Reward, addiction, withdrawal to nicotine

Abstract

Nicotine is the principal addictive component that drives continued tobacco use despite users' knowledge of the harmful consequences. The initiation of addiction involves the mesocorticolimbic dopamine system, which contributes to the processing of rewarding sensory stimuli during the overall shaping of successful behaviors. Acting mainly through nicotinic receptors containing the α4 and β2 subunits, often in combination with the α6 subunit, nicotine increases the firing rate and the phasic bursts by midbrain dopamine neurons. Neuroadaptations arise during chronic exposure to nicotine, producing an altered brain condition that requires the continued presence of nicotine to be maintained. When nicotine is removed, a withdrawal syndrome develops. The expression of somatic withdrawal symptoms depends mainly on the α5, α2, and β4 (and likely α3) nicotinic subunits involving the epithalamic habenular complex and its targets. Thus, nicotine taps into diverse neural systems and an array of nicotinic acetylcholine receptor (nAChR) subtypes to influence reward, addiction, and withdrawal.

Figure 1

Nicotine increases the action potential firing rate and phasic burst firing of putative midbrain dopamine (DA) neurons in freely moving rats. (a) The normalized average firing rate of DA neurons in response to administration of nicotine (0.4–0.5 mg/kg, i.p., free-base equivalent). (b) In vivo, chronic tetrode recording from a putative DA neuron, indicating that the DA neuron fires more phasic bursts (gray arrows) after nicotine administration (red trace) than before (blue control trace). Adapted from Zhang et al. (2009b).

Figure 2

Different dopamine (DA) release properties in the dorsal striatum and NAc shell. DA release was evoked by a single electrical stimulus pulse (1p) or by a stimulus train of 5 pulses delivered at 20 Hz (5p @ 20Hz) to brain slices. The traces represent DA concentration measured in brain slices by carbon-fiber voltammetry. Example measurements are shown of the DA signal evoked by 1p (gray traces) or by 5p at 20 Hz (green traces). In the NAc shell, the DA signal evoked by 1p is much smaller than that evoked by 5p (as measured by the area under the curve) curve). In the dorsal striatum, the DA signal evoked by 1p is only slightly slight smaller than that evoked by a 5p train. Adapted from data within Zhang et al (2009b).

Figure 3

The burst firing by dopamine (DA) neurons measured in vivo that is induced by nicotine causes a greater increase of DA release in the NAc shell than in the dorsal striatum. The traces represent DA concentration measured in brain slices by carbon-fiber voltammetry. Electrical stimulus patterns used to evoke DA release were designed to mimic the in vivo firing patterns (vertical tick marks below) of DA neurons measured from freely moving rats before (control) and after nicotine injections. Patterned stimulus trains based on the in vivo DA-unit recordings are shown below the evoked DA release in the absence (control) or presence of nicotine in the dorsal striatum (a) or the NAc shell (b). (c) The relative DA signal (calculated as the area under the curve) was unchanged by nicotine in the dorsal striatum dorsal striatum but was increased in the NAc shell. Adapted from Zhang et al. (2009b).