The Effect of mGluR5 Antagonism During Binge Drinkingon Subsequent Ethanol Intake in C57BL/6J Mice: Sex- and Age-Induced Differences.
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.
Department of Behavioral Neuroscience (DKC, MNS-K, MAT, JGH, KMW, DAF), Oregon Health & Science University, Portland, Oregon; Department of Veterans Affairs Medical Research (JGH, KMW, DAF), Veterans Affairs Medical Center, Portland, Oregon; and Portland Alcohol Research Center (DAF), Portland, Oregon.
Debra K
DK
Cozzoli
Department of Behavioral Neuroscience (DKC, MNS-K, MAT, JGH, KMW, DAF), Oregon Health & Science University, Portland, Oregon; Department of Veterans Affairs Medical Research (JGH, KMW, DAF), Veterans Affairs Medical Center, Portland, Oregon; and Portland Alcohol Research Center (DAF), Portland, Oregon.
Moriah N
MN
Strong-Kaufman
Department of Behavioral Neuroscience (DKC, MNS-K, MAT, JGH, KMW, DAF), Oregon Health & Science University, Portland, Oregon; Department of Veterans Affairs Medical Research (JGH, KMW, DAF), Veterans Affairs Medical Center, Portland, Oregon; and Portland Alcohol Research Center (DAF), Portland, Oregon.
Michelle A
MA
Tanchuck
Department of Behavioral Neuroscience (DKC, MNS-K, MAT, JGH, KMW, DAF), Oregon Health & Science University, Portland, Oregon; Department of Veterans Affairs Medical Research (JGH, KMW, DAF), Veterans Affairs Medical Center, Portland, Oregon; and Portland Alcohol Research Center (DAF), Portland, Oregon.
Joel G
JG
Hashimoto
Department of Behavioral Neuroscience (DKC, MNS-K, MAT, JGH, KMW, DAF), Oregon Health & Science University, Portland, Oregon; Department of Veterans Affairs Medical Research (JGH, KMW, DAF), Veterans Affairs Medical Center, Portland, Oregon; and Portland Alcohol Research Center (DAF), Portland, Oregon.
Kristine M
KM
Wiren
Department of Behavioral Neuroscience (DKC, MNS-K, MAT, JGH, KMW, DAF), Oregon Health & Science University, Portland, Oregon; Department of Veterans Affairs Medical Research (JGH, KMW, DAF), Veterans Affairs Medical Center, Portland, Oregon; and Portland Alcohol Research Center (DAF), Portland, Oregon.
Deborah A
DA
Finn
D000367:Age Factors; D000818:Animals; D063425:Binge Drinking / Q000188:drug therapy* / Q000503:physiopathology; D000431:Ethanol / Q000008:administration & dosage* / Q000097:blood; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009714:Nucleus Accumbens / Q000737:chemistry; D011725:Pyridines / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000032:analysis; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D012737:Sex Factors; D013844:Thiazoles / Q000008:administration & dosage*
C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; C578936:Grm5 protein, mouse; D011725:Pyridines; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; D016194:Receptors, N-Methyl-D-Aspartate; D013844:Thiazoles; D000431:Ethanol
Adolescent; Adult; Alcohol; Glutamate; MTEP
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