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R(+)-Baclofen, but Not S(-)-Baclofen, Alters Alcohol Self-Administration in Alcohol-Preferring Rats.

Lorrai I, Maccioni P, Gessa GL, Colombo G - Front Psychiatry (2016)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Institute, National Research Council of Italy - Cagliari Section , Monserrato , Italy.

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.

No MeSH data available.


Effect of treatment with racemic baclofen [(±)-baclofen], R(+)-baclofen, and S(−)-baclofen on number of lever responses for alcohol (top panel) and estimated amount of self-administered alcohol (bottom panel) in selectively bred Sardinian alcohol-preferring (sP) rats. Rats were initially trained to lever respond for oral alcohol (15% v/v, in water) [fixed ratio 4 (FR4)] and water (FR1) in daily 30-min sessions. Test session was conducted under the above FR schedules of reinforcement. Each bar is the mean ± SEM of n = 12 rats. *P < 0.05, **P < 0.005, and ***P < 0.0001 in comparison to vehicle-treated rats (Tukey’s test).
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Figure 1: Effect of treatment with racemic baclofen [(±)-baclofen], R(+)-baclofen, and S(−)-baclofen on number of lever responses for alcohol (top panel) and estimated amount of self-administered alcohol (bottom panel) in selectively bred Sardinian alcohol-preferring (sP) rats. Rats were initially trained to lever respond for oral alcohol (15% v/v, in water) [fixed ratio 4 (FR4)] and water (FR1) in daily 30-min sessions. Test session was conducted under the above FR schedules of reinforcement. Each bar is the mean ± SEM of n = 12 rats. *P < 0.05, **P < 0.005, and ***P < 0.0001 in comparison to vehicle-treated rats (Tukey’s test).

Mentions: 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). Treatment with 0.75, 1.5, and 3 mg/kg R(+)-baclofen produced a dose-related reduction in number of lever responses for alcohol, reaching statistical significance at the doses of 1.5 (P < 0.05, Tukey’s test) and 3 (P < 0.0001, Tukey’s test) mg/kg, in correspondence of which the magnitude of the reducing effect – in comparison to vehicle treatment – averaged approximately 50 and 80%, respectively (Figure 1, top panel). Conversely, treatment with 6, 12, and 24 mg/kg S(−)-baclofen did not alter, in comparison to vehicle treatment, the number of lever responses for alcohol (Figure 1, top panel).


R(+)-Baclofen, but Not S(-)-Baclofen, Alters Alcohol Self-Administration in Alcohol-Preferring Rats.

Lorrai I, Maccioni P, Gessa GL, Colombo G - Front Psychiatry (2016)

Effect of treatment with racemic baclofen [(±)-baclofen], R(+)-baclofen, and S(−)-baclofen on number of lever responses for alcohol (top panel) and estimated amount of self-administered alcohol (bottom panel) in selectively bred Sardinian alcohol-preferring (sP) rats. Rats were initially trained to lever respond for oral alcohol (15% v/v, in water) [fixed ratio 4 (FR4)] and water (FR1) in daily 30-min sessions. Test session was conducted under the above FR schedules of reinforcement. Each bar is the mean ± SEM of n = 12 rats. *P < 0.05, **P < 0.005, and ***P < 0.0001 in comparison to vehicle-treated rats (Tukey’s test).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834306&req=5

Figure 1: Effect of treatment with racemic baclofen [(±)-baclofen], R(+)-baclofen, and S(−)-baclofen on number of lever responses for alcohol (top panel) and estimated amount of self-administered alcohol (bottom panel) in selectively bred Sardinian alcohol-preferring (sP) rats. Rats were initially trained to lever respond for oral alcohol (15% v/v, in water) [fixed ratio 4 (FR4)] and water (FR1) in daily 30-min sessions. Test session was conducted under the above FR schedules of reinforcement. Each bar is the mean ± SEM of n = 12 rats. *P < 0.05, **P < 0.005, and ***P < 0.0001 in comparison to vehicle-treated rats (Tukey’s test).
Mentions: 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). Treatment with 0.75, 1.5, and 3 mg/kg R(+)-baclofen produced a dose-related reduction in number of lever responses for alcohol, reaching statistical significance at the doses of 1.5 (P < 0.05, Tukey’s test) and 3 (P < 0.0001, Tukey’s test) mg/kg, in correspondence of which the magnitude of the reducing effect – in comparison to vehicle treatment – averaged approximately 50 and 80%, respectively (Figure 1, top panel). Conversely, treatment with 6, 12, and 24 mg/kg S(−)-baclofen did not alter, in comparison to vehicle treatment, the number of lever responses for alcohol (Figure 1, top panel).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Institute, National Research Council of Italy - Cagliari Section , Monserrato , Italy.

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.

No MeSH data available.