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
- Howard Florey Institute, University of Melbourne, Victoria, Australia (M.S.C., A.J.L.); and Department of Pharmacology, Monash University, Victoria, Australia (E.D.)
- Address correspondence to:
Dr. Andrew J. Lawrence, Howard Florey Institute, Royal Parade, University of Melbourne, Victoria 3010, Australia. E-mail: andrew.lawrence{at}hfi.unimelb.edu.au
Abstract
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 α-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 D2-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.
Footnotes
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These studies were supported by the National Health and Medical Research Council, Australia (program Grant 236805), of which A.J.L. is a Senior Research Fellow and M.S.C. is a C.J. Martin Fellow.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.090449.
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ABBREVIATIONS: mGlu5, metabotropic glutamate 5 receptor; CHPG, (R,S)-2-chloro-5-hydroxyphenylglycine; MPEP, 2-methyl-6-(phenylethynyl)-pyridine; MTEP, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine; LTP, long-term potentiation; FH, Fawn-Hooded rat; iP, inbred alcohol-preferring rat; DMSO, dimethyl sulfoxide; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate; NMDA, N-methyl-d-aspartate; [125I]RTI-55, 2β-carbomethoxy-3β-(4-iodophenyl)tropane; GBR12935, 1-(2-diphenylmethoxyethyl)-4-(3-phenylpropyl)piperazine; [125I]SCH23982, (1R)-(+)-1-phenyl-3-methyl-7-[125I]iodo-8-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine; SKF77434, (±)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; [125I]NCQ298, S(-)3-iodo-N-[(l′-ethyl-2′-pyrrolidinyl)]methyl-2-hydroxy-5,6-dimethoxybenzamide; DAT, dopamine transporter; NCQ634, S-N-[(1′-ethyl-2′-pyrrolidinyl)]methyl-2-hydroxy-5,6-dimethoxybenzamide.
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↵1 These authors contributed equally to this work.
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- Received June 2, 2005.
- Accepted July 12, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
