Neurobiological Effects

Cellular Mechanism of Action

At the cellular level, one hypothesis for the mechanism by which nicotine activates the mesocorticolimbic dopamine system may also involve N-methyl-D-aspartate (NMDA) receptors (in the ventral tegmental area). Acute nicotine administration activates nAChRs located presynaptically on glutamatergic terminals, leading to increased glutamate release. In turn, glutamate increases the firing rate of dopamine neurons and increases subsequent dopamine release in the nucleus accumbens. The blockade of NMDA receptors with an NMDA receptor antagonist injected systemically or directly into the ventral tegmental area dose-dependently attenuated nicotine-induced dopamine release in the nucleus accumbens. The blockade of NMDA receptors also decreased intravenous nicotine self-administration and the nicotine-induced lowering of brain reward thresholds. Such data indicate that the activation of nAChRs on glutamatergic terminals may be a key component of the nicotine/mesocorticolimbic dopamine interaction in the ventral tegmental area that is important for the acute reinforcing properties of nicotine.

Figure 7.20 Intravenous self-administration of cocaine and nicotine in β2−/− knockout mice (mutant nicotine) and their wildtype (WT) siblings with a history of cocaine self-administration. (A) Number of active nosepoke responses per session. Dashed lines represent the average of the last three sessions of cocaine self-administration in all of the groups of mice (cocaine) or spontaneous nosepoke behavior in naive, sham-operated mice (naive). (B) Percentage of the number of active responses compared with the sum of active and inactive responses per session. Values of 50% indicate a lack of discrimination between active and inactive detectors. β2−/− mice differed significantly from wildtype mice that self-administered nicotine in either the active nosepoke (p < 0.05) or discrimination (p < 0.01) index but did not differ from wildtype mice during saline-induced extinction. The increase in the variability of nosepoke responses in β2−/− mice on the first day of nicotine treatment was attributable to the increased responding of some mice, usually interpreted as a transient overresponse to reinforcer devaluation. ∗p < 0.05, significant difference between β2−/− group and wildtype nicotine group. These data show that mice with knockout of the β2 nicotinic receptor will not self-administer nicotine, establishing this receptor subtype as a key initial site for the actions of nicotine. [Taken with permission from Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, Pich EM, Fuxe K, Changeux JP. Acetylcholine receptors containing the β2 subunit are involved in the reinforcing properties of nicotine. Nature, 1998, (391), 173–177.]

Figure 7.21 Effects of bilateral 6-hydroxydopamine lesions or ascorbate vehicle infusions into the dopamine terminal field in the nucleus accumbens on nicotine self-administration in rats. Each rat was lesioned on one of two days, as indicated by the arrows. Notice that although the number of nicotine infusions increased at the beginning of the second and third weeks of testing, this increase was not sustained. Over the 3 week test period, a marked difference was observed between the control and lesion groups. These data show that the removal of dopaminergic terminals in the mesocorticolimbic dopamine system in the nucleus accumbens with a neurotoxin that selectively destroys monoamine axons and terminals causes rats to stop taking nicotine. The rats extinguished their drug-seeking behavior although nicotine was readily available. [Taken with permission from Corrigall WA, Franklin KBJ, Coen KM, Clarke PBS. The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology, 1992, (107), 285–289.]

Inhibitory GABA neurotransmission may also play a role in nicotine/dopamine interactions. GABAergic afferents to dopaminergic neurons in the ventral tegmental area and medium spiny GABAergic neurons in the nucleus accumbens inhibit mesocorticolimbic dopamine release. Pharmacological enhancement of GABAergic neurotransmission blocked the reinforcing effects of nicotine in conditioned place preference and self-administration studies and blocked nicotine-induced increases in dopamine in the nucleus accumbens (Figure 7.22).

As noted above, nicotine increases the firing rate of dopaminergic neurons in the ventral tegmental area, and substantia nigra, and this excitatory effect appears to occur through the α4β2 subtype. In an in vitro study in which nicotine was directly applied onto a midbrain dopamine neuron in a slice preparation of the ventral tegmental area at a concentration that was equivalent to the nicotine concentration that a smoker would achieve, nicotine activated and then desensitized nicotinic receptors. Also in slice preparations, nicotine enhanced the firing of both dopamine and non-dopamine (presumably GABAergic) neurons, but the non-dopamine neurons desensitized more rapidly. This may contribute to prolonged activation of dopamine neurons through a disinhibitory effect.

Figure 7.22 Interconnecting brain pathways, receptors, and synapses mediate neuroadaptive changes that accompany nicotine addiction. (A) Neural systems implicated in addiction and behavioral sensitization. Dopamine neurons (pink) located in the midbrain ventral tegmental area project to the limbic forebrain and cortical regions, such as the prefrontal cortex, amygdala, and nucleus accumbens. These structures are connected by glutamatergic pathways (green). The cholinergic pathways (blue) include cell bodies in the pedunculopontine nucleus (PPT) and lateral dorsal tegmentum (LDT) that project to the ventral tegmental area and cortical regions. A second major cholinergic pathway arises from the basal forebrain and reaches widespread cortical and limbic regions. A third source of forebrain acetylcholine constitutes the intrinsic neurons of the nucleus accumbens, a brain reward region. (B) Two different types of neuronal nicotinic receptors commonly found in the cholinergic pathways described above and proposed to be involved in the brain’s response to drugs of abuse. (C) Potential interactions between acetylcholine, glutamate, and dopamine cells in the midbrain. Acetylcholine release in this area could activate both presynaptic nicotinic α7 receptors located on glutamatergic terminals (GLU) and postsynaptic α4β2 nicotinic receptors located on dopamine cell bodies. Complex interactions between the acetylcholine, dopamine, and glutamate systems are likely to set the addiction process in motion.
[Panels A and B taken with permission from Kelley AE. Nicotinic receptors: addiction’s smoking gun? Nature Medicine, 2002, (8), 447–449.] [Based on Mansvelder HD, McGehee DS. Cellular and synaptic mechanisms of nicotine addiction. Journal of Neurobiology, 2002, (53), 606–617.]

Another cellular hypothesis that may explain the overall actions of nicotine in the ventral tegmental area is that nicotine binds to α7 nAChRs on presynaptic glutamate terminals in the ventral tegmental area and induces long-term potentiation of excitatory glutamate transmission in midbrain dopamine neurons. Thus, nicotine’s combined effects on glutamate and GABA neurons can produce powerful and prolonged activation of dopamine neurotransmission in the mesocorticolimbic dopamine system (Figure 7.22).

Another motivation-related brain area that is activated by nicotine is the dorsal raphe. Nicotine has shown some stimulatory effects on dorsal raphe serotonin neurons, which may involve both direct effects on serotonin neurons and indirect effects on glutamate/GABA interactions as above. Such effects of nicotine on serotonin neurotransmission may be part of the reason why nicotine apparently has antidepressant-like effects in animal models and humans.

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