Ventral tegmental area α6β2 nicotinic acetylcholine receptors modulate phasic dopamine release in the nucleus accumbens core

Abstract

Rationale: Phasic dopamine (DA) signaling underlies reward learning. Cholinergic and glutamatergic inputs into the ventral tegmental area (VTA) are crucial for modulating burst firing activity and subsequent phasic DA release in the nucleus accumbens (NAc), but the specific VTA nicotinic receptor subtypes that regulate phasic DA release have not been identified.

Objective: The goal was to determine the role of VTA N-methyl-D-aspartate receptors (NMDARs) and specific subtypes of nicotinic acetylcholine receptors (nAChRs) in regulating phasic DA release in the NAc core.

Methods: Fast-scan cyclic voltammetry in anesthetized rats was combined with intra-VTA micro-infusion to evaluate the ability of glutamatergic and cholinergic drugs to modulate stimulated phasic DA release in the NAc core.

Results: VTA NMDAR blockade with AP-5 decreased, while VTA NMDAR activation with NMDA increased NAc peak phasic DA release. Intra-VTA administration of the nonspecific nAChR antagonist mecamylamine produced a persistent decrease in phasic DA release. Infusion of the α6-selective antagonist α-conotoxin MII (α-ctx MII) produced a robust, but transient decrease in phasic DA, whereas infusion of selective doses of either the α4β2-selective antagonist, dihydro-beta-erythroidine, or the α7 antagonist, methyllycaconitine, had no effect. Co-infusion of AP-5 and α-ctx MII produced a similar phasic DA decrease as either drug alone, with no additive effect.

Conclusions: The results suggest that VTA α6β2 nAChRs, but not α4β2 or α7 nAChRs, regulate phasic DA release in the NAc core and that VTA α6β2 nAChRs and NMDA receptors act at a common site or target to regulate NAc phasic DA signaling.

Fig 1

A. Timeline of experiment. B. Effect of VTA SAL and LID (41 ng) infusion on phasic DA release in NAc core. [DA]_max after SAL and LID infusion. Inset top left: Representative dopamine traces during the first baseline period and after saline infusion. Inset top right: Representative dopamine traces of second baseline period and after LID (41 ng) infusion. Triangle indicates VTA stimulation. C. Bottom: Time course of [DA]_max response after saline (SAL) and lidocaine (LID) infusion. Data are presented as the mean ± SEM. For all figures: *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.

Fig 2

VTA MEC infusion attenuates evoked phasic DA in the NAc core. A. Top: [DA]_max after MEC (0.3 μg) infusion. Bottom: [DA]_max time course after SAL and MEC infusion. B. Top [DA]_max after MEC (3 μg) infusion. Bottom: [DA]_max time course after SAL and MEC infusion. C. Top [DA]_max after MEC (30 μg) infusion. Bottom: [DA]_max time course after SAL and MEC (30 μg) infusion. Data represent the mean ± SEM.

Fig 3

VTA α-ctx MII infusion modulates evoked phasic DA in the NAc core. A. Top [DA]_max after α-ctx MII (17.1 ng) infusion. Bottom: [DA]_max time course after SAL and α-ctx MII infusion. B. Top [DA]_max after α-ctx MII (171 ng) infusion. Bottom: [DA]_max time course after SAL and α-ctx MII infusion. Data represent the mean ± SEM.

Fig 4

VTA infusion of DHβE or MLA does not modulate evoked phasic DA in the NAc core. A. Top [DA]_max after DHβE (17.5 μg) infusion. Bottom: [DA]_max time course after SAL and DHβE infusion. B. Top [DA]_max after MLA (6.875 μg) infusion. Bottom: [DA]_max time course after SAL and MLA infusion.

Fig 5

A. VTA NMDA infusion enhances evoked phasic DA in the NAc core. Top: Effect of NMDA (500 ng) infusion on [DA]_max. Bottom: Time course of [DA]_max after SAL and NMDA infusion. B. AP-5 infusion attenuates evoked phasic DA in the NAc core. Top: [DA]_max after AP-5 (1 μg) infusion. Bottom: Time course of [DA]_max response after SAL and AP-5 infusion. C. VTA co-administration of AP-5 and α-ctx MII infusion does not further decrease phasic DA release compared to AP-5 infusion alone. Top [DA]_max after AP-5 (1 μg) and a cocktail of AP-5 (1 μg) plus α-ctx MII (171 ng) infusion. Bottom: [DA]_max time course after AP-5 and AP-5 + α-ctx MII infusion

Fig 6

Representative NAc carbon fiber placements as determined by post-experiment, 20 μA lesions in 40 – 50 μm coronal slices that were created at the recording site (Adapted from Paxinos and Watson 2007).