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The Journal of Neuroscience, May 28, 2008, 28(22):5762-5771; doi:10.1523/JNEUROSCI.0575-08.2008

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Behavioral/Systems/Cognitive
Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence

Marisa Roberto,^1,3 Nicholas W. Gilpin,¹ Laura E. O'Dell,⁴ Maureen T. Cruz,¹ Andrew C. Morse,⁵ George R. Siggins,² and George F. Koob^1,3

¹Committee on the Neurobiology of Addictive Disorders, ²Department of Molecular and Integrative Neurosciences, and ³Pearson Center for Alcoholism and Addiction Research, The Scripps Research Institute, La Jolla, California 92037, ⁴Department of Psychology, University of Texas at El Paso, El Paso, Texas 79902, and ⁵BrainCells, San Diego, California 92121

Correspondence should be addressed to Dr. Marisa Roberto, The Scripps Research Institute, SP-30-1160, 10550 North Torrey Pines Road, La Jolla, CA 92037. Email: mroberto{at}scripps.edu

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.

Key words: amygdala; ethanol dependence; IPSC; paired-pulse facilitation; anxiety; ethanol-self administration

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Received Jan. 17, 2007; revised April 21, 2008; accepted April 21, 2008.

Correspondence should be addressed to Dr. Marisa Roberto, The Scripps Research Institute, SP-30-1160, 10550 North Torrey Pines Road, La Jolla, CA 92037. Email: mroberto{at}scripps.edu

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