Limits...
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 cumulative response pattern of self-administration for alcohol 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 schedules of reinforcement. Each point is the mean ± SEM of n = 12 rats.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4834306&req=5

Figure 2: Effect of treatment with racemic baclofen [(±)-baclofen], R(+)-baclofen, and S(−)-baclofen on cumulative response pattern of self-administration for alcohol 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 schedules of reinforcement. Each point is the mean ± SEM of n = 12 rats.

Mentions: Treatment with 3 mg/kg (±)-baclofen produced a robust reduction in alcohol self-administration in alcohol-preferring sP rats: both the number of lever responses for alcohol and estimated amount of self-administered alcohol were indeed suppressed by treatment with 3 mg/kg (±)-baclofen. Additionally, analysis of cumulative response patterns indicated a markedly reduced frequency in lever responding for alcohol, over the entire first half of the self-administration session, in the rat group treated with 3 mg/kg (±)-baclofen in comparison to vehicle-treated rat group (Figure 2). These results closely replicate previous findings obtained in sP rats exposed to experimental procedures of operant, oral alcohol self-administration identical to those used in the present study (24, 26). Notably, previous experiments demonstrated that acute treatment with 3 mg/kg (±)-baclofen did not affect, even minimally, spontaneous locomotor activity in sP rats (17, 18), suggesting that the suppressive effect on alcohol self-administration observed in the present study was not due to any motor-impairing or sedative effect. Together, these data suggest that 3 mg/kg is a dose of (±)-baclofen suitable for functioning as reference when testing baclofen enantiomers in sP rats.


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 cumulative response pattern of self-administration for alcohol 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 schedules of reinforcement. Each point is the mean ± SEM of n = 12 rats.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Effect of treatment with racemic baclofen [(±)-baclofen], R(+)-baclofen, and S(−)-baclofen on cumulative response pattern of self-administration for alcohol 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 schedules of reinforcement. Each point is the mean ± SEM of n = 12 rats.
Mentions: Treatment with 3 mg/kg (±)-baclofen produced a robust reduction in alcohol self-administration in alcohol-preferring sP rats: both the number of lever responses for alcohol and estimated amount of self-administered alcohol were indeed suppressed by treatment with 3 mg/kg (±)-baclofen. Additionally, analysis of cumulative response patterns indicated a markedly reduced frequency in lever responding for alcohol, over the entire first half of the self-administration session, in the rat group treated with 3 mg/kg (±)-baclofen in comparison to vehicle-treated rat group (Figure 2). These results closely replicate previous findings obtained in sP rats exposed to experimental procedures of operant, oral alcohol self-administration identical to those used in the present study (24, 26). Notably, previous experiments demonstrated that acute treatment with 3 mg/kg (±)-baclofen did not affect, even minimally, spontaneous locomotor activity in sP rats (17, 18), suggesting that the suppressive effect on alcohol self-administration observed in the present study was not due to any motor-impairing or sedative effect. Together, these data suggest that 3 mg/kg is a dose of (±)-baclofen suitable for functioning as reference when testing baclofen enantiomers in sP rats.

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.