Combined α2-adrenergic/D2 dopamine receptor blockade fails to reproduce the ability of clozapine to reverse phencyclidine-induced deficits in prepulse inhibition of startle

Rationale: The combination of idazoxan, a specific alpha(2)-adrenoceptor antagonist with raclopride, a selective D-2/D-3 receptor antagonist, has been recently proposed to produce an "atypical" antipsychotic profile comparable to that of clozapine, based on an animal study which analysed dopamine efflux in the medial prefrontal cortex and the preclinical test of conditioned avoidance response (CAR) for evaluation of antipsychotic potential. Accordingly, the combination of a "typical" antipsychotic with idazoxan has been proposed as an augmentation strategy in treatment-resistant schizophrenia, although its therapeutic potential remains difficult to predict. Objectives: Given the momentum stimulated by these reports, the present study investigated whether the combination of idazoxan with raclopride is indeed sufficient to mimic the ability of clozapine to reverse prepulse inhibition (PPI) deficits in rats, a behavioral paradigm that models PPI deficits observed in the schizophrenia spectrum, and currently the only test which reliably appears to distinguish between "typical" antipsychotics and compounds with "atypical" antipsychotic potential. Methods: The effects of the combination idazoxan/raclopride were examined in two PPI paradigms: 1) phencyclidine (PCP)-induced disruption of PPI, which has been shown to be preferentially reversed by "atypical" antipsychotics; 2) apomorphine-induced disruption of PPI which can be reversed by either "typical" high-potency D-2 dopamine antagonists or "atypical" antipsychotics. Results: In contrast to clozapine, combining idazoxan with raclopride failed to reverse PCP-induced deficits in PPI In addition, there was no evidence of an enhancing effect of idazoxan on the blockade of apomorphine-induced disruption of PPI by raclopride. Conclusion: The present results challenge the hypothesis that simple alpha(2)/D-2 blockade is sufficient to produce clozapine-like "atypical" antipsychotic activities, and support the consensus that the PPI paradigm represents the most sophisticated behavioral preclinical test for detecting selective "atypical" profile of antipsychotics.