The metabotropic glutamate 5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine reduces ethanol self-administration in multiple strains of alcohol-preferring rats and regulates olfactory glutamatergic systems.
The metabotropic glutamate 5 receptor (mGlu5) receptor has been implicated as having a role in pain modulation, anxiety, and depression, as well as drug-seeking behavior. In the present study, we examined the effect of the selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) on operant ethanol self-administration by two strains of rats, the Fawn-Hooded (FH) rat and the inbred alcohol-preferring (iP) rat. MTEP (2 mg/kg i.p.) caused a significant reduction in responding for ethanol by both strains of rats; however, in the iP rats, MTEP also induced apparent sedation at this dose, although still reduced alcohol responding at lower doses. Chronic MTEP (2 mg/kg/day) caused a significant reduction in ethanol consumption by FH rats in a two-bottle preference test; however, chronic treatment with this dose had no effect on anxiety-like behavior or depressive-like behavior in FH rats, suggesting the dose used was subthreshold for anxiolytic or antidepressive-like effects. Finally, repeated dosing with MTEP (2 mg/kg i.p.) caused significant reductions in expression of the mRNA encoding the NR1 subunit of the N-methyl-D-aspartate receptor and the GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor in the cingulate cortex. A significant decrease in NR1 expression also occurred in the piriform cortex. Chronic MTEP also caused a significant decrease in mGlu5 gene expression and a significant increase in dopamine transporter and dopamine D(2)-like receptor binding within the olfactory tubercle. Collectively, these data suggest that MTEP can reduce alcohol-seeking behavior in different rodent models of alcoholism, and this effect is associated with regulation of cortical glutamate systems, particularly those in olfactory-related regions.
Cowen
Michael S
MS
Howard Florey Institute, Royal Parade, University of Melbourne, Victoria, Australia.
Djouma
Elvan
E
Lawrence
Andrew J
AJ
D000428:Alcohol Drinking / Q000235:genetics* / Q000523:psychology*; D000437:Alcoholism / Q000188:drug therapy* / Q000523:psychology; D000818:Animals; D001345:Autoradiography; D015415:Biomarkers; D001923:Brain Chemistry / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D003863:Depression / Q000188:drug therapy / Q000523:psychology; D004326:Drinking / Q000187:drug effects; D018698:Glutamic Acid / Q000502:physiology*; D017403:In Situ Hybridization; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012903:Smell / Q000187:drug effects* / Q000502:physiology*; D013550:Swimming / Q000523:psychology; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D015415:Biomarkers; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; D018698:Glutamic Acid