Metabotropic glutamate 2/3 receptors in the ventral tegmental area and the nucleus accumbens shell are involved in behaviors relating to nicotine dependence

Abstract

The motivation to maintain nicotine self-administration and dependence may involve alterations in glutamatergic neurotransmission. Metabotropic glutamate (mGlu) 2/3 receptors regulate glutamate and dopamine release in the ventral tegmental area (VTA) and the nucleus accumbens (NAc) shell, two brain areas critically involved in reward and motivational processes. We found that acute systemic, as well as intra-VTA or intra-NAc, administration of the mGlu2/3 receptor agonist LY379268 [(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate] decreased nicotine, but not food, self-administration in rats. In addition, nicotine self-administration downregulated mGlu2/3 receptor function in corticolimbic rat brain sites including the VTA and the NAc, demonstrated by decreased coupling of mGlu2/3 receptors to G-proteins in the [35S]GTPgammaS binding assay. Furthermore, repeated treatment with LY379268 reduced nicotine self-administration at the beginning of a 14 d treatment period; however, the number of nicotine infusions earned gradually returned to baseline levels, indicating tolerance to the effects of repeated LY379268 treatment. Finally, LY379268 administration decreased both cue-induced reinstatement of nicotine- and food-seeking behavior. Together, these findings indicate an important role for mGlu2/3 receptors in the posterior VTA and the NAc shell in the mediation of the rewarding effects of nicotine and potentially in cue-induced nicotine-seeking behavior.

Figure 1.

Diagrams of coronal sections from the rat brain (Paxinos and Watson, 1998). Black circles indicate histologically confirmed locations of injector tips inside the NAc shell (bregma 1.70–1.60 mm) and the VTA (bregma −5.80 to −6.72 mm).

Figure 2.

Systemic LY379268 injection decreased nicotine (A, black bars; n = 7, timeout 20 s) but not food self-administration, except at the highest LY379268 dose (A, white bars; n = 8, timeout 210 s). LY379268 injection into the NAc shell (B; n = 9) or the VTA (C; n = 9) decreased nicotine self-administration. Control injection of 1 μg of LY379268 2 mm above the NAc shell into the lateral septal nucleus had no effect on nicotine self-administration (B; Co, control injection; n = 9). Injection of 0.6 μg 2 mm above the VTA into the red nucleus had no effect on nicotine self-administration (C; Co, control injection; n = 7). Number of food pellets earned after systemic LY379268 (D; n = 8), intra-NAc shell (E; n = 9), or intra-VTA (F; n = 9) injection under the FR5 TO20 s schedule of reinforcement. *p < 0.05, **p < 0.01, ***p < 0.001, different from 0 mg/kg LY379268; ⁺p < 0.05, different from 1 mg/kg LY379268. ^#p < 0.06, ^##p < 0.001, different from control injection.

Figure 3.

Effects of repeated LY379268 administration on nicotine and food self-administration. A, LY379268 (1 mg/kg) decreased nicotine self-administration (*p < 0.05, **p < 0.01, ***p < 0.001, different from vehicle condition, LY379268 at 0 mg/kg; ⁺p < 0.05, ⁺⁺p < 0.01, ⁺⁺⁺ p < 0.001, different from baseline responding), but tolerance developed over the 14 d period (n = 12 per dose). B, LY379268 (1 mg/kg) had no effect on food-maintained responding (n = 8 per dose). Line under data points (days 1–14) depicts the days when LY379268 administration occurred. B, Baseline responding (mean of preceding 3 days) and responding on days after LY379268 administration.

Figure 4.

Effects of nicotine and LY379268 on functional coupling of mGlu2/3 receptors to G-proteins. Stimulation of [³⁵S]GTPγS binding by the mGlu2/3 receptor agonist LY354740 was significantly decreased in rats self-administering nicotine compared with animals responding for food, suggesting mGlu2/3 receptor downregulation in all assessed brain areas (LY354740 × reward interactions; ^#p < 0.05, ^###p < 0.001; *p < 0.05, **p < 0.01, ***p < 0.001, different from food). Repeated LY379268 administration also decreased [³⁵S]GTPγS binding in the prefrontal cortex and increased [³⁵S]GTPγS binding in the nucleus accumbens and amygdala (LY354740 × LY379268 interactions, ^†p < 0.05, ^†††p < 0.001; ⁺p < 0.05, ⁺⁺p < 0.01, ⁺⁺⁺p < 0.001, different from food). Data represent mean ± SEM; n = 6.

Figure 5.

Effects of LY379268 on cue-induced reinstatement of nicotine and food seeking. LY379268 blocked reinstatement for both nicotine (A; n = 32; within-subject comparison) and food (B; n = 10 per dose; between-subject comparison) seeking. A, Inset, Reinstatement for nicotine seeking for the first of the four reinstatement test sessions (n = 8 per dose; between-subjects comparison; for details, see Materials and Methods). ⁺p < 0.05, ⁺⁺p < 0.01, different from extinction. *p < 0.5, ***p < 0.001, different from 0 mg/kg LY379268. EXT, Extinction; Responses, total of active lever presses including responses during the cue presentation.