Sex differences and the role of dopamine receptors in the reward-enhancing effects of nicotine and bupropion

Nicotine underlies tobacco addiction, influences tobacco use patterns, and is used as a pharmacological aid to smoking cessation. The absorption, distribution and disposition characteristics of nicotine from tobacco and medicinal products are reviewed. Nicotine is metabolized primarily by the liver enzymes CYP2A6, UDPglucuronosyltransferase (UGT), and flavin-containing monooxygenase (FMO). In addition to genetic factors, nicotine metabolism is influenced by diet and meals, age, sex, use of estrogen-containing hormone preparations, pregnancy and kidney disease, other medications, and smoking itself. Substantial racial/ethnic differences are observed in nicotine metabolism, which are likely influenced by both genetic and environmental factors. The most widely used biomarker of nicotine intake is cotinine, which may be measured in blood, urine, saliva, hair, or nails. The current optimal plasma cotinine cut-point to distinguish smokers from non-smokers in the general US population is 3 ng ml(-1). This cut-point is much lower than that established 20 years ago, reflecting less secondhand smoke exposure due to clear air policies and more light or occasional smoking.

In female rats the gonadal hormones estrogen and progesterone modulate dopamine (DA) activity in the striatum and nucleus accumbens. For example, there is estrous cycle-dependent variation in basal extracellular concentration of striatal DA, in amphetamine (AMPH)-stimulated DA release, and in striatal DA-mediated behaviors. Ovariectomy attenuates basal extracellular DA, AMPH-induced striatal DA release, and behaviors mediated by the striatal DA system. Estrogen rapidly and directly acts on the striatum and accumbens, via a G-protein-coupled external membrane receptor, to enhance DA release and DA-mediated behaviors. In male rats, estrogen does not affect striatal DA release, and removal of testicular hormones is without effect. These effects of estrogen also result in gender differences in sensitization to psychomotor stimulants. The effects of the gonadal hormones on the striatum and ascending DA systems projecting to the striatum and nucleus accumbens are hypothesized to occur as follows: estrogen induces a rapid change in neuronal excitability by acting on membrane receptors located in intrinsic striatal GABAergic neurons and on DA terminals. The effect of these two actions results in enhanced stimulated DA release through modulation of terminal excitability. These effects of gonadal hormones are postulated to have important implications for gender differences in susceptibility to addiction to the psychomotor stimulants. It is suggested that hormonal modulation of the striatum may have evolved to facilitate reproductive success in female rats by enhancing pacing behavior.

The nigrostriatal dopamine (DA) system is sexually dimorphic. In female but not male rats, striatal DA activity is modulated by gonadal steroid hormones. Ovariectomy (OVX) decreases striatal DA release and turnover. Estrogen replacement restores the response to that of the intact female in estrus. In contrast, castration (CAST) of male rats has no effect on the stimulated release of DA from striatal tissue. This report addresses the question: Does estrogen act directly on the striatum to induce changes in DA release? Physiological concentrations of 17 beta-estradiol and other steroids or a nonsteroidal estrogen analog were applied directly to striatal tissue maintained in an in vitro superfusion system. The effect of hormonal treatments on the responsiveness of striatal DA terminals to stimulation was examined in tissue from OVX females and intact and CAST male rats. The results are summarized as follows: (1) Infusion of 17 beta-estradiol (p less than 0.01) and diethylstilbestrol (p less than 0.05) increased amphetamine (AMPH)-stimulated striatal DA release from striatal tissue of OVX female rats compared with the effect of cholesterol. 17 alpha-Estradiol also tended to potentiate the striatal DA response to AMPH, but this result was not statistically significant (p less than 0.062). 17 beta-Estradiol had no effect on AMPH-stimulated DA release from striatal tissue of intact male rats. (2) The KCl-stimulated release of DA from striatal tissue of OVX rats exposed in vitro to 100 pg/ml 17 beta-estradiol (a physiological dose) was significantly greater (p less than 0.05) than the response after exposure to vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)