Enhanced cortical dopamine output and antipsychotic-like effects of raclopride by α2 adrenoceptor blockade

Clozapine exerts superior clinical efficacy and markedly enhances cortical dopamine output compared with classical antipsychotic drugs, Here the alpha(2) adrenoceptor antagonist idazoxan was administered to rats alone or in combination with the D-2/3 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.