COMBINED EFFECTS OF ETHANOL AND COCAINE ON FOS-LIKE PROTEIN AND COCAETHYLENE BIOSYNTHESIS IN THE RAT

To study the simultaneous effects of ethanol and cocaine on striatal F OS-like protein, rats were exposed to an (8.7%) ethanol solution for 1 5 days followed by single or daily cocaine injections (20 mg/kg; IP). Ethanol consumption reduced the induction of the nuclear protein under both temporal regimens of cocaine administration. In contrast, sucros e pair-fed or ad libitum control groups exhibited a robust induction o f FOS-like protein throughout the striatum, particularly in dorsal-cen tral quadrants of the caudate putamen. This pattern of combined drug u se produced blood ethanol concentrations in the range of 22-370 mg/dl, corresponding with those associated with mild intoxication in humans. Under both cocaine regimens, the presence of ethanol led to the trans esterification of cocaine into the active metabolite, cocaethylene (31 -121 ng/ml). Plasma levels of this metabolite did not exceed those of cocaine (17-1024 ng/ml), suggesting that under this drug regimen at le ast, cocaethylene formation is relatively low and perhaps dependent up on specific levels of ethanol and cocaine in hepatic microsomes. In ad dition, systemic administration of cocaethylene to rats (60 mu mol/kg; molar equivalent of 20 mg/kg cocaine) induced widespread FOS-like pro tein in the caudate putamen. Induction of the transcription factor pro tein by cocaethylene was similar in magnitude and anatomic distributio n to that of cocaine, suggesting that these two drug congeners share c ommon molecular mechanisms of gene expression.