The goal of this project is to characterize the effects of cocaine on intracellular estrogen and progestin receptor systems in brain. The proposed studies are based on preliminary experiments in which cocaine caused a robust, tissue-specific suppression of cytosol progestin receptor (cPR) binding in hypothalamus-preoptic area (HPOA) and anterior pituitary gland (AP) of intact female rats and of ovariectomized/adrenalectomized, estradiol-treated rats. The progestin receptor is an estrogen-inducible protein in HPOA and AP and the cocaine- induced suppression of binding appears to be due to a gender-specific impairment of some aspect of estradiol-receptor-DNA interactions in those tissues. These neuroendocrine abnormalities were evident even though only a single, moderately high dose of cocaine was administered and measurements of cPR were taken 18 hours later; i.e. at a time point beyond that typically associated with acute actions of cocaine. These effects of cocaine are particularly intriguing because steroid hormone receptors function not only as signal transducers but, more importantly, as transcription factors. Thus, cocaine could gain functional access to the genome and modulate transcription of specific genes through effects on steroid receptors.
Our specific aims are: 1) To characterize cocaine's effects on cPR and to explore possible mechanisms through which cocaine might affect cPR binding; 2) To localize the effects of cocaine on progestin receptors in HPOA; 3) To determine whether the cocaine-induced suppression of cPR binding in HPOA and AP is physiologically significant; 4) To characterize cocaine effects on nuclear estrogen receptor (nER) binding in HPOA and AP and to determine whether, in addition to impairing some aspect of estradiol-receptor-DNA interaction, cocaine causes an estradiol-independent activation of ER; 5) To establish the impact of cocaine on estrogen receptors under normal endocrine conditions; 6) To establish whether cocaine effects on steroid receptor systems are gender specific. The proposed project could have significant clinical relevancy. Although there is clear recognition of the deleterious effects of cocaine abuse, little is known about the neuronal adaptations associated with cocaine addiction. Our success in establishing an animal model for assessing cocaine's effects on steroid receptor systems could be instrumental in focusing attention on the role of this group of transcription factors. Since steroid receptors are likely to regulate a large number of regulatory (early) and structural (late) genes, they have the potential for markedly amplifying the effects of cocaine and precipitating a cascade of genomic modifications which could have enduring behavioral and physiological consequences that extend well beyond the presence of cocaine in the body.
| Nock, B; Cicero, T J; Wich, M (1998) Chronic exposure to morphine decreases physiologically active corticosterone in both male and female rats but by different mechanisms. J Pharmacol Exp Ther 286:875-82 |
| Nock, B; Wich, M; Cicero, T J (1997) Chronic exposure to morphine increases corticosteroid-binding globulin. J Pharmacol Exp Ther 282:1262-8 |
| Cicero, T J; Nock, B; Meyer, E R (1997) Sex-related differences in morphine's antinociceptive activity: relationship to serum and brain morphine concentrations. J Pharmacol Exp Ther 282:939-44 |
| Cicero, T J; Nock, B; Meyer, E R (1996) Gender-related differences in the antinociceptive properties of morphine. J Pharmacol Exp Ther 279:767-73 |
