Stoker_2012_Psychopharmacology.(Berl)_221_317

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.