BNST specific mGlu5 receptor knockdown regulates sex-dependent expression of negative affect produced by adolescent ethanol exposure and adult stress

Adolescent alcohol use is one of the strongest predictors for the development of an alcohol use disorder (AUD). Notably, this period of risk coincides with the development of affective disorders, which disproportionately impact and drive problematic drinking behavior in women. Stress is a particularly salient factor that drives relapse during periods of abstinence. Previous work in our lab has shown that adolescent intermittent ethanol vapor (AIE) produces sex-dependent changes in glutamatergic activity in the bed nucleus of the stria terminalis (BNST) and behavioral outcomes following acute restraint stress in adulthood. In females, AIE disrupts group 1 metabotropic glutamate (mGlu1/5) receptor activity and enhances anhedonia-like behavior. The current study site-specifically knocked down mGlu5 receptors in the BNST of male and female Grm5loxp mice, exposed them to AIE, and observed the interaction of AIE and stress on negative affect-like behaviors in adulthood. These negative affect-like behaviors included the novelty-induced hypophagia task following acute restraint stress, open field activity, and contextual fear conditioning. Overall, we replicated our previous findings that AIE enhanced anhedonia-like activity in the novelty-induced hypophagia task in females and fear acquisition in males. The primary effect of BNST-mGlu5 receptor knockdown was that it independently enhanced anhedonia-like activity in females. Correlation analyses revealed that behavior in these paradigms showed poor interdependence. These results indicate that preclinical models of negative affective-like states encompass distinct features that may have independent, clinically relevant mechanisms. Further, modulating mGlu5 receptors is a prospective treatment target for females experiencing anhedonic-like states that make them susceptible to alcohol relapse.

Effects of the Positive Allosteric Modulator of Metabotropic Glutamate Receptor 5, VU-29, on Maintenance Association between Environmental Cues and Rewarding Properties of Ethanol in Rats

Metabotropic glutamate subtype 5 (mGlu5) receptors are implicated in various forms of synaptic plasticity, including drugs of abuse. In drug-addicted individuals, associative memories can drive relapse to drug use. The present study investigated the potential of the mGlu5 receptor positive allosteric modulator (PAM), VU-29 (30 mg/kg, i.p.), to inhibit the maintenance of a learned association between ethanol and environmental context by using conditioned place preference (CPP) in rats. The ethanol-CPP was established by the administration of ethanol (1.0 g/kg, i.p. ×10 days) using an unbiased procedure. Following ethanol conditioning, VU-29 was administered at various post-conditioning times (ethanol free state at the home cage) to ascertain if there was a temporal window during which VU-29 would be effective. Our experiments indicated that VU-29 did not affect the expression of ethanol-induced CPP when it was given over two post-conditioning days. However, the expression of ethanol-CPP was inhibited by 10-day home cage administration of VU-29, but not by first 2-day or last 2-day injection of VU-29 during the 10-day period. These findings reveal that VU-29 can inhibit the maintenance of ethanol-induced CPP, and that treatment duration contributes to this effect of VU-29. Furthermore, VU-29 effect was reversed by pretreatment with either MTEP (the mGlu5 receptor antagonist), or MK-801 (the N-methyl-D-aspartate-NMDA receptor antagonist). Thus, the inhibitory effect of VU-29 is dependent on the functional interaction between mGlu5 and NMDA receptors. Because a reduction in ethanol-associated cues can reduce relapse, mGlu5 receptor PAM would be useful for therapy of alcoholism. Future research is required to confirm the current findings.

mGlu5 receptor availability in youth at risk for addictions: effects of vulnerability traits and cannabis use

The excitatory neurotransmitter glutamate has been implicated in experience-dependent neuroplasticity and drug-seeking behaviors. Type 5 metabotropic glutamate (mGlu5) receptors might be particularly important. They are critically involved in synaptic plasticity and their availability has been reported to be lower in people with alcohol, tobacco, and cocaine use disorders. Since these reductions could reflect effects of drug use or pre-existing traits, we used positron emission tomography to measure mGlu5 receptor availability in young adults at elevated risk for addictions. Fifty-nine participants (age 18.5 ± 0.6) were recruited from a longitudinal study that has followed them since birth. Based on externalizing traits that predict future substance use problems, half were at low risk, half were at high risk. Cannabis use histories varied markedly and participants were divided into three subgroups: zero, low, and high use. Compared to low risk volunteers, those at elevated risk had lower [11C]ABP688 binding potential (BPND) values in the striatum, amygdala, insula, and orbitofrontal cortex (OFC). Cannabis use by risk group interactions were observed in the striatum and OFC. In these regions, low [11C]ABP688 BPND values were only seen in the high risk group that used high quantities of cannabis. When these high risk, high cannabis use individuals were compared to all other participants, [11C]ABP688 BPND values were lower in the striatum, OFC, and insula. Together, these results provide evidence that mGlu5 receptor availability is low in youth at elevated risk for addictions, particularly those who frequently use cannabis.