Cellular and behavioral interactions of gabapentin with alcohol dependence.
Gabapentin is a structural analog of GABA that has anticonvulsant properties. Despite the therapeutic efficacy of gabapentin, its molecular and cellular mechanisms of action are unclear. The GABAergic system in the central nucleus of the amygdala (CeA) plays an important role in regulating voluntary ethanol intake. Here, we investigated the effect of gabapentin on GABAergic transmission in CeA slices, on ethanol intake, and on an anxiety measure using animal models of ethanol dependence. Gabapentin increased the amplitudes of evoked GABA receptor-mediated IPSCs (GABA-IPSCs) in CeA neurons from nondependent rats, but decreased their amplitudes in CeA of ethanol-dependent rats. Gabapentin effects were blocked in the presence of a specific GABA(B) receptor antagonist. The sensitivity of the GABA-IPSCs to a GABA(B) receptor antagonist and an agonist was decreased after chronic ethanol, suggesting that ethanol-induced neuroadaptations of GABA(B) receptors associated with ethanol dependence may account for the differential effects of gabapentin after chronic ethanol. Systemic gabapentin reduced ethanol intake in dependent, but not in nondependent, rats and reversed the anxiogenic-like effects of ethanol abstinence using an acute dependence model. Gabapentin infused directly into the CeA also blocked dependence-induced elevation in operant ethanol responding. Collectively, these findings show that gabapentin reverses behavioral measures of ethanol dependence and, in turn, dependence reverses the effects of gabapentin on CeA neurons, and suggest that gabapentin represents a potential medication for treatment of alcoholism.
Roberto
Marisa
M
Committee on the Neurobiology of Addictive Disorders, Pearson Center for Alcoholism and Addiction Research, The Scripps Research Institute, La Jolla, California 92037, USA. mroberto@scripps.edu
Gilpin
Nicholas W
NW
O'Dell
Laura E
LE
Cruz
Maureen T
MT
Morse
Andrew C
AC
Siggins
George R
GR
Koob
George F
GF
D000437:Alcoholism / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D000588:Amines / Q000494:pharmacology*; D000679:Amygdala / Q000473:pathology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000431:Ethanol / Q000008:administration & dosage / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D000077206:Gabapentin; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010721:Phosphinic Acids / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D000588:Amines; D002492:Central Nervous System Depressants; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D010721:Phosphinic Acids; D011412:Propanolamines; C085075:CGP 55845A; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin