Enhanced cortical dopamine output and antipsychotic-like effects of raclopride by alpha(2) 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 c ombination with the D-2/3 dopamine receptor antagonist raclopride. Dopamine efflux in the medial prefrontal cortex and conditioned avoidance respondin g were analyzed. Idazoxan selectively potentiated the cortical output of do pamine and augmented the suppression of conditioned avoidance responding in duced by raclopride. These results challenge basic assumptions underlying t he dopamine hypothesis of schizophrenia and provide insight into clozapine' s mode of action.