Abstract
Racemic baclofen [(±)-baclofen] has repeatedly been reported to suppress several alcohol-motivated behaviors, including alcohol drinking and alcohol self-administration, in rats and mice. Recent data suggested that baclofen may have bidirectional, stereospecific effects, with the more active enantiomer, R(+)-baclofen, suppressing alcohol intake and the less active enantiomer, S(−)-baclofen, stimulating alcohol intake in mice. The present study was designed to investigate whether this enantioselectivity of baclofen effects may also extend to the reinforcing properties of alcohol in rats. To this end, selectively bred Sardinian alcohol-preferring (sP) rats were initially trained to lever respond on a fixed ratio 4 (FR4) schedule of reinforcement for alcohol (15%, v/v) in daily 30-min sessions. Once responding had stabilized, rats were tested with vehicle, (±)-baclofen (3 mg/kg), R(+)-baclofen (0.75, 1.5, and 3 mg/kg), and S(−)-baclofen (6, 12, and 24 mg/kg) under the FR4 schedule of reinforcement. Treatment with 3 mg/kg (±)-baclofen reduced the number of lever responses for alcohol and estimated amount of self-administered alcohol by approximately 60% in comparison to vehicle treatment. R(+)-baclofen was approximately twice as active as (±)-baclofen: treatment with 1.5 mg/kg R(+)-baclofen decreased both variables to an extent similar to that of the decreasing effect of 3 mg/kg (±)-baclofen. Conversely, treatment with all doses of S(−)-baclofen failed to affect alcohol self administration. These results (a) confirm that non-sedative doses of (±)-baclofen effectively suppressed the reinforcing properties of alcohol in sP rats and (b) apparently do not extend to operant alcohol self-administration in sP rats the capability of S(−)-baclofen to stimulate alcohol drinking in mice.
Highlights
Over the last 15 years, multiple lines of experimental evidence have demonstrated, with relatively few exceptions, that treatment with non-sedative doses of the prototypic GABAB receptor agonist, baclofen, suppressed several alcohol-related behaviors – including alcohol drinking, operant alcohol self-administration, reinstatement of alcohol-seeking behavior, and alcohol-induced conditioned place preference – in rats, mice, and monkeys [1,2,3]
Two recent studies demonstrated that acute treatment with the two baclofen enantiomers, R(+)-baclofen, and S(−)-baclofen, resulted in clearly opposite effects on alcohol drinking in mice: equal doses of the more active enantiomer, R(+)-baclofen, suppressed alcohol intake and of the less active enantiomer, S(−)-baclofen, stimulated alcohol intake in (a) C57BL/6J mice exposed to an experimental procedure inducing binge-like drinking and (b) selectively bred high alcohol preferring (HAP) mice exposed to chronic alcohol drinking [14, 15]; this differential effect was observed after both parenteral administration [15] and infusion into the shell of the nucleus accumbens [14] of the two baclofen enantiomers
Treatment with 3 mg/kg (±)-baclofen produced a reduction of approximately 60%, in comparison to vehicle treatment, in number of lever responses for alcohol (P < 0.005, Tukey’s test) (Figure 1, top panel)
Summary
Over the last 15 years, multiple lines of experimental evidence have demonstrated, with relatively few exceptions, that treatment with non-sedative doses of the prototypic GABAB receptor agonist, baclofen, suppressed several alcohol-related behaviors – including alcohol drinking, operant alcohol self-administration, reinstatement of alcohol-seeking behavior, and alcohol-induced conditioned place preference – in rats, mice, and monkeys [1,2,3]. Variability in baclofen effect on alcohol consumption and craving has been observed in clinical studies, both among different studies [reductions [36, 37]; lack of effect [38, 39]] and within the same cohort of patients [40]
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