Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence
The Journal of Neuroscience, May 28, 2008, 28(22):5762-5771
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.
Read Full AbstractRequest Reprint E-Mail: mroberto@scripps.edu
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