Behavioral and neurochemical interactions between Group 1 mGluR antagonists and ethanol: potential insight into their anti-addictive properties.
Blockade of the mGluR5 subtype of Group 1 metabotropic glutamate receptor (mGluRs) reduces the rewarding effects of ethanol (EtOH), while the effects of mGluR1a blockade remain under-investigated. The present study compared the effects of pretreatment with the mGluR5 antagonist MPEP and the mGluR1a antagonist CPCCPOEt upon behavioral and neurochemical variables associated with EtOH reward in alcohol-preferring C57BL/6J mice. Pretreatment with either antagonist (0-10 mg/kg, IP) dose-dependently reduced measures of EtOH reward in an operant self-administration paradigm and the maximally effective antagonist dose (10 mg/kg) also blocked the expression of EtOH-induced place conditioning, as well as EtOH consumption under 24-h free-access conditions. MPEP pretreatment did not significantly alter the EtOH dose-locomotor response function; however, it prevented EtOH-induced changes in extracellular dopamine, glutamate and GABA in the nucleus accumbens (NAC). In contrast, CPCCOEt shifted the EtOH dose-response function downwards, enhanced the capacity of higher EtOH doses to elevate NAC levels of GABA and lowered extracellular dopamine and glutamate below baseline following EtOH injection. It is suggested that the "anti-alcohol" effects of MPEP may involve an attenuation of the neurochemical signals mediating EtOH reward, whereas those of CPCCOEt may involve an increased sensitivity to the inhibitory effects of EtOH upon brain and behavior.
Lominac
Kevin D
KD
Department of Psychology, University of California Santa Barbara, Santa Barbara, CA 93106-9660, USA.
Kapasova
Zuzana
Z
Hannun
Reem A
RA
Patterson
Cole
C
Middaugh
Lawrence D
LD
Szumlinski
Karen K
KK
D000427:Alcohol Deterrents / Q000494:pharmacology*; D000437:Alcoholism / Q000503:physiopathology*; D000818:Animals; D002867:Chromones / Q000494:pharmacology*; D003214:Conditioning, Classical / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C117789:7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; D000427:Alcohol Deterrents; D002867:Chromones; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D000431:Ethanol; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C121465:6-methyl-2-(phenylethynyl)pyridine; D004298:Dopamine