Repeated administration of haloperidol and olanzapine causes a progressively enhanced disruption of conditioned avoidance responding and a progressively enhanced inhibition of phencyclidine (PCP)-induced hyperlocomotion in rats. Both actions are thought to reflect the intrinsic antipsychotic activity.

The present study examined to the extent to which antipsychotic-induced sensitization in one model (e.g. conditioned avoidance response model) can be transferred or maintained in another (e.g. PCP hyperlocomotion model).

Methods: We first induced behavioral sensitization in one model through repeated administration of haloperidol or olanzapine to male Sprague-Dawley rats, then tested its expression in another model, and finally retested its expression back in the first model.

Repeated haloperidol and olanzapine induced a robust behavioral sensitization in both models. Its expression was highly situational specific as it only manifested itself in the model in which it was being induced.

Based on these and other findings, we propose that three behavioral mechanisms regulate antipsychotic sensitization and its situational specificity:

1. (1) Repeated antipsychotic treatment induces an unconditioned and nonassociative enhanced behavioral effect (i.e. sensitization) by progressively decreasing motivational salience of stimuli, an effect attributable to the direct pharmacological action of a drug;

2. (2) Distinct contextual cues develop an association with unconditional drug effects via a Pavlovian conditioning process, thus acquiring the ability to elicit antipsychotic-like effects. This associative learning process may potentiate the sensitized behavioral response in an expected situation;

3. (3) Contextual stimuli and interoceptive drug state also serve as occasion-setters to modulate the expression of sensitized responses.