Chronic treatment with three antidepressants—desipramine, imipramine, and zimelidine—altered behavioral responses to serotonin (5-HT) agonists in rats, with effects depending on agonist dose and the behavior measured. At a high dose of the 5-HT agonist 5-MeO-DMT (4 mg/kg), all three drugs reduced head twitches, while at a low dose (1 mg/kg) or with a low dose of the 5-HT precursor 5-HTP (12.5 mg/kg), head twitches increased. Zimelidine and imipramine enhanced hyperlocomotion at the high agonist dose but reduced it at the low dose. Long-term zimelidine treatment produced subsensitivity in avoidance learning but enhanced responses in the tail-flick test, though overall it shortened response latency, suggesting decreased 5-HT activity.
Repeated low-dose phencyclidine (PCP) impairs spatial learning and memory in mice without causing sensorimotor deficits, while higher doses produce severe motor disturbances that prevent testing. The atypical antipsychotic clozapine, but not the typical antipsychotic haloperidol, blocks the spatial impairment caused by low-dose PCP. This dissociation may help model declarative memory disturbances in schizophrenia and clarify differences between antipsychotic drug classes.