Tiagabine reduces ethanol reward in C57BL/6 mice under acute and chronic administration regimens

Abstract

Three experiments conducted on male C57BL/6 (B6) mice examined the effects of subcutaneous injections of the GABA uptake inhibitor, tiagabine, on appetitive (lever responding) and consummatory behavior (fountain contacts) of food restricted B6 mice for 12% ethanol and water rewards (Exp-1), and for food reward (Exp-2) delivered on a fixed ratio 4 schedule of reinforcement. Effects of acute injections (1,3,6,9 mgkg) and chronic administration (6,9 mg/kg) was examined. Exp-3 examined tiagabine effects on the voluntary consumption of continuously available 12% ethanol, and on the interactive effects of tiagabine and ethanol on motor activity of non-food restricted B6 mice. Results of Exp-1 and Exp-2 indicated that tiagabine can reduce appetitive behavior for ethanol reward with no evidence of tolerance upon chronic exposure. Tiagabine doses that reduced ethanol reward had less effect on behavior maintained by either water or food, and had no effect on motor activity. In contrast to the absence of tolerance to its effect on appetitive behavior for ethanol, mice rapidly developed tolerance to tiagabine's initial reduction of the consummatory response for ethanol (Exp-1), and the intake of freely available ethanol exceeded pre-tiagabine levels after several daily injections (Exp-3). Importantly, mice developed tolerance to tiagabine's sedative effect after three daily injections and its sedation was not enhanced when combined with ethanol, an effect consistent with the lack of a tiagabine + ethanol interaction previously reported for humans. The results of the experiments suggest that in addition to reducing alcohol withdrawal symptoms, tiagabine might also reduce the potency of ethanol-conditioned cues that drive appetitive behavior for ethanol.

Operant, oral alcoholic beer self-administration by C57BL/6J mice: effect of BHF177, a positive allosteric modulator of GABAB receptors

“…First is the use of freefed mice. Food restriction is a common strategy to increases rodents' operant responding in self-administration procedures (Caine et al, 1993;Elmer et al, 1986;Hayward et al, 2004;Heidbreder et al, 2007;Nguyen et al, 2005;Middaugh et al, 1999;Thomsen and Caine, 2007). However, the fact that this can alter the neurochemical pathways mediating drug-reinforcing properties is often overlooked: a 20-50% decrease in extracellular dopamine (DA) levels was observed in the nucleus accumbens (NAc) of food-restricted rats (Pothos et al, 1995).…”

Tiagabine does not attenuate alcohol-induced activation of the human reward system

“…In contrast, tiagabine increased the numbers of drugfree urines in two previous pilot trials on cocaine-dependent patients (Gonzalez et al 2003;Winhusen et al 2005). In addition, chronic tiagabine administration reduces appetitive behavior for ethanol in alcohol preferring C57BL/6J (B6) mice (Nguyen et al 2005). Thus and third, tiagabine's relapse prevention property might result independent of its effects within the mesolimbic dopamine system.…”

Effects of vigabatrin, an irreversible GABA transaminase inhibitor, on ethanol reinforcement and ethanol discriminative stimuli in mice

“…Mice were tested in chambers with stainless-steel grid floors enclosed in light- and sound-controlled boxes as previously described in detail (Middaugh et al , 1999a,b; Nguyen et al , 2005; Price et al , 2004). Briefly, the computer-controlled chambers recorded the number of presses at a single lever and licking behavior ( e.g.…”

“…For this experiment, mice were individually housed and maintained on a 12-hr reverse light/dark cycle, lights off from 11.00 to 23.00h and given 21 h of access daily to ethanol (12% v/v) with water as the alternative choice, in a procedure previously described in detail (Nguyen et al , 2005). The amounts of ethanol, water and food consumed were determined by weighing the food and the tubes containing either water or ethanol before and after the daily 21 h observation periods (08.00 h).…”