Dissociable effects of the 5-HT(2) antagonist mianserin on associative learning and performance in the rabbit

Serotonin 5-HT(2) antagonists that significantly retard the acquisition of classically conditioned responses (CRs) also impair the performance of the unconditioned response (UR). Effects on the UR appear to be due to an inverse agonist action at the 5-HT(2) receptor. These findings raised the possibility that the learning deficits were either secondary to a performance deficit and/or that the retardation of learning was not due to actions at the serotonin 5-HT(2) receptor. In this study, we examined the effects of the 5-HT(2)-receptor antagonists, namely mianserin and D-2-bromolysergic acid diethylamide hydrogen tartrate (BOL), on CR acquisition. We also determined whether the retarded acquisition of CRs produced by mianserin (a) was due to an action at the 5-HT(2) receptor and (b) was secondary to a performance deficit. Effects of drugs on CR acquisition, maintenance, and retention were determined during trace-conditioning of the rabbit's nictitating membrane (NM) response. BOL (0.058 to 5.8 micromol/kg) had no effect on CR acquisition, whereas mianserin (0.1 to 10 micromol/kg) produced a significant and dose-dependent retardation of CR acquisition. The retarded CR acquisition produced by mianserin (10 micromol/kg) was due to its actions at the 5-HT(2) receptor, because this effect was completely blocked by a dose of BOL (5.8 micromol/kg) that had no effect when given alone. Neither maintenance nor retention of learning was affected by mianserin treatment during acquisition. We conclude that mianserin acts as an inverse agonist at the serotonin 5-HT(2) receptor to produce both a retardation of CR acquisition and an impairment of the UR. However, the learning and performance effects of mianserin are separable.