Involvement of metabotropic glutamate receptor 5 in brain reward deficits associated with cocaine and nicotine withdrawal and somatic signs of nicotine withdrawal

Abstract

Rationale: The involvement of metabotropic glutamate 5 (mGlu5) receptors has been suggested in the reinforcing effects of psychostimulants. However, little is known about the role of these receptors in psychostimulant withdrawal.

Objectives: The role of mGlu5 receptors was assessed in the anhedonic and somatic aspects of psychostimulant withdrawal.

Methods: Anhedonia was assessed with the discrete-trial current-intensity intracranial self-stimulation (ICSS) procedure after the termination of cocaine (180 mg kg(-1) day(-1), salt, 3 days, i.p.) or nicotine (40 mg kg(-1) day(-1), base, 28 days, s.c.) administration via osmotic minipumps in mGlu5 receptor knockout (mGluR5(-/-)) and wild-type (mGluR5(+/+)) mice. Somatic signs were assessed during nicotine withdrawal. The effects of the nicotinic acetylcholine receptor antagonist mecamylamine on ICSS thresholds were assessed during chronic nicotine administration.

Results: Nicotine-treated mGluR5(+/+) and mGluR5(-/-) mice demonstrated similar threshold elevations during mecamylamine-precipitated withdrawal compared with their saline-treated counterparts. During spontaneous nicotine and cocaine withdrawal, thresholds in drug-withdrawing mGluR5(+/+), but not mGluR5(-/-), mice were elevated up to 72 h of nicotine/cocaine withdrawal and then returned to baseline, indicating attenuation of withdrawal-induced anhedonia in mGluR5(-/-) mice. Nicotine-withdrawing mGluR5(+/+), but not mGluR5(-/-), mice showed increases in somatic signs compared with saline-treated counterparts.

Conclusions: mGlu5 receptor null mutation attenuates the anhedonic and somatic effects of psychostimulant withdrawal. This attenuated withdrawal in mGluR5(-/-) mice may result from the lack of drug-induced adaptations in mGlu5 receptor function that may occur in mGluR5(+/+) mice with chronic drug administration. Thus, these results suggest the involvement of mGlu5 receptors in psychostimulant dependence and the mediation of the anhedonic and somatic signs of psychostimulant withdrawal.

Figure 1

Effects of chronic cocaine/saline administration and withdrawal on ICSS thresholds in mGluR5^-/- and mGluR5^+/+ mice. The data are expressed as a percentage of baseline thresholds (mean ± SEM). (A) Effects of chronic cocaine/saline administration (180 mg/kg/day, base, 3 days) on ICSS thresholds in mGluR5^-/- and mGluR5^+/+ mice. Asterisk indicates a significant difference between saline- and cocaine-treated mGluR5^+/+ mice (*p < 0.05). Pound sign indicates a significant difference between saline- and cocaine-treated mGluR5^-/- mice (^#p < 0.05). (B) Effects of cocaine/saline withdrawal on ICSS thresholds in mGluR5^-/- and mGluR5^+/+ mice. Asterisks (**p < 0.01) indicate a significant differences between cocaine- and saline-treated mGluR5^+/+ mice at a specific time-point using Newman-Keuls post hoc comparisons after a significant Genotype × Cocaine/Saline Exposure interaction effect. Thresholds in cocaine-withdrawing mGluR5^+/+ mice were significantly elevated compared with their saline-treated counterparts at 3-6 h, 8-12 h, 24-28 h, 48-52 h, and 120 h after pump removal (p < 0.01). Pound signs (^#p < 0.05, ^##p < 0.01) indicate significant differences between cocaine-treated mGluR5^+/+ and mGluR5^-/- mice at 3-6 h (p < 0.01) and 8-12 h (p < 0.05). Inset to B: Area-under-the-curve calculated as the sum of threshold values 3-120 h post-pump removal. Newman-Keuls post hoc analysis after a significant Genotype × Nicotine/Saline Exposure interaction demonstrated a significant elevation of thresholds in cocaine-withdrawing mGluR5^+/+ mice compared with cocaine-withdrawing mGluR5^-/- mice (*p < 0. 05) and saline-treated mGluR5^+/+ mice (**p < 0.01).

Figure 2

Effects of chronic nicotine/saline administration, and precipitated and spontaneous nicotine withdrawal on ICSS thresholds in mGluR5^-/- and mGluR5^+/+ mice. The data are expressed as a percentage of baseline thresholds (mean ± SEM). (A) Effects of chronic nicotine/saline administration (40 mg/kg/day, base, 28 days) on ICSS thresholds in mGluR5^-/- and mGluR5^+/+ mice. ANOVA indicated a significant Genotype × Nicotine/Saline Exposure × Administration Day interaction, but post hoc analyses did not reveal significant differences in ICSS thresholds between the experimental groups at any time point. (B) Effects of mecamylamine-precipitated nicotine/saline withdrawal on ICSS thresholds in mGluR5^-/- and mGluR5^+/+ mice. Asterisks (**p < 0.01) indicate a significant main effect of Mecamylamine in an ANOVA. (C) Effects of spontaneous nicotine/saline withdrawal on ICSS thresholds in mGluR5^-/- and mGluR5^+/+ mice. Asterisks (*p < 0.05 and **p < 0.01) indicate significant differences between nicotine- and saline-treated mGluR5^+/+ mice at specific time-points with pre-planned comparisons after an ANOVA indicate a significant main effect of Nicotine/Saline Exposure (^##p < 0.01). Nicotine-withdrawing mGluR5^+/+ mice exhibited elevated thresholds compared with saline-treated mGluR5^+/+ mice. Although no statistically significant difference was found between nicotine-withdrawing mGluR5^-/- mice and mGluR5^+/+ mice, thresholds in mGluR5^-/- mice did not differ significantly from thresholds in their saline-treated counterparts. Inset to C: Area-under-the-curve calculated as the sum of threshold values exhibited 3-100 h post-pump removal. Asterisks indicate a significant elevation of the area-under-the-curve in nicotine-withdrawing mGluR5^+/+ mice compared with saline-treated controls (*p < 0.05) with pre-planned analyses after an ANOVA revealed a significant main effect of Nicotine/ Saline Exposure.

Figure 3

Somatic signs at 24 h of nicotine/saline withdrawal in mGluR5^-/- and mGluR5^+/+ mice. The data are represented as mean ± SEM. Asterisks indicate a significant difference between saline- and nicotine-treated mGluR5^+/+ mice (*p < 0.05) and between nicotine-treated mGluR5^-/- and mGluR5^+/+ mice (**p < 0.01) with pre-planned comparisons after significant main effects of Genotype (p < 0.01) and Nicotine/Saline Exposure (p < 0.05) in an ANOVA.