Enhancement of antipsychotic-like effects by combined treatment with the alpha1-adrenoceptor antagonist prazosin and the dopamine D2 receptor antagonist raclopride in rats.
Blockade of central alpha1-adrenoceptors has been implicated as a possible factor contributing to the atypical antipsychotic profile of clozapine. Thus, in the present study we examined the effects of concomitant alpha1-adrenoceptor and dopamine D2 receptor blockade on conditioned avoidance response performance, as an index of antipsychotic-like activity, and on the induction of catalepsy, as a test for extrapyramidal side effect liability, in rats. It was found that pretreatment with the alpha1-adrenoceptor antagonist prazosin (0.2mg kg(-1) s.c.) caused an enhancement of a suppression of conditioned avoidance response in the presence of the dopamine D2 receptor antagonist raclopride (0.05-0.20 mg kg(-1) s.c.). The effect was most prominent at a subthreshold dose of raclopride (0.05 mg kg(-1)). At these doses, prazosin or raclopride by themselves, or in combination, did not produce catalepsy. In addition, pretreatment with prazosin (0.2mgkg(-1) s.c.) did not alter the catalepsy produced by a higher dose of raclopride (1.0 mg kg(-1) s.c.). It is suggested that, in the presence of low dopamine D2 receptor occupancy, additional alpha1-adrenoceptor blockade might improve antipsychotic efficacy, and thereby improve the therapeutic window with regard to parkinsonism.
Wadenberg
M L
ML
Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden.
Hertel
P
P
Fernholm
R
R
Hygge Blakeman
K
K
Ahlenius
S
S
Svensson
T H
TH
D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D002375:Catalepsy / Q000139:chemically induced; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology*; D008297:Male; D011224:Prazosin / Q000494:pharmacology*; D011618:Psychotic Disorders / Q000188:drug therapy*; D020891:Raclopride / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism
D058668:Adrenergic alpha-1 Receptor Antagonists; D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D018340:Receptors, Adrenergic, alpha-1; D017448:Receptors, Dopamine D2; D020891:Raclopride; D011224:Prazosin