Review. Neurobiology of nicotine dependence

Abstract

Nicotine is a psychoactive ingredient in tobacco that significantly contributes to the harmful tobacco smoking habit. Nicotine dependence is more prevalent than dependence on any other substance. Preclinical research in animal models of the various aspects of nicotine dependence suggests a critical role of glutamate, gamma-aminobutyric acid (GABA), cholinergic and dopamine neurotransmitter interactions in the ventral tegmental area and possibly other brain sites, such as the central nucleus of the amygdala and the prefrontal cortex, in the effects of nicotine. Specifically, decreasing glutamate transmission or increasing GABA transmission with pharmacological manipulations decreased the rewarding effects of nicotine and cue-induced reinstatement of nicotine seeking. Furthermore, early nicotine withdrawal is characterized by decreased function of presynaptic inhibitory metabotropic glutamate 2/3 receptors and increased expression of postsynaptic glutamate receptor subunits in limbic and frontal brain sites, while protracted abstinence may be associated with increased glutamate response to stimuli associated with nicotine administration. Finally, adaptations in nicotinic acetylcholine receptor function are also involved in nicotine dependence. These neuroadaptations probably develop to counteract the decreased glutamate and cholinergic transmission that is hypothesized to characterize early nicotine withdrawal. In conclusion, glutamate, GABA and cholinergic transmission in limbic and frontal brain sites are critically involved in nicotine dependence.

Figure 1

Reward thresholds in nicotine-dependent rats treated with nAChR antagonist+cues. Conditioned nicotine withdrawal decreased the activity of brain reward systems. Rats trained in the ICSS procedure were prepared with subcutaneous osmotic minipumps containing nicotine (3.16 mg kg⁻¹ per day base) or saline. Several days were allowed to elapse so that nicotine dependence would develop in the nicotine-treated rats. Then, all rats were treated with the nAChR antagonist DHβE and allowed to perform in the ICSS procedure again while a flashing light was on for the duration of the ICSS session. In this graph, only data from rats that were nicotine dependent and were treated with DHβE paired with the flashing lights are presented (n=8). The results indicated a gradual increase in nAChR antagonist precipitated nicotine withdrawal with repeated pairings of the cue flashing lights with DHβE administration. On the test day, rats were injected with saline and presented with the cue lights. The presentation of the cue light alone was sufficient to induce a small but statistically significant elevation in brain reward thresholds, similar in direction but smaller in magnitude than nicotine withdrawal precipitated by administration of the nAChR antagonist. Data from three control groups, including a group that was not nicotine dependent and did not experience explicit pairings of the cue lights with the nAChR antagonist injection, did not show such conditioned effects. Data are shown as per cent change from baseline ICSS thresholds (+s.e.m.) in paired rats on the preconditioning day (pre), during the cue/injection pairings (DHβE+cues), and on the test day when rats were presented with the cues and injected with saline. ^***p<0.001, ^**p<0.01, ^*p<0.05, compared with thresholds obtained on the preconditioning day (post hoc test after significant one-way analysis of variance); ^#p<0.05, compared with preconditioning day (paired t-test). Adapted from Kenny & Markou (2005).

Figure 2

Nicotine–acetylcholine–glutamate–GABA–dopamine interactions in the VTA. Schematic depicting neurotransmitter interactions in the VTA, which are hypothesized to be critically involved in mediating various effects of nicotine with relevance to nicotine dependence and withdrawal. Neuroadaptations have been shown to develop to several of these receptor and transmitter systems with the development of nicotine dependence. Adapted from Mansvelder & McGehee (2002); see text for details.

Figure 3

Effects of 24-hour withdrawal from nicotine or food self-administration on functional coupling of mGlu2/3 receptors to G-proteins. Stimulation of [³⁵S]GTPγS binding by the mGlu2/3 receptor agonist LY354740 was significantly decreased in rats self-administering nicotine (filled circles) compared with animals responding for food (open circles), suggesting mGlu2/3 receptor downregulation in all assessed brain areas (LY354740×reward interactions, ^#p<0.05, ^###p<0.001, ^*p<0.05, ^**p<0.01, ^***p<0.001, difference from food). Data are expressed as mean±s.e.m., n=6. Adapted from Liechti et al. (2007). (a) Prefrontal cortex, (b) nucleus accumbens, (c) VTA, (d) amygdala.

Figure 4

Acute administration of the GABA_B receptor agonist CGP44532 decreased nicotine self-administration and cue-induced reinstatement of nicotine seeking. (a) Primary rewarding effects: nicotine was available for self-administration at either of two doses (0.01 or 0.03 mg kg⁻¹ per infusion base). Rats were trained to respond for nicotine or food under a fixed ratio 5, time out 20 s schedule of reinforcement. CGP44532 administration decreased both nicotine and food self-administration but affected nicotine self-administration at doses lower than those that decreased food self-administration. Data are expressed as percentage of baseline responding (mean+s.e.m.). ^*p<0.05, difference from vehicle pretreatment condition. ^#p<0.05, difference from the group that responded for food and received the same CGP44532 dose. Adapted from Paterson et al. (2004). Open bars, 0.03 mg kg⁻¹ per infusions of nicotine (n=10); hatched bars, 0.01 mg kg⁻¹ per infusions of nicotine (n=8); filled bars, food (n=12). (b) CGP44532 administration blocked cue-induced reinstatement of nicotine seeking in rats. A within-subjects design was used where all rats (n=8) received all doses of CGP44532. Between drug treatments, rats were returned to extinction conditions. ^*p<0.05, ^**p<0.01, difference from saline pretreatment. ^#p<0.05, difference between the test day and the preceding 3-day baseline. Data are expressed as mean number of lever presses +s.e.m. Adapted from Paterson et al. (2005b). Open bars, extinction conditions (n=8); filled bars, conditioned stimulus presentation.