Distinct neural mechanisms underlying acute and repeated administration of antipsychotic drugs in rat avoidance conditioning

Abstract

Rationale Acute antipsychotic treatment disrupts conditioned avoidance responding, and repeated treatment induces a sensitization- or tolerance-like effect. However, the neurochemical mechanisms underlying both acute and repeated antipsychotic effects remain to be determined. Objective The present study examined the neuroreceptor mechanisms of haloperidol, clozapine, and olanzapine effect in a rat two-way conditioned avoidance model. Methods Well-trained Sprague–Dawley rats were administered with haloperidol (0.05 mg/kg, sc), clozapine (10.0 mg/kg, sc), or olanzapine (1.0 mg/kg, sc) together with either saline, quinpirole (a selective dopamine D2/3 agonist, 1.0 mg/kg, sc), or 2,5-dimethoxy-4-iodo-amphetamine (DOI; a selective 5-HT2A/2C agonist, 2.5 mg/kg, sc), and their conditioned avoidance responses were tested over 3 days. After 2 days of drug-free retraining, the repeated treatment effect was assessed in a challenge test. Results Pretreatment of quinpirole, but not DOI, attenuated the acute haloperidol-induced disruption of avoidance responding and to a lesser extent, olanzapine-induced disruption. In contrast, pretreatment of DOI, but not quinpirole, attenuated the acute effect of clozapine. On the repeated effect, pretreatment of DOI, but not quinpirole, attenuated the potentiated disruption of haloperidol, whereas pretreatment of quinpirole attenuated the potentiated disruption of olanzapine but enhanced the tolerance-like effect of clozapine. Conclusions These findings suggest that acute haloperidol and olanzapine disrupt avoidance responding primarily by blocking dopamine D2 receptors, whereas acute clozapine exerts its disruptive effect primarily by blocking the 5-HT2A receptors. The repeated haloperidol effect may be mediated by 5-HT2A/2C blockade-initiated neural processes, whereas the repeated clozapine and olanzapine effect may be mediated by D2/3 blockade-initiated neural processes.

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

“…In the present study as well as our previous ones (Sun et al, 2009;Li et al, 2010), we have observed no differences in behavioral responsiveness to OLZ and CLZ in the induction phase (ie, the repeated drug treatment period), but differences in the expression phase (ie, the challenge test). For example, during the drug treatment period in both the CAR and the PCP-induced hyperlocomotion model (ie, the induction phase), repeated OLZ and CLZ treatment persistently inhibited avoidance response and PCP-induced hyperlocomotion.…”

“…Two doses of OLZ (1.0 and 2.0 mg/ kg) and CLZ (10 and 20 mg/kg) were tested. These doses of OLZ and CLZ produce a reliable and comparable disruption on avoidance responding (Li et al, 2004;Li et al, 2007;Li et al, 2009b;Li et al, 2010;Mead and Li, 2010;Zhang and Li, 2012). On the basis of data from the striatal dopamine D 2 receptor occupancy study in rats (Kapur et al, 2003), we estimated that both drugs at these doses would give rise to a 40-80% striatal D 2 occupancy, which is comparable to values observed in schizophrenic patients (Kapur et al, 1999).…”

“…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).…”

“…Using such a paradigm, we show that repeated treatment of haloperidol and olanzapine (OLZ) induce a sensitization effect in both the induction and expression phases (Li et al, 2009b;Li et al, 2009a;Sun et al, 2009;Li et al, 2010;Mead and Li, 2010;Zhao et al, 2012). In contrast, repeated treatment of clozapine (CLZ) does not cause an apparent sensitization or tolerance during the induction phase (Sun et al, 2009;Li et al, 2010).…”

“…In contrast, repeated treatment of clozapine (CLZ) does not cause an apparent sensitization or tolerance during the induction phase (Sun et al, 2009;Li et al, 2010). But in the expression phase when all rats are injected with a low dose of CLZ, rats previously treated with CLZ exhibit a tolerance effect, as they often make significantly more avoidance responses and exhibit higher PCP-induced hyperlocomotion than those that are treated with CLZ for the first time .…”