metabolism, caused a greater than 30-fold leftward shift in the dose-response curve for both the reinforcement rate and the response rate. These results suggest that the parent compound and not the trazodone metabolite m-CPP, mediates the antidepressant-like effects of trazodone on DRL 72-s behavior.
Li
A A
AA
University of Chicago, Department of Pharmacological and Physiological Sciences, IL 60637.
Marek
G J
GJ
Hand
T H
TH
Seiden
L S
LS
D000818:Animals; D000928:Antidepressive Agents; D001522:Behavior, Animal / Q000187:drug effects*; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012055:Reinforcement Schedule; D014196:Trazodone / Q000494:pharmacology*
D000928:Antidepressive Agents; D010879:Piperazines; D011335:Proadifen; C015068:1-(3-chlorophenyl)piperazine; D014196:Trazodone