Conflicting evidence for the dopamine release theory of nicotine/tobacco dependence

At the present time, the dopamine theory of nicotine/tobacco dependence is widely accepted by most pharmacologists and neuroscientists. It seems foolhardy to question it. However, nicotine releases a large variety of hormones, neuromodulators and neurotransmitters. Nevertheless, brain dopamine release, by far, has been emphasized as the most important mechanism for tobacco dependence in man. As a basic and clinical pharmacologist, one must evaluate all data on this issue from isolated preparations and intact animals such as rodents and primates and, finally, studies in humans. A review of the published data is appropriate to evaluate the basis for the current widely held view that nicotine/tobacco, like much stronger central nervous system stimulants including amphetamine and cocaine, acts primarily through a brain dopamine release mechanism. Nicotine produces marked locomotor effects in rodents. In mice, the locomotion stimulant or depressant effects of nicotine are strain dependent. In most strains of rats, if naïve to nicotine, locomotor activity is usually markedly depressed. Upon repeated nicotine administration, rats show locomotor stimulant effects, a phenomenon known as behavioral sensitization. In monkeys, nicotine behavioral sensitization is very poorly developed. It has not been described in humans. Nevertheless, rat behavioral sensitization is postulated to be an excellent model of human dependence to various drugs. The data for a primary role of nicotine release of brain dopamine are unimpressive compared to that of amphetamines and cocaine in conscious unanesthetized primates, both subhuman and human.