Clozapine, but not olanzapine, disrupts conditioned avoidance response in rats by antagonizing 5-HT2A/2C receptors

Abstract

The present study was designed to assess the role of 5-HT(2A/2C) receptors in the acute and repeated effect of clozapine and olanzapine in a rat conditioned avoidance response model, a validated model of antipsychotic activity. Male Sprague-Dawley rats that were previously treated with either phencyclidine (0.5-2.0 mg/kg, sc), amphetamine (1.25-5.0 mg/kg, sc), or saline and tested in a prepulse inhibition of acoustic startle study were used. They were first trained to acquire avoidance response to a white noise (CS1) and a pure tone (CS2) that differed in their ability to predict the occurrence of footshock. Those who acquired avoidance response were administered with clozapine (10.0 mg/kg, sc) or olanzapine (1.0 mg/kg, sc) together with either saline or 1-2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT(2A/2C) agonist, 1.0 or 2.5 mg/kg, sc), and their conditioned avoidance responses were tested for four consecutive days. After two drug-free retraining days, the long-term repeated effect was assessed in a challenge test during which all rats were injected with a low dose of clozapine (5 mg/kg, sc) or olanzapine (0.5 mg/kg). Results show that pretreatment of DOI dose-dependently reversed the acute disruptive effect of clozapine on both CS1 and CS2 avoidance responses, whereas it had little effect in reversing the acute effect of olanzapine. On the challenge test, pretreatment of DOI did not alter the clozapine-induced tolerance or the olanzapine-induced sensitization effect. These results confirmed our previous findings and suggest that clozapine, but not olanzapine, acts on through 5-HT(2A/2C) receptors to achieve its acute avoidance disruptive effect and likely its therapeutic effects. The long-term clozapine tolerance and olanzapine sensitization effects appear to be mediated by non-5-HT(2A/2C) receptors.

Figure 1. Effects of pretreatment of DOI on acute clozapine-induced disruption of CS1 avoidance (A) and CS2 avoidance (B)

Mean (+SEM) numbers of avoidance responses of the four groups of rats on the last CAR training day (pre-drug), four drug test days (Day 1 to Day 3), and two drug-free test days (Drug-free CS-only and Drug-free retraining). * P<0.05 significantly different from the VEH+VEH group; # P<0.05 significantly different from the VEH+CLZ group.

Figure 2. Effects of pretreatment of DOI on the repeated treatment effect of clozapine on CS1 and CS2 avoidance responses

Data are mean (+SEM) numbers of avoidance responses on the challenge test day. Rats that were previously treated with double vehicles, vehicle plus clozapine (10.0 mg/kg), or DOI (1.0 or 2.5 mg/kg) plus clozapine (10.0 mg/kg) were challenged with clozapine (5.0 mg/kg). * P<0.05 significantly different from the corresponding VEH+VEH group.

Figure 3. Effects of pretreatment of DOI on acute olanzapine-induced disruption of CS1 avoidance (A) and CS2 avoidance (B)

Mean (+SEM) numbers of avoidance responses of the four groups of rats on the last CAR training day (pre-drug), four drug test days (Day 1 to Day 3), and two drug-free test days (Drug-free CS-only and Drug-free retraining). * P<0.05 significantly different from the VEH+VEH group.

Figure 4. Effects of pretreatment of DOI on the repeated treatment effect of olanzapine on CS1 and CS2 avoidance responses

Data are mean (+SEM) numbers of avoidance responses on the challenge test day. Rats that were previously treated with double vehicles, vehicle plus olanzapine (1.0 mg/kg), or DOI (2.5 mg/kg) plus olanzapine (1.0 mg/kg) were challenged with olanzapine (0.5 mg/kg). * P<0.05 significantly different from the corresponding VEH+VEH group.