Abstract
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.
Highlights
Compulsive drug use and associated maladaptive behaviors are cardinal features of methamphetamine (METH) addiction, and have been strongly associated with the neurochemical consequences of repeated METH abuse[1,2,3]
We evaluated the effect of the metabotropic glutamate receptor 5 (mGluR5) positive allosteric modulator (PAM) 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) and the mGluR5 negative allosteric modulator (NAM) fenobam on the expression of behavioral sensitization to METH
Locomotion was significantly elevated from Day 1 levels (2110 ± 284) on Day 5 (3117 ± 401, p < 0.05, Fisher’s LSD test) and Day 7 (3432 ± 433, p < 0.01), but not Day 9 (Figure 2A and Effect of mGluR5 modulation on locomotor sensitization to METH In the CDPPB experiment, rats with a history of repeated METH treatments exhibited a greater number of quarter turns following a probe injection of 0.5 mg/kg METH, evidence of locomotor sensitization (Figure 2C and Table S5–Table S6)
Summary
Compulsive drug use and associated maladaptive behaviors are cardinal features of methamphetamine (METH) addiction, and have been strongly associated with the neurochemical consequences of repeated METH abuse[1,2,3]. Among the various neurotransmitter systems affected by METH exposure is the glutamate system, where long-lasting drug-induced changes are suspected factors underlying craving and persistent vulnerability to relapse[4]. Due to their dual roles in mediating glutamatergic synaptic plasticity and control of synaptic glutamate release, the metabotropic glutamate receptors (mGluRs) have emerged as therapeutic targets of interest in the study of drug addiction[5]. Antagonizing the excitatory postsynaptic metabotropic glutamate receptor 5 (mGluR5) has been recently shown to attenuate the reinforcing effects of METH on a progressive ratio schedule, as well as attenuating drug-seeking behavior in rats previously trained to self-administer METH6. This study investigated the role of mGluR5 in the behavioral changes induced by repeated exposure to METH, using positive and negative allosteric modulators of mGluR5 function in separate experiments
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