Muscarinic, but not nicotinic, acetylcholine receptor blockade in the ventral tegmental area attenuates cue-induced sucrose-seeking

Abstract

The mesolimbic dopamine (DA) system is known to play a role in cue-mediated reward-seeking for natural rewards and drugs of abuse. Specifically, cholinergic and glutamatergic receptors in the ventral tegmental area (VTA) have been shown to regulate cue-induced drug-seeking. However, the potential role of these VTA receptors in regulating cue-induced reward seeking for natural rewards is unknown. Here, we examined whether blockade of VTA acetylcholine receptors (AChRs) and N-methyl-d-aspartate receptors (NMDARs) would alter cue-induced sucrose seeking in male Sprague-Dawley rats. Subjects underwent 10 days of sucrose self-administration training (fixed ratio 1 schedule) followed by 7 days of forced abstinence. On withdrawal day 7, rats received bilateral VTA infusion of vehicle, the muscarinic AChR antagonist scopolamine (2.4 or 24 μg/side), the nicotinic AChR antagonist mecamylamine (3 or 30 μg/side), or the NMDAR antagonist AP-5 (0.1 or 1 μg/side) immediately prior to examination of cue-induced sucrose-seeking. Scopolamine infusion led to robust attenuation, but did not completely block, sucrose-seeking behavior. In contrast, VTA administration of mecamylamine or AP-5 did not alter cue-induced sucrose-seeking. Together, the data suggest that VTA muscarinic AChRs, but not nicotinic AChRs nor NMDARs, facilitate the ability of food-associated cues to drive seeking behavior for a food reward.

Keywords: Mecamylamine; Mesolimbic dopamine system; NMDA receptor; Reward-seeking behavior; Scopolamine.

Fig. 1

A) Experimental timeline. B) Representative VTA cannula placements. C) Acquisition of sucrose-self administration behavior (FR 1) over 10 days (main effect of lever and training day, p < 0.0001; lever x day interaction, p < 0.0001).

Fig. 2

Examination of cue-induced sucrose-seeking during VTA infusion of cholinergic receptor or NMDA receptor antagonists. Scopolamine infusion attenuated cue-induced sucrose-seeking (N = 23) A) over a 1 hr period (main effect of treatment p < 0.0005, main effect of lever p < 0.0001, treatment x lever interaction p < 0.01) and B) at specific 5 min bins. In contrast, mecamylamine infusion did not alter sucrose-seeking (N = 22) C) over a 1 hr session or D) at any of the 5 min bins. AP-5 infusion also did not alter sucrose-seeking (N= 24) E) during a 1 hr session or F) at any 5 min bins.