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-HT2A/2C receptors in the acute and repeated effect of clozapine and olanzapine in a rat conditioned avoidance response model (CAR), 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-HT2A/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-HT2A/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-HT2A/2C receptors.

Olanzapine Sensitization and Clozapine Tolerance: From Adolescence to Adulthood in the Conditioned Avoidance Response Model

“…What account for their differences is not entirely clear. On the basis of our previous work on the neuroceptor mechanisms of OLZ sensitization and CLZ tolerance in adult rats Li et al, 2012), we speculate that their differential (even opposing) actions on dopamine D 2/3 receptors may be one of the factors, as we show that pretreatment of quinpirole, a selective D 2 /D 3 dopaminergic receptor agonist, attenuated OLZ sensitization but enhanced CLZ tolerance on avoidance response. Future work should investigate the role of dopamine D 2/3 receptors in the mediation of OLZ sensitization and CLZ tolerance in adolescence.…”

“…The answer to both questions is yes. We demonstrated that OLZ sensitization and CLZ tolerance could be induced in adolescent rats using the same procedure (ie, an induction phase followed by a challenge test) as employed in adult rats (Li et al, 2004;Li et al, 2007;Li et al, 2009a;Li et al, 2009b;Li et al, 2010;Mead and Li, 2010;Li et al, 2012;Zhang and Li, 2012). They mainly manifested in the avoidance response (a behavioral measure of antipsychotic activity) and/or intertrial crossing (a behavioral measure of motor function/sedation), but not in the 22 kHz USV (an index of anxiolytic property), suggesting that they are behaviorally specific (Stewart and Badiani, 1993).…”

“…This experiment examined whether repeated OLZ treatment could induce a sensitization effect in adolescent rats in the CAR model as previously found in adult rats Mead and Li, 2010;Li et al, 2012;Swalve and Li, 2012;Zhang and Li, 2012). It consisted of three phases: avoidance training, induction of OLZ sensitization, and sensitization assessment.…”

“…OLZ sensitization was assessed 1 day later (BP 50) when all rats were injected with a challenge dose of OLZ 0.5 mg/kg and tested for avoidance performance, 22 kHz USV, and intertrial crossings in the CS-only condition (30 trials) 1 h later. This procedure of using a lower challenge dose of OLZ has been successfully used in our previous studies Li et al, 2012;Sparkman and Li, 2012;Swalve and Li, 2012;Zhang and Li, 2012). It also avoided the floor effect (ie, a high dose may cause a maximal avoidance disruption, leaving no room to show a sensitization or tolerance effect).…”

“…This experiment examined whether repeated CLZ treatment could induce a tolerance effect in adolescent rats in the CAR model as previously found in adult rats Li et al, 2012). The basic procedure was identical to that of Experiment 1, with the exceptions that 27 adolescent rats were used and 2 doses of CLZ (10 and 20 mg/kg, sc) were administered during the adolescence period.…”