NEURAL AND ENDOCRINE MECHANISMS OF COCAINE-INDUCED 70-KDA HEAT-SHOCK PROTEIN EXPRESSION IN AORTA AND ADRENAL-GLAND

Cocaine has properties of a physiologic stressor that are reflected by its ability to activate both the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. We have previously reported that a ctivation of the hypothalamic-pituitary-adrenal axis and sympathetic n ervous system by restraint and pharmacologic agents induces expression of a set of highly conserved cellular stress response proteins (heat shock proteins, HSP) in the adrenal gland and aorta. In the adrenal gl and, HSP expression appears to be mediated by stress-induced increases in adrenocorticotropic hormone whereas expression in the aorta involv es noradrenergic neurotransmission. In this report we capitalize on th e ability of cocaine to stimulate physiologic stress responses to defi ne further mechanisms regulating HSP70 expression in these tissues. We report the novel observation that cocaine administration induces both adrenal and vascular HSP70 mRNA expression. Elevated HSP70 mRNA was p receded by activation of factors capable of binding to the heat shock transcriptional control element and was followed by an elevation in HS P70 protein. Cocaine significantly increased plasma adrenocorticotroph ic hormone whereas hypophysectomy eliminated cocaine-induced expressio n in the adrenal gland suggesting that in this tissue, the effect of c ocaine on HSP70 expression is also mediated via adrenocorticotrophic h ormone. In the aorta, depletion of catecholamines by reserpine pretrea tment paradoxically augmented cocaine-induced HSP70 expression. Based on these results, it appears that HSP70 expression in the aorta occurs through direct actions of cocaine on vascular cells that are ultimate ly transduced to activation of the HSP70 gene rather than indirectly t hrough alterations in catecholamine reuptake and release. The ability to manipulate HSP70 expression in mammalian tissues by hormones and ph armacologic agents suggests that the homeostatic maintenance propertie s of HSP are manifest at the physiologic as well as the cellular level .