Modulation of brain dopamine transmission by sex steroids

Sex steroid hormones influence the dopaminergic systems of the hypothalamus as well as the extrahypothalamic regions of the brain in controlling movement and behavior in both humans and animals. This review focuses on the effects of sex steroids on dopaminergic activity in extrahypothalamic brain areas. Among sex steroids, estrogens have been most extensively investigated, and many studies report that estrogens affect behaviors mediated by the basal ganglia, such as in humans suffering from extrapyramidal disorders. Epidemiological and clinical evidence also suggests an influence of estrogens on the vulnerability threshold for schizophrenia and sex differences in the clinical expression of this disease. Clinical observations point to a role of androgenic hormones in Gilles de la Tourette's syndrome. In normal humans, sex steroids were also shown to influence motor and cognitive performance. Biochemical and behavioral studies in animals have also shown the effect of sex steroids on dopaminergic activity in the basal ganglia; however, both activating and inhibiting effects have been reported. This may partly be explained by effects of the dose, duration of treatment, interval between steroid administration and testing the behavior measured, and the part of the basal ganglia from which the behavior is elicited. In view of the numerous variables that influence net dopaminergic response to steroids, focus will be on the literature using similar experimental conditions to assess the effect of in vivo chronic steroid treatment, acute short-term steroid treatment and the estrous cycle as well as in vitro effects of steroids on dopamine receptors. These experimental paradigms point to two general mechanisms of action of steroids: a rapid short-term non-genomic membrane effect and a slower long-term possibly genomic effect of steroids on dopamine systems. Combining dopaminergic drugs with sex steroids could improve efficacy or reduce side effects associated with these drugs. Examples of such combined treatments in rats and monkeys are presented for delta 9-tetrahydrocannabinol, cocaine, neuroleptics, apomorphine and L-DOPA. A better understanding of steroid-dopamine interactions and the possible isolation of conditions to have only pro or anti dopaminergic activity could then be used to develop combined therapies or to optimize drug treatments that would take into account the patient's sex and endocrine status.