Chronic ethanol reduces nicotine-induced dopamine release in PC12 cells

Background: There is a high correlation between alcohol and nicotine use; that is, alcohol use is associated with high levels of smoking. One important aspect of nicotine addiction appears to be the activation of nicotinic acetylcholine receptors on dopaminergic neurons projecting from the ventral tegmental area to the nucleus accumbens. The release of dopamine from these neurons is thought to mediate, at least in part, the reward of nicotine consumption. If chronic alcohol consumption affects the amount of dopamine released in response to nicotine, it could contribute to the high level of smoking seen in alcoholics. Methods: We have used an in vitro model system to study the effects of chronic ethanol exposure on acute nicotine‐induced dopamine release and the withdrawal from ethanol. A pheochromocytoma cell line (PC12 cells) was exposed to ethanol for periods of 3 to 96 hr, followed by a 5 min exposure to nicotine. Dopamine released in response to nicotinic stimulation was measured by high‐pressure liquid chromatography. Results: Exposure of PC12 cells to chronic ethanol resulted in a time‐ and dose‐dependent inhibition of nicotine‐induced dopamine release. A moderate dose of ethanol (50 mM) resulted in a significant reduction in as little as 3 hr. The cells demonstrated a form of cross‐tolerance in that they showed diminished response to nicotine even though they had never been exposed to nicotine. After ethanol was withdrawn from the cells after a chronic exposure (96 hr), dopamine release slowly returned to normal levels but demonstrated a significant period of “overshoot” or hyperresponsiveness between 24 and 48 hr after withdrawal. Conclusions: These results show that chronic ethanol exposure decreases nicotine‐induced dopamine release and demonstrate a period of hyperresponsiveness during withdrawal from ethanol. These studies suggest potential interactions between chronic ethanol and nicotine that may provide insight into such phenomena as cross‐tolerance and increased use of nicotine by alcoholics.