Evidence that GABA(A) but not GABA(B) receptor activation in the dorsal raphe nucleus modulates ethanol intake in Wistar rats.
Injection of the GABA(A) agonist muscimol into the dorsal raphe nucleus produces a marked and selective increase in voluntary ethanol intake. The purpose of the present study was threefold: first, to demonstrate that the effect of muscimol on ethanol consumption is mediated by GABA(A) receptors; secondly, to test the generalizability of this effect by examining the effects of another GABA(A) agonist, THIP, on ethanol drinking; and finally, to examine whether GABA(B) receptors within the dorsal raphe also play a role in modifying voluntary ethanol consumption under the same experimental conditions. Rats were trained to drink a 12% ethanol solution in a limited access paradigm with water concurrently available. Muscimol (50ng) injected into the dorsal raphe enhanced intake by at least 100%. Peripheral administration of the GABA(A) antagonist bicuculline (4mg/kg), but not the 5-HT(1A) antagonist (+)- WAY100135 (1 and 3mg/kg), antagonized the stimulatory effect of muscimol at a dose which, when administered alone, did not alter ethanol intake. This supports the suggestion that the effect of muscimol is mediated via GABA(A) receptors. This conclusion was further supported by the finding that another GABA(A) agonist, THIP (500ng), also selectively increased ethanol intake in this paradigm. Injection of bicuculline (60ng) into the dorsal raphe reduced ethanol intake, but also appeared to reduce water intake. Finally, intra-dorsal raphe injection of the GABA(B) agonist baclofen (62.5 and 125ng) did not produce any change in ethanol or water consumption. Together, these findings suggest that enhancement of GABAergic activity in the dorsal raphe increased voluntary ethanol intake via activation of GABA(A) but not GABA(B) receptors.
Addiction Research Foundation, 33 Russell Street, Toronto, Ontario M5S 2S1, Canada.
D.M.
DM
Tomkins
P.J.
PJ
Fletcher