D-Amphetamine and Antipsychotic Drug Effects on Latent Inhibition in Mice Lacking Dopamine D2 Receptors

Drugs that induce psychosis, such as D-amphetamine (AMP), and those that alleviate it, such as antipsychotics, are suggested to exert behavioral effects via dopamine receptor D-2 (D-2). All antipsychotic drugs are D-2 antagonists, but D-2 antagonism underlies the severe and debilitating side effects of these drugs; it is therefore important to know whether D-2 is necessary for their behavioral effects. Using D-2-null mice (Drd(2)-/-), we first investigated whether D-2 is required for AMP disruption of latent inhibition (LI). LI is a process of learning to ignore irrelevant stimuli. Disruption of LI by AMP models impaired attention and abnormal salience allocation consequent to dysregulated dopamine relevant to schizophrenia. AMP disruption of LI was seen in both wild-type (WT) and Drd(2)-/-. This was in contrast to AMP-induced locomotor hyperactivity, which was reduced in Drd(2)-/-. AMP disruption of LI was attenuated in mice lacking dopamine receptor D-1 (Drd(1)-/-), suggesting that D1 may play a role in AMP disruption of LI. Further supporting this possibility, we found that D1 antagonist SKF83566 attenuated AMP disruption of LI in WT. Remarkably, both haloperidol and clozapine attenuated AMP disruption of LI in Drd(2)-/-. This demonstrates that antipsychotic drugs can attenuate AMP disruption of learning to ignore irrelevant stimuli in the absence of D-2 receptors. Data suggest that D-2 is not essential either for AMP to disrupt or for antipsychotic drugs to reverse AMP disruption of learning to ignore irrelevant stimuli and further that D-1 merits investigation in the mediation of AMP disruption of these processes.