Antipsychotic drugs selectively suppress conditioned avoidance response. Using a two-way active avoidance response paradigm, we examined the role of drug-induced interoceptive state in the mediation of avoidance-suppressive effect. In Experiment 1, we found that rats intermittently treated with olanzapine (OLZ) (1.0 mg/kg, s.c.) or haloperidol (0.03 mg/kg, s.c.) on the 1st day of a 3-day cycle for seven cycles exhibited a progressive across-session decline in avoidance responding, despite the fact that they exhibited a comparable high level of avoidance responding on the 3rd day of each cycle during the drug-free retraining session. In Experiments 2 and 3, rats that were previously treated with OLZ (0.5—2.0 mg/kg, s.c.) or risperidone (0.2—1.0 mg/kg) during the acquisition phase of avoidance conditioning exhibited significantly fewer avoidance responses when they were retested 3 weeks later to the same drug in comparison to rats that were previously treated with nonantipsychotic drugs (chlordiazepoxide, 10 mg/kg, citalopram 10 mg/kg, or sterile water). Overall, these findings indicate a ‘drug memory’-like mechanism that maintains the avoidance-suppressing effect of antipsychotics over time. This mechanism is likely driven by the interoceptive state caused by the antipsychotics, which may also be an important behavioral mechanism mediating the clinical effects of antipsychotic treatments.

The rat conditioned avoidance response model is a well-established preclinical behavioral model predictive of antipsychotic efficacy. All clinically approved antipsychotic drugs disrupt conditioned avoidance responding – a feature that distinguishes them from other psychotherapeutics. We previously showed that the typical antipsychotic drug haloperidol disrupts avoidance responding by progressively attenuating the motivational salience of the conditioned stimulus (CS) in normal rats. In this study, using two pharmacological rat models of schizophrenia [e.g. phencyclidine (PCP) or amphetamine sensitization], we examined whether atypicals such as olanzapine or risperidone disrupt avoidance responding through the same behavioral mechanism. Rats were first pretreated with PCP, amphetamine, or saline under one of two different injection schedules for either 1 or 3 weeks. They were then trained to acquire avoidance responding to two types of CS (CS1 and CS2) that differed in their ability to predict the occurrence of the unconditioned stimulus. Finally, rats were tested repeatedly under olanzapine (1.0 mg/kg, subcutaneously) or risperidone (0.33 mg/kg, subcutaneously) daily for 5 or 7 consecutive days. We found that repeated olanzapine or risperidone treatment produced a progressive across-session decline in avoidance responding to both CS1 and CS2. Olanzapine and risperidone disrupted the CS2 (a less salient CS) avoidance to a greater extent than the CS1 avoidance. Pretreatment with PCP and amphetamine did not affect the disruptive effect of olanzapine or risperidone on avoidance responding. On the basis of these findings, we suggest that the atypical drugs olanzapine and risperidone, like the typical drug haloperidol, also disrupt avoidance responding primarily by attenuating the motivational salience of the CS.

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.

Antipsychotic drugs at noncataleptic doses selectively suppress conditioned avoidance response in rats. In our previous study, we had used a two-way active avoidance response paradigm to show that the antipsychotic-induced interoceptive state is one of the mechanisms underlying the avoidance-disruptive effect of antipsychotics. In this study, we sought to further examine this mechanism using a novel drug–drug conditioning procedure. We made use of the fact that both the typical neuroleptic haloperidol and the atypical neuroleptic olanzapine disrupt conditioned avoidance responding, whereas chlordiazepoxide (an anxiolytic) does not. We reasoned that if the antipsychotic interoceptive state is important in causing a disruption on avoidance responding (an index of antipsychotic efficacy), pairing chlordiazepoxide (a cueing drug conditional stimulus) with haloperidol or olanzapine (a cued drug unconditional stimulus) should engender chlordiazepoxide to exhibit this property and behave like an antipsychotic drug. Chlordiazepoxide exhibited an acquired antipsychotic-like property in disrupting avoidance responding after being repeatedly paired with haloperidol, but not with olanzapine. In contrast, it significantly attenuated the antiavoidance efficacy of olanzapine but not haloperidol after being repeatedly paired with these drugs. This study suggests that the haloperidol-induced interoceptive drug state is directly involved in its antiavoidance action, and chlordiazepoxide may attenuate the antiavoidance efficacy of antipsychotics (especially olanzapine). To the extent that the antiavoidance effect predicts clinical effects of antipsychotic treatment, this study suggests that the antipsychotic-induced interoceptive drug state may be an important behavioral mechanism mediating the clinical effects of antipsychotic treatments.

No abstract