Combined alpha 2-adrenergic/D2 dopamine receptor blockade fails to reproduce the ability of clozapine to reverse phencyclidine-induced deficits in prepulse inhibition of startle.
BACKGROUND
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.


OBJECTIVE
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.


CONCLUSIONS
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.
Ballmaier
M
M
Division of Pharmacology, Department of Biomedical Sciences & Biotechnologies, Brescia University Medical School, Via Valsabbina 19, 25123 Brescia, Italy. mballm@med.unibs.it
Zoli
M
M
Mazzoncini
R
R
Gennarelli
M
M
Spano
F
F
D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000494:pharmacology*; D008297:Male; D010622:Phencyclidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000502:physiology; D013216:Reflex, Startle / Q000187:drug effects* / Q000502:physiology
D058669:Adrenergic alpha-2 Receptor Antagonists; D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D006213:Hallucinogens; D018341:Receptors, Adrenergic, alpha-2; D017448:Receptors, Dopamine D2; D010622:Phencyclidine; D003024:Clozapine