Enhanced cortical dopamine output and antipsychotic-like effects of raclopride by alpha2 adrenoceptor blockade.
Clozapine exerts superior clinical efficacy and markedly enhances cortical dopamine output compared with classical antipsychotic drugs. Here the alpha2 adrenoceptor antagonist idazoxan was administered to rats alone or in combination with the D2/3 dopamine receptor antagonist raclopride. Dopamine efflux in the medial prefrontal cortex and conditioned avoidance responding were analyzed. Idazoxan selectively potentiated the cortical output of dopamine and augmented the suppression of conditioned avoidance responding induced by raclopride. These results challenge basic assumptions underlying the dopamine hypothesis of schizophrenia and provide insight into clozapine's mode of action.
Hertel
P
P
Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institute, S-171 77 Stockholm, Sweden.
Fagerquist
M V
MV
Svensson
T H
TH
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D003213:Conditioning, Psychological; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D019329:Idazoxan / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D020891:Raclopride; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D012457:Salicylamides / Q000494:pharmacology*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D018341:Receptors, Adrenergic, alpha-2; D012457:Salicylamides; D020891:Raclopride; D004298:Dopamine; D019329:Idazoxan