The mGluR5 antagonist MPEP decreases operant ethanol self-administration during maintenance and after repeated alcohol deprivations in alcohol-preferring (P) rats.
BACKGROUND
Recent research indicates that blockade of mGluR5 modifies the reinforcing properties of ethanol.


OBJECTIVE
The present studies examined the effects of mGluR5 receptor blockade in a genetic model of high ethanol intake, the alcohol-preferring (P) rat, on the maintenance of operant ethanol self-administration. In addition, we determined the effect of 2-methyl-6-(phenylethyl)-pyridine (MPEP) on the repeated alcohol deprivation effect.


METHODS
Twelve male (P) rats were trained in experimental sessions to self-administer 10% w/v ethanol via a sucrose-fading procedure. After the establishment of operant ethanol self-administration, subjects were treated with various metabotropic glutamate receptor (mGluR) subtype antagonists immediately prior to experimental sessions: the mGluR5 antagonist MPEP (1, 3, and 10 mg/kg); the mGluR2--3 antagonist LY-341495 (1, 3, and 10 mg/kg); and the mGluR1 antagonist CPCCOEt (1, 3, and 10 mg/kg). After determining the role of mGluR5 in the maintenance of operant ethanol self-administration, we examined the role of this receptor in relapse following repeated periods of alcohol deprivation by depriving subjects of ethanol exposure for three 2-week deprivation periods.


RESULTS
The mGluR5 antagonist MPEP dose-dependently decreased operant ethanol self-administration. In addition, rats that received saline immediately prior to repeated alcohol deprivation sessions self-administered ethanol at increasing levels that were above those achieved in the last operant-conditioning session prior to the initial 2-week deprivation period. This repeated alcohol deprivation effect was prevented in subjects pretreated with MPEP (10 mg/kg).


CONCLUSIONS
These findings suggest that mGluR5 receptors may modulate both the maintenance of operant ethanol self-administration and abstinence-induced increases in ethanol intake.
Schroeder
Jason P
JP
Department of Psychiatry and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Overstreet
David H
DH
Hodge
Clyde W
CW
D000428:Alcohol Drinking / Q000235:genetics* / Q000523:psychology*; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects*; D000431:Ethanol / Q000008:administration & dosage*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D011493:Protein Kinase C / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000502:physiology; D012054:Reinforcement, Psychology; D012646:Self Administration
D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D000431:Ethanol; C121465:6-methyl-2-(phenylethynyl)pyridine; D011493:Protein Kinase C
Brain Res Bull. 1993;30(1-2):133-41
8093596
Q J Stud Alcohol. 1968 Dec;29(4):863-7
5705408
Neuropsychopharmacology. 2005 Apr;30(4):747-57
15549054
Science. 2000 Jun 9;288(5472):1832-5
10846166
Alcohol Alcohol Suppl. 1987;1:91-6
3426760
Trends Pharmacol Sci. 2001 Jul;22(7):331-7
11431019
Alcohol Clin Exp Res. 1993 Apr;17(2):370-5
8098187
J Neurophysiol. 1997 Jul;78(1):63-75
9242261
J Neurosci. 1995 Oct;15(10):6879-89
7472445
Nat Neurosci. 2001 Sep;4(9):873-4
11528416
Synapse. 2003 Mar;47(3):240-2
12494407
Alcohol Clin Exp Res. 2001 May;25(5 Suppl ISBRA):132S-136S
11391062
Alcohol Clin Exp Res. 2002 Mar;26(3):386-93
11923593
Neuropsychopharmacology. 2001 Feb;24(2):97-129
11120394
Neuroscience. 2001;106(3):579-87
11591458
Mol Pharmacol. 2005 Feb;67(2):349-55
15548766
J Pharmacol Exp Ther. 2001 Oct;299(1):12-20
11561058
Neurochem Int. 1999 Aug;35(2):107-13
10405994
Mol Pharmacol. 1998 Jan;53(1):148-56
9443943
J Neurosci. 2004 May 19;24(20):4723-7
15152032
Behav Genet. 1993 Mar;23(2):231-6
8390239
Behav Genet. 2002 Sep;32(5):363-88
12405517
Psychopharmacology (Berl). 2004 Sep;175(3):310-8
15024550
Alcohol Clin Exp Res. 1998 Aug;22(5):1170-6
9726292
Cereb Cortex. 2004 Feb;14 (2):189-98
14704216
Pharmacol Biochem Behav. 1994 May;48(1):141-50
7913224
Eur J Pharmacol. 2001 Feb 9;413(1):81-9
11173066
Alcohol Clin Exp Res. 1986 Aug;10(4):436-42
3530023
Alcohol Res Health. 2000;24(2):124-31
11199279
Pharmacol Biochem Behav. 1996 Apr;53(4):971-7
8801605
Neuropsychopharmacology. 2004 Jul;29(7):1259-69
15010696
Eur J Neurosci. 2002 Dec;16(11):2241-4
12473093
Drug News Perspect. 2004 May;17 (4):251-7
15334174
Alcohol Alcohol Suppl. 1993;2:353-8
7538302
Pharmacol Biochem Behav. 2002 Sep;73(2):375-80
12117592
Br J Pharmacol. 1996 Jun;118(4):1035-43
8799579
J Biol Chem. 2003 Jul 25;278(30):27742-9
12740378
Neuroreport. 1996 Sep 2;7(13):2115-8
8930970
Prog Neurobiol. 1999 Sep;59(1):55-79
10416961
Neurotoxicology. 2001 Oct;22(5):601-5
11770881
Pharmacol Biochem Behav. 2002 Sep;73(2):359-66
12117590
J Neurophysiol. 2001 Nov;86(5):2405-12
11698530
Psychopharmacology (Berl). 2003 May;167(3):257-64
12682710
J Pharmacol Exp Ther. 1986 Apr;237(1):92-8
3007745
Alcohol. 1989 Nov-Dec;6(6):505-9
2597353
Neuropharmacology. 2002 Dec;43(8):1199-209
12527469
Alcohol Clin Exp Res. 2000 May;24(5):706-15
10832913
Life Sci. 1995 Mar 17;56(17):1373-83
8847948
Neuroscience. 2001;106(3):481-503
11591452
Neuropsychopharmacology. 2004 May;29(5):921-8
14735132
Alcohol Clin Exp Res. 1997 Sep;21(6):1083-91
9309321
Neuropharmacology. 1995 Jan;34(1):1-26
7623957
Br J Pharmacol. 2001 Apr;132(7):1423-30
11264235
Biochem J. 2001 Nov 1;359(Pt 3):465-84
11672421
Brain Res. 1997 Oct 31;773(1-2):82-9
9409708
Psychopharmacology (Berl). 1992;109(1-2):92-8
1365677
Neuropsychopharmacology. 2003 Sep;28(9):1614-21
12799615
Neurochem Int. 1999 Aug;35(2):115-23
10405995
Neuroreport. 2000 Nov 9;11(16):3611-4
11095529
Mol Chem Neuropathol. 1998 Feb;33(2):99-111
9565968
Vis Neurosci. 2000 May-Jun;17 (3):473-82
10910113
Neurochem Int. 2000 Nov-Dec;37(5-6):509-33
10871702
N Engl J Med. 2001 Dec 13;345(24):1734-9
11742047
J Neurosci. 2002 Nov 15;22(22):9679-86
12427823
Stress. 2003 Sep;6(3):189-97
13129812
J Pharmacol Exp Ther. 2000 Feb;292(2):545-52
10640291
Neuropharmacology. 2002 Dec;43(8):1210-7
12527470