Positive or negative allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) does not alter expression of behavioral sensitization to methamphetamine.

We investigated the role of metabotropic glutamate receptor type 5 (mGluR5) in methamphetamine-induced behavioral sensitization. The mGluR5 positive allosteric modulator (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) and negative allosteric modulator fenobam were tested in separate experiments. Sprague-Dawley rats were repeatedly injected with 1 mg/kg methamphetamine or saline, and then given a locomotor challenge test using a dose of 0.5 mg/kg methamphetamine. Prior to the challenge test session, rats were injected with CDPPB, fenobam, or a vehicle.  Doses from previous studies showed reduced drug-conditioned behavior; however in this study neither CDPPB nor fenobam pretreatment resulted in an altered expression of behavioral sensitization, indicating a lack of mGluR5 involvement in sensitized methamphetamine-induced locomotion. Additionally, the high dose (30 mg/kg) of fenobam resulted in decreased methamphetamine-induced locomotion in rats regardless of drug exposure history, which suggests evidence of nonspecific behavioral inhibition.

Attenuation of methamphetamine seeking by the mGluR2/3 agonist LY379268 in rats with histories of restricted and escalated self-administration.

Recent findings implicate group II metabotropic glutamate receptors (mGluR(2/3)) in the reinforcing effects of psychostimulants and have identified these receptors as potential treatment targets for drug addiction. Here, we investigated the effects of mGluR(2/3) stimulation on cue- and drug-primed reinstatement in rats with different histories of methamphetamine (METH) self-administration training, under two conditions: 16 daily sessions of short access (90 min/day, ShA), or 8 daily sessions of short access followed by 8 sessions of long access (6 h/day, LgA). Following self-administration and subsequent extinction training, rats were pretreated with the selective mGluR(2/3) agonist LY379268 (variable dose, 0-3 mg/kg), exposed to METH-paired cues or a priming injection of METH (1 mg/kg), and tested for reinstatement of METH-seeking behavior. LgA rats self-administered greater amounts of METH during the second half of training, but when pretreated with vehicle, ShA and LgA rats showed cue- and drug-primed reinstatement at equivalent response rates. However, LgA rats demonstrated greater sensitivity to mGluR(2/3) stimulation with attenuated responding during cue-induced reinstatement after 0.3 mg/kg and higher doses of LY379268, whereas ShA rats decreased cue-induced reinstatement behavior following 1.0 mg/kg and 3.0 mg/kg LY379268. Additionally, both LgA and ShA rats exhibited decreased METH-primed reinstatement behavior following 0.3 mg/kg and higher doses of LY379268. A separate group of control rats was trained to self-administer sucrose pellets, and demonstrated attenuated cue-induced sucrose-seeking behavior following 1.0 and 3.0 mg/kg LY379268. Together, the results indicate that LY379268 has differential attenuating effects on cue-induced reinstatement behavior in rats with different histories of METH intake. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.