Mesolimbic dopamine and habenulo-interpeduncular pathways in nicotine withdrawal

Abstract

The majority of people who attempt to quit smoking without some assistance relapse within the first couple of weeks, indicating the increased vulnerability during the early withdrawal period. The habenula, which projects via the fasciculus retroflexus to the interpeduncular nucleus, plays an important role in the withdrawal syndrome. Particularly the α2, α5, and β4 subunits of the nicotinic acetylcholine receptor have critical roles in mediating the somatic manifestations of withdrawal. Furthermore, withdrawal from nicotine induces a hypodopaminergic state, but there is a relative increase in the sensitivity to phasic dopamine release that is caused by nicotine. Therefore, acute nicotine re-exposure causes a phasic DA response that more potently reinforces relapse to smoking during the withdrawal period.

Figure 1.

Measurements of DA release by fast-scan cyclic voltammetry from brain slices. The burst firing by DA neurons was measured in vivo and then was used to construct stimulus trains to evoke DA release in the presence and absence of nicotine (0.1 µm). The stimulus trains were applied to brain slices containing either (A) the dorsolateral striatum (d. striatum) or (B) the nucleus accumbens shell (NAc shell). The DA traces shown in bold are those expected biologically in the absence (a1, b1) or in the presence (a4, b4) of nicotine. 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 bathing the slices. Scale bar, 0.1 µm, 1 sec. The relative DA signal (area-under-curve) is normalized to a1 (horizontal line) in C, the dorsal striatum and to b1 (horizontal line) in D, the NAc shell. The relative (i.e., area under the curve) DA signal was unchanged by nicotine in the dorsal striatum (a4 relative to a1) but was increased in the NAc shell (b4 relative to b1) with p < 0.01. (Modified and adapted from Zhang et al. 2009b.)

Figure 2.

Measurements of DA concentrations by in vivo microdialysis in freely moving mice. Nicotine was self-administrated via the drinking water for 4 or 12 wk followed by 1 d of withdrawal. (A) Dialysate DA concentrations at baseline and after an i.p. injection of saline and nicotine (1 mg/kg) following 1 d of withdrawal from 4 or 12 wk (wk) of chronic nicotine. Nicotine withdrawal decreased basal DA levels compared with the control. (B) Normalization of the dialysate DA signals revealed that the response to acute nicotine was enhanced in both withdrawal groups compared with the control. (C) The peak nicotine-induced DA responses are re-plotted as bar graphs showing that the nicotine evoked peak was higher in both withdrawal groups than in the control. *p < 0.05 by t-test. (Modified and adapted from Zhang et al. 2012.)

Figure 3.

Lack of β4, α5, or α2 nAChR subunits protect against nicotine withdrawal-induced somatic signs. nAChR null mice and their wild type littermates were treated chronically with nicotine (24 mg/kg/d free base) or saline using a mini-osmotic pump for 2 wk. On day 14, mice received a 3 mg/kg injection of the nonselective nicotinic antagonist, mecamylamine. Somatic signs, which include scratching, shaking, chewing, grooming, ptosis, head nodding, and jumping, were measured for 20 min. Mecamylamine injection produced an increase in somatic signs in wild-type, β2 null, and α7 null mice treated with nicotine. Similar increases were not observed in the β4, α5, or α2 null mice suggesting that nAChRs that contain these subunits play a role in the modulation of nicotine withdrawal signs. *p < 0.05. (Modified and adapted from Salas et al. , , .)