The group II metabotropic glutamate receptor agonist LY379268 reduces toluene-induced enhancement of brain-stimulation reward and behavioral disturbances

Abstract

Toluene, a widely abused solvent with demonstrated addictive potential in humans, has been reported to negatively modulate N-methyl-D-aspartate receptors (NMDARs) and alter glutamatergic neurotransmission. The group II metabotropic glutamate receptor (mGluR) agonist LY379268 has been shown to regulate glutamate release transmission and NMDAR function and block toluene-induced locomotor hyperactivity. However, remaining unknown is whether group II mGluRs are involved in the toluene-induced reward-facilitating effect and other behavioral manifestations. The present study evaluated the effects of LY379268 on toluene-induced reward enhancement, motor incoordination, recognition memory impairment, and social interaction deficits. Our data demonstrated that LY379268 significantly reversed the toluene-induced lowering of intracranial self-stimulation (ICSS) thresholds and impairments in novel object recognition, rotarod performance, and social interaction with different potencies. These results indicate a negative modulatory role of group II mGluRs in acute toluene-induced reward-facilitating and behavioral effects and suggest that group II mGluR agonists may have therapeutic potential for toluene addiction and the prevention of toluene intoxication caused by occupational or intentional exposure.

Negative allosteric modulation of GABAA receptors inhibits facilitation of brain stimulation reward by drugs of abuse in C57BL6/J mice

“…As expected based on prior studies, methamphetamine, toluene and diazepam all significantly facilitated ICSS responding (Robinson et al 2012; Chan et al 2012; Bauer et al 2013; Tracy et al 2014; Chan et al 2015). Methamphetamine and toluene vapor produced comparably robust ICSS facilitation whereas the effect of diazepam on ICSS was modest relative to previous studies (Straub et al 2010; Tracy et al 2014).…”

The Role of Metabotropic Glutamate Receptors in Social Behavior in Rodents

“…Anxiolytic-like effects of LY354740 have also been reported in social contexts, where pretreatment with LY354740 prevented sodium-lactate-induced decrease in social interaction in rats [91] (Table 1). Another mGluR2/3 agonist, LY379268, reversed the deficits in social interaction induced by toluene [92] and by prenatal repeated episodes of restraint stress in mice [93]. These prenatally restrained mice also showed decreased mGluR2 and mGluR3 mRNA and protein levels in the frontal cortex, which could be normalized by LY379268 [93].…”