Disruption of FR-40 by 5-HT agonists. I. Effects of chronic imipramine or trazodone

Doses of LSD, quipazine, 8-OHDPAT and TFMPP were established that prominently disrupted FR-40 operant response pattern in two groups of rats. Subsequently, one group received daily intraperitoneal (IP) injections of imipramine, 2.5 mg/kg, for 4 weeks, then 10 mg/kg for 2 additional weeks. The second group received 5 mg/kg/day, IP, of trazodone for the first 4 weeks, then 20 mg/kg/day for the next two weeks. For these periods and the 3 weeks after discontinuing the chronic drug treatments (washout), test doses of the 4 agonists were evaluated twice weekly in random order for their effects to decrease FR-40 reinforcements and increase pauses. No consistent, systematic changes in sensitivity to the agonist effects on FR-40 behavior were observed during chronic drug treatments, although significant effects were at times observed. However, during the washout period in the imipramine group, both LSD and 8-OHDPAT effects on reinforcements were reversed to baseline levels. The effect of 5-OHDPAT on pauses during washout in this group was also attenuated. During washout in the trazodone group, the 8-OHDPAT-induced pausing and loss of reinforcements was reduced so as to be not significantly different from baseline values. Previous studies have demonstrated antagonism of LSD- and quipazine-induced disruption of FR-40 by pretreating with the 5-HT2-selective antagonist pirenperone (28). Since chronic antidepressants down-regulate brain 5-HT2 binding sites, the effects of LSD and quipazine were expected to be attenuated, which was not the case.(ABSTRACT TRUNCATED AT 250 WORDS)