The Effect of mGluR5 Antagonism During Binge Drinking on Subsequent Ethanol Intake in C57BL/6J Mice: Sex‐ and Age‐Induced Differences

Abstract

Background Binge ethanol (EtOH) intake during adolescence leads to an array of behavioral and cognitive consequences including elevated intake of EtOH during adulthood, with female mice showing greater susceptibility than males. Administration of the metabotropic glutamate receptor 5 (mGluR5) antagonist 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) has been shown to reduce EtOH self-administration in adult male mice, but little is known about its effect on female and adolescent mice. Methods MTEP (0, 10, 20 mg/kg, i.p.) was repeatedly administered to female and male, adult and adolescent C57BL/6J mice during binge sessions using the scheduled high alcohol consumption paradigm. Next, we assessed whether MTEP administration during binge altered the subsequent 24-hour EtOH intake following a period of abstinence. Finally, we investigated whether MTEP administration during binge followed by an abstinence period altered mRNA of glutamatergic genes within the nucleus accumbens of female mice. Results MTEP significantly decreased binge EtOH intake in all mice, but only female mice exhibited altered subsequent 24-hour EtOH intake. Interestingly, the alteration in subsequent EtOH intake in female animals was age dependent, with adolescent exposure to MTEP during binge decreasing 24-hour intake and adult exposure to MTEP during binge increasing 24-hour intake. Finally, while there were no effects of MTEP pretreatment on the genes examined, there was a robust age effect found during analysis of mGluR1 (Grm1), mGluR5 (Grm5), the NR2A subunit of the NMDA receptor (Grin2a), phosphatidylinositol 3-kinase (Pik3r1), mammalian target of rapamycin (Mtor), and extracellular signal-regulated kinase (Mapk1) mRNA, with adolescent female animals having lower expression than their adult counterparts. Conclusions Collectively, the present findings add to existing evidence implicating the contribution of long-term effects of adolescent binge drinking to enhance alcohol abuse in adulthood, while suggesting that mGluR5 antagonism may not be the best pharmacotherapy to treat binge alcohol consumption in female and adolescent animals.

Functional regulation of PI3K-associated signaling in the accumbens by binge alcohol drinking in male but not female mice

“…Thus, the sex differences in the binge alcohol-induced down regulation in mGlu5 mRNA and protein might differentially alter the expression of multiple genes beyond those implicated in glutamatergic signaling. Related to this point, female mice were sensitive to the ability of an mGlu5 antagonist to decrease binge alcohol consumption (Cozzoli et al, 2014a), but they were insensitive to the ability of an antagonist of a molecule in the PI3K signaling cascade (i.e., rapamycin; mTOR inhibitor) to decrease binge drinking (present findings). These findings indicate that in female mice, an alternate signaling pathway that is independent of PI3K and that links group 1 mGlus to transcriptional changes in the nucleus (i.e., protein kinase A, calcium calmodulin dependent protein kinase, or mitogen-activated protein kinase (MAPK); see Wang and Zhuo, 2012) is influenced by repeated binge alcohol consumption.…”

“…Recent work found that mGlu5 antagonism decreased binge alcohol consumption in adult and adolescent male and female C57BL/6J mice, but that sex and age differences existed in the consequence of mGlu5 antagonism on later alcohol intake after a period of abstinence (Cozzoli et al, 2014a). Based on this result and reports that alcohol consumption in adolescent rodents can increase alcohol intake during adulthood (e.g., Broadwater et al, 2013; Moore et al, 2010; Strong et al, 2010), it is possible that male and female adult and adolescent mice have similar sensitivity to mGlu5 antagonists at the receptor level while the signaling downstream of mGlu5 might differ.…”

Sex and the Lab: An Alcohol‐Focused Commentary on the NIH Initiative to Balance Sex in Cell and Animal Studies

“…This study examined the biological implication of sexually divergent changes in the effect of repeated binge drinking on signaling molecules downstream of mGlu5 in adult male and female C57BL/6J mice (Figure 2A). Initial studies determined that the mGlu5 antagonist MTEP [3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine] was equally effective to decrease binge ethanol intake in male and female mice (Figure 2B), but that later ethanol intake after a period of abstinence was increased in females and unaltered in males (Cozzoli et al, 2014a). Thus, it is possible that male and female mice have similar sensitivity to mGlu5 antagonists at the receptor level while the signaling downstream of mGlu5 might differ between the sexes.…”

“…Values are the mean ± SEM for the number of animals on the figure. **p<0.01 versus respective saline group; adapted from (Cozzoli et al, 2014a). Panel C: Intra-accumbens rapamycin dose-dependently decreased binge ethanol intake during a 30-min binge session in male but not female mice, with a 28% decrease in binge ethanol intake following the 100 ng/side dose in male mice.…”

Rodent models and mechanisms of voluntary binge-like ethanol consumption: Examples, opportunities, and strategies for preclinical research

“…One of a handful of drugs currently approved to treat ethanol use disorders, acamprosate acts partly by blocking NMDA/metabotropic glutamate receptor (mGluR) signaling, and systemic administration significantly reduced DID ethanol intake in male B6 mice (Gupta et al, 2008). Systemic administration of mGluR5 antagonists reduces binge-like ethanol intake across multiple paradigms and mouse genotypes (Gupta et al, 2008; Tanchuck et al, 2011), however, a recent investigation suggests that their efficacy may be influenced by age and sex (Cozzoli et al, 2014b). Local infusion of an mGluR5 antagonist directly into the nucleus accumbens shell has also been shown to mirror this effect (Cozzoli et al, 2009).…”