SUPPRESSION OF GLUCOCORTICOID SECRETION AND ANTIPSYCHOTIC-DRUGS HAVE SIMILAR EFFECTS ON THE MESOLIMBIC DOPAMINERGIC TRANSMISSION

Specific antagonists of central dopaminergic receptors constitute the major class of antipsychotic drugs (APD), Two principal effects of APD are used as criteria for the pre-clinical screening of their antipsyc hotic action: (i) inhibition of basal and depolarization-induced activ ity of mesolimbic dopaminergic neurons; (ii) antagonism of the locomot or effects of dopaminergic agonists, Given that glucocorticoid hormone s in animals increase dopamine release and dopamine-mediated behaviors and that high levels of glucocorticoids can induce psychotic symptoms In humans, these experiments examined whether inhibition of endogenou s glucocorticoids might have AD-like effects on mesolimbic dopaminergi c transmission in rats, It is shown that suppression of glucocorticoid secretion by adrenalectomy profoundly decreased (by greater than 50%) : (i) basal dopaminergic release and the release of dopamine induced b y a depolarizing stimulus such as morphine (2 mg/kg, s.c.), as measure d in the nucleus accumbens of freely moving animals by microdialysis; (ii) the locomotor activity induced by the direct dopaminergic agonist apomorphine, The effects of adrenalectomy were glucocorticoid specifi c given that they were reversed by the administration of glucocorticoi ds at doses within the physiological range, Despite its profound dimin ution of dopaminergic neurotransmission, adrenalectomy neither modifie d the number of mesencephalic dopaminergic neurons nor induced gliosis in the mesencephalon or In the nucleus accumbens, as shown by tyrosin e hydroxylase and glial fibrillary acidic protein immunostaining. In c onclusion, these findings suggest that blockade of central effects of glucocorticoids might open new therapeutic strategies of behavioral di sturbances.