Dopaminergic and cholinergic learning mechanisms in nicotine addiction

Abstract

Nicotine addiction drives tobacco use by one billion people worldwide, causing nearly six million deaths a year. Nicotine binds to nicotinic acetylcholine receptors that are normally activated by the endogenous neurotransmitter acetylcholine. The widespread expression of nicotinic receptors throughout the nervous system accounts for the diverse physiological effects triggered by nicotine. A crucial influence of nicotine is on the synaptic mechanisms underlying learning that contribute to the addiction process. Here, we focus on the acquisition phase of smoking addiction and review animal model studies on how nicotine modifies dopaminergic and cholinergic signaling in key nodes of the reinforcement circuitry: ventral tegmental area, nucleus accumbens (NAc), amygdala, and hippocampus. Capitalizing on mechanisms that subserve natural rewards, nicotine activates midbrain dopamine neurons directly and indirectly, and nicotine causes dopamine release in very broad target areas throughout the brain, including the NAc, amygdala, and hippocampus. In addition, nicotine orchestrates local changes within those target structures, alters the release of virtually all major neurotransmitters, and primes the nervous system to the influence of other addictive drugs. Hence, understanding how nicotine affects the circuitry for synaptic plasticity and learning may aid in developing reasoned therapies to treat nicotine addiction.

Keywords: VTA; acetylcholine; dopamine; hippocampus; memory; nucleus accumbens.

Figure 1

Animals learn multiple associations among stimuli (S), response (R), and outcome (O). These associations can be binary (A) such as S–R, R–O, and S–O, or higher order (B) such as S–(R–O). Adapted with permission from Ref. 16.

Figure 2

A simplified and incomplete schematic diagram (top panel) that highlights components of the circuitry contributing to reinforcement learning in rodents. Top panel: Sagittal section of a rodent brain didactically depicting strategic connections. Bottom panels: Coronal sections approximately at the anterior–posterior axis levels indicated by the dashed arrows, adapted from Figs. 20 and 74 of Ref. 29. Ac, anterior commissure; Amg, amygdala; LDTg, lateral dorsal tegmentum; NAc, nucleus accumbens; PFC, prefrontal cortex; PPTg, pedunculopontine tegmentum; SNc, substantia nigra pars compacta; VP, ventral pallidum; VTA, ventral tegmental area.

Figure 3

Nicotine increases burst firing in putative DA neurons within the VTA of freely moving rats. (A) Normalized average firing rate before (control, black) and after (nicotine, red) intraperitoneal (i.p.) injection of 0.4–0.5 mg/kg nicotine. Error bars represent SEM. (B) Representative traces from a single putative DA neuron before (black) and after (red) nicotine injection. Reproduced from Ref. 41.

Figure 4

Nicotine (0.6 mg/kg, i.p.) increases DA release in the nucleus accumbens shell of freely moving rats as measured by microdialysis with HPLC. Error bars represent SEM. Modified with permission from Ref. 40.

Figure 5

AMPA/NMDA ratio measured in slices prepared from mice that were given a single (A) or seven daily doses (B) of nicotine (0.17 mg/kg, i.p, filled bars) or saline (open bars). Error bars represent SEM. Modified with permission from Ref. 86.

Figure 6

Greatly simplified and incomplete schematic diagram of hippocampal connections. EC, entorhinal cortex; CA, cornu ammonis; DG, dentate gyrus. The pyramidal neuron in the dotted rectangle is shown on the right with the different strata labeled (s = stratum in the labels).

Figure 7

Nicotine's facilitation of LTP in the Schaffer collateral pathway depends on OLM interneurons. The inset shows the stimulating electrode placed in the Schaffer collateral (SC) path and the recording electrode in the stratum radiatum (SR) in a hippocampal slice. LTP was induced by weak theta burst stimulation (wTBS) and was quantified by comparing the slopes of field EPSPs in the presence and absence (baseline) of nicotine in the perfusate. Compared to the control condition (open circles), nicotine (filled squares) enhanced LTP in the Chrna2‐cre mice. Removing inhibition from OLM cells (filled triangles) abolished the LTP‐enhancing effect of nicotine. Error bars represent SEM. Modified with permission from Ref. 112.

Figure 8

Nicotine's ability to enhance LTP in the medial perforant path‐DG synapse depends on DA in freely moving mice. (A) Nicotine enhances LTP in vivo. Top row: field potential traces showing population spike (PS). Black, blue, and red traces indicate evoked responses after saline, 0.1 mg/kg nicotine, and 1 mg/kg nicotine injection (i.p.), respectively. Gray traces show the baseline evoked response. Bottom row: Normalized PS amplitude measured a day prior to nicotine injection (–1 day), on the day of nicotine injection (arrow, 0 day), and 1 (1 day), or 2 days (2 days) after the treatment. (B) Blocking VTA neuronal action potential with tetrodotoxin (TTX) abolishes nicotine‐induced LTP (n = 5). (C) Blockade of DA D1 receptors by local hippocampal infusion of SCH23390 also abolishes nicotine‐induced LTP (n = 6). Error bars represent SEM. Modified with permission from Ref. 117.