Intermittent nicotine exposure upregulates nAChRs in VTA dopamine neurons and sensitises locomotor responding to the drug.

Dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) mediate the behavioral and motivational effects of many drugs of abuse, including nicotine. Repeated intermittent administration of these drugs, a pattern often associated with initial drug exposure, sensitises the reactivity of dopamine (DA) neurons in this pathway, enhances the locomotor behaviors the drugs emit, and promotes their pursuit and self-administration. Here we show that activation of nicotinic acetylcholine receptors (nAChRs) in the VTA, but not the NAcc, is essential for the induction of locomotor sensitisation by nicotine. Repeated intermittent nicotine exposure (4 × 0.4 mg/kg, base, i.p., administered over 7 days), a regimen leading to long-lasting locomotor sensitisation, also produced upregulation of nAChRs in the VTA, but not the NAcc, in the hours following the last exposure injection. Functional nAChR upregulation was observed selectively in DA but not GABA neurons in the VTA. These effects were followed by long-term potentiation of excitatory inputs to these cells and increased nicotine-evoked DA overflow in the NAcc. Withdrawal symptoms were not observed following this exposure regimen. Thus, intermittent activation and upregulation by nicotine of nAChRs in DA neurons in the VTA may contribute to the development of behavioral sensitisation and increased liability for nicotine addiction.

Blockade of group II metabotropic glutamate receptors in the nucleus accumbens produces hyperlocomotion in rats previously exposed to amphetamine.

The neurotransmitter glutamate is known to participate in both the induction and expression of locomotor sensitization by psychostimulant drugs like amphetamine. Previously, it was reported that subtype nonselective blockade of metabotropic glutamate receptors (mGluRs) in the nucleus accumbens (NAcc) produces hyperlocomotion in rats previously exposed to amphetamine. The present experiments examined whether group II mGluRs may contribute to this effect. Rats in different groups were administered five injections of either saline or amphetamine (1.0 mg/kg, i.p.), one injection given every third day. Two weeks later, they were tested for 2 h following an injection of either saline or the group II mGluR antagonist LY341495. In one experiment, test injections were administered systemically (saline or LY341495, 1.0 mg/kg, i.p.). Rats previously exposed to amphetamine showed a greater locomotor response to LY341495 on the test compared to controls previously exposed to saline. This hyperlocomotor response was absent in rats tested with a combination of LY341495 and the group II mGluR agonist LY379268 (1.0 mg/kg, i.p.). In a second experiment, different rats were tested following microinjections into the NAcc (saline or LY341495, 0.1, 10 or 100 microg/0.5 microl/side). Again, rats previously exposed to amphetamine showed a greater dose-dependent locomotor response to LY341495 on the test relative to saline-exposed controls. Locomotor activity in saline-exposed rats challenged with LY341495 did not differ from that observed in rats previously exposed and tested with saline in either experiment. These results indicate that group II mGluRs, particularly those found in the NAcc, are well positioned to modulate the expression of locomotor sensitization by amphetamine.

Differential effects of nicotine on alcohol consumption in men and women.

RATIONALE: Nicotine and alcohol are frequently co-used, suggesting that use of one drug may facilitate use of the other. Furthermore, because men and women differ in their responses to both drugs, it is possible that men and women also differ in their responses to the combination of nicotine and alcohol. OBJECTIVE: This experiment was designed to investigate the effects of nicotine on consumption and subjective and physiological effects of alcohol in healthy male and female social drinkers. MATERIALS AND METHODS: Healthy light smoking, social drinkers (22 men and 12 women) participated in a three-session, double-blind within-subject study. They were pretreated with transdermal nicotine (7 or 14 mg) or placebo, followed two h later by an alcoholic beverage, and subsequent opportunities to "purchase" and consume more of the same drink. Outcome measures included the number of alcoholic beverages consumed and subjective and physiological effects. RESULTS: Nicotine increased alcohol consumption in men, whereas it decreased alcohol consumption in women. These effects were even more pronounced after excluding participants reporting nausea after nicotine administration. Nicotine alone increased subjective arousal in men but decreased positive mood in women. Nicotine increased the sedative-like effects of alcohol in both sexes. CONCLUSIONS: These findings indicate that both the subjective effects of nicotine and the effects of nicotine on alcohol consumption differ markedly in men and women. The findings extend existing data on sex differences in the effects of either nicotine or cigarette smoking on alcohol consumption, and support the idea that the pharmacological effects of nicotine may differ in men and women.

Mecamylamine and ethanol preference in healthy volunteers.

BACKGROUND: Recent evidence suggests that some of the behavioral effects of alcohol may be mediated through actions on nicotinic acetylcholine receptors. Mecamylamine, a nicotinic acetylcholine receptor antagonist, reduces alcohol preference and consumption in alcohol-preferring rats, and in humans, mecamylamine dampens some of the subjective, or mood-altering, effects of alcohol. This experiment was designed to investigate the effects of mecamylamine on consumption of alcohol in healthy social drinkers. METHODS: Healthy volunteers (12 men, 12 women) participated in a choice procedure in which they chose between an alcoholic beverage and money (low, medium, or high amounts) after pretreatment with mecamylamine (7.5 or 15 mg) or placebo. Outcome measures were the number of alcoholic beverages consumed and the subjective effects of alcohol. RESULTS: Mecamylamine (15 mg) decreased blood alcohol levels (BALs) after a small fixed dose of alcohol (0.2 g/kg). Even when the lower BALs were taken into account, mecamylamine reduced ratings of stimulation after alcohol (Addiction Research Center Inventory A scale). Mecamylamine did not significantly reduce choice for alcohol versus money. However, there was a tendency for the drug to decrease alcohol choice among participants who reported the greatest stimulant-like effects from alcohol. CONCLUSION: These results provide only limited support for the idea that nicotinic acetylcholine receptors are involved in the rewarding effects of alcohol.

Mecamylamine attenuates the subjective stimulant-like effects of alcohol in social drinkers.

BACKGROUND: Recent studies have implicated central nicotinic cholinergic receptor systems in the reinforcing properties of alcohol. In laboratory animals, mecamylamine, a central nicotinic receptor antagonist, reduces the consumption of and preference for alcohol. This study investigated the effect of mecamylamine on the subjective responses to alcohol in humans. It was hypothesized that mecamylamine (7.5 and 15 mg) would attenuate the stimulant-like subjective effects of alcohol (0.8 g/kg) and decrease the self-reported desire to consume additional alcohol beverages. METHODS: Fourteen male and 13 female nonsmokers participated in 6 laboratory sessions. During each session, subjects received, in randomized order under double-blinded conditions, a capsule containing mecamylamine (7.5 or 15 mg) or placebo followed by a beverage containing alcohol (0.8 g/kg) or placebo. Physiologic and subjective-effect measures were taken at 30-min intervals for 2 hr after beverage consumption. RESULTS: Mecamylamine attenuated the stimulant and euphoric effects of alcohol and reduced the self-reported desire to consume additional alcohol beverages. This effect was most pronounced in men, even though women exhibited greater physiologic reactions to mecamylamine. CONCLUSIONS: These findings suggest that nicotinic cholinergic receptors are involved in mediating some of the stimulant-like effects of alcohol.