Figure (1).

Schematic illustration of the hypothesized effects of acute and chronic alcohol, both with and without topiramate, on the cortico-mesolimbic dopamine (DA) reward circuit [57]. (Upper left) Acute alcohol suppresses the firing rate of ventral tegmental area (VTA) gamma-aminobutyric acid (GABA) neurons, which leads to less suppression of VTA DA neuronal activity. This disinhibition leads to VTA DA neuronal firing and DA release in the nucleus accumbens (N Acc.) [57]. (Lower left) With chronic drinking, VTA GABA neurons are hyperexcitable, mainly because of increased glutamatergic input, less GABA tone from the N Acc., and rebound firing of GABA neurons because of their long-term suppression from repeated alcohol ingestion. This leads to VTA DA hypofunction and decreased release (compared with the acute condition) of DA in the N Acc. [57]. (Upper right) During acute drinking, the GABAergic influence of topiramate probably predominates, particularly in the N Acc. This leads to greater inhibition of N Acc. DA neurons, and greater GABA tone from the N Acc. to the VTA suppresses VTA DA cell firing. Topiramate concomitantly inhibits the excitatory effects of glutamatergic neurons on DA neurons in the VTA and N Acc. These combined actions of topiramate should lead to profound suppression of DA neuronal activity and DA release in the N Acc. Hence, topiramate reduces the DA-mediated reinforcing effects of acute alcohol [57]. (Lower right) During chronic drinking, the predominant neuronal activity resides with the hyperexcitable state of VTA GABA neurons. Because of GABA-mediated inhibition and glutamatergic blockade of these neurons, topiramate “normalizes” VTA GABA neuronal activity. Although this would, at first, suggest that DA release in the N Acc. would be enhanced, this does not occur, and DA release in the N Acc. is most likely reduced because these N Acc. terminals are contemporaneously inhibited by GABA inhibition and blockade of glutamate (GLU). In the chronic drinker, the anti-glutamatergic and L-type calcium channel effects of topiramate to block sensitization might predominate. Hence, topiramate would make it easier for a chronic alcoholic to withdraw from alcohol because rebound DA release would not occur (if drinking were ceased abruptly), and topiramate would aid in relapse prevention because alcohol's reinforcing effects would be decreased [57]. Line weights represent relative strengths of neuronal activity (heavy, medium, and light). The broken line represents decreased tone. VP, ventral pallidum. Reprinted from Johnson [57] with the permission of John Wiley & Sons, Inc.