Inhibition of alcohol self-administration by positive allosteric modulators of the GABAB receptor in rats: lack of tolerance and potentiation of baclofen

Maccioni, Paola; Vargiolu, Daniela; Thomas, Andrew W.; Malherbe, Pari; Mugnaini, Claudia; Corelli, Federico; Leite‐Morris, Kimberly A.; Gessa, Gian Luigi; Colombo, Giancarlo

doi:10.1007/s00213-014-3815-8

Cited by 34 publications

(24 citation statements)

References 28 publications

(51 reference statements)

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“…Data from Experiment 2 extend to binge-like drinking, the capacity of non-sedative doses of GS39783 to reduce alcohol drinking under the standard, 2-bottle choice procedure with unlimited access (Orrù et al, 2005), and oral alcohol self-administration under multiple operant procedures (Maccioni et al, 2007, 2008, 2010, 2012, 2015) in sP rats. These data are also consistent with those recently reported by Linsenbardt and Boehm (2014) on the ability of acutely administered GS39783 to selectively suppress binge-like drinking in C57BL/6J mice.…”

Section: Discussionmentioning

confidence: 99%

“…GS39783 (synthesized in-house by CM and FC) was suspended in 2 mL/kg distilled water with a few drops of Tween 80, and administered by gavage at the doses of 0, 25, 50, and 100 mg/kg 60 min before the start of the drinking session. GS39783 dose-range, pretreatment time, and route of administration were identical to those used in several previous studies testing GS39783 on different alcohol-motivated behaviors in sP rats (Maccioni et al, 2007, 2008, 2010, 2012, 2015). Alcohol, water, and food intake were recorded immediately after the test session and expressed in g/kg, mL/kg, and g/kg, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…GS39783 is an in vivo effective, positive allosteric modulator (PAM) of the GABA B receptor (GABA B PAM) (Urwyler et al, 2003). During recent years, several behavioral studies have depicted an interesting pharmacological profile for GS39783: its acute or repeated administration (a) exerted anxiolytic-like effects in some rat and mouse models of anxiety (Cryan et al, 2004; Mombereau et al, 2004; see, however, Paterson & Hanania, 2010; Sweeney, O’Leary, & Cryan, 2013), and (b) suppressed several alcohol-related behaviors, including alcohol drinking in sP rats exposed to the 2-bottle “alcohol vs. water” choice regimen with unlimited access (Orrù et al, 2005) and operant, oral alcohol self-administration in alcohol-preferring sP, Indiana P, and Alko Alcohol (AA) rats (Maccioni et al, 2007, 2008, 2010, 2012, 2015). Notably, with regard to the aims of the present study, a recent investigation (Linsenbardt & Boehm, 2014) found that acute treatment with GS39783 suppressed binge-like drinking in C57BL/6J mice exposed to the “Drinking-in-the-Dark” procedure (i.e., daily exposure to a single alcohol bottle in daily 2- or 4-h drinking sessions, occurring early in the dark phase [see Thiele & Navarro, 2014]).…”

Section: Introductionmentioning

confidence: 99%

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Anxiety-like behaviors at the end of the nocturnal period in sP rats with a “history” of unpredictable, limited access to alcohol

Colombo

Lobina

Maccioni

et al. 2015

Alcohol

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Recent research found that exposure of selectively bred, Sardinian alcohol-preferring (sP) rats to multiple alcohol concentrations (10%, 20%, and 30%, v/v), under the 4-bottle “alcohol vs. water” choice regimen, in daily 1-h drinking sessions with an unpredictable time schedule, promoted high intakes of alcohol (≥2 g/kg) when the drinking session occurred over the final hours of the dark phase of the light/dark cycle. The present study was aimed at investigating whether these high intakes of alcohol (a) were associated with alterations in rats’ emotional state (Experiment 1) and (b) were pharmacologically manipulable (Experiment 2). In both experiments, over a period of 12 days, sP rats were initially exposed daily to a1-h drinking session performed during the 12-h duration of the dark phase; time of alcohol exposure was changed each day and was unpredictable to rats. The day after this 12-day drinking phase, rats were (a) exposed to the Social Interaction (SI) test at the 1st or 12th hour of the dark phase with no alcohol available (Experiment 1) or (b) treated acutely with the positive allosteric modulator of the GABAB receptor, GS39783 (0, 25, 50, and 100 mg/kg, intragastrically [i.g.]), and exposed to a drinking session at the 12th hour of the dark phase (Experiment 2). In Experiment 1, rats exposed to the SI test during the 12th hour spent approximately 35% less time in “social” behaviors than rats exposed to the SI test during the 1st hour. No difference in “social” behaviors was observed between alcohol-naive sP rats exposed to the SI test at the 1st and 12th hour. In Experiment 2, all doses of GS39783 selectively reduced alcohol intake. These results suggest that (a) expectation of alcohol availability likely exacerbated the anxiety-like state of sP rats and (b) the GABAB receptor is part of the neural substrate underlying these exceptionally high intakes of alcohol in sP rats.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anxiety-like behaviors at the end of the nocturnal period in sP rats with a “history” of unpredictable, limited access to alcohol

Colombo

Lobina

Maccioni

et al. 2015

Alcohol

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“…: Maccioni et al 2012; 2015). These comparisons suggest how powerfully the experimental procedure used in the present study produced an escalation in the reinforcing properties of alcohol in sP rats.…”

Section: Discussionmentioning

confidence: 99%

Elevated reinforcing and motivational properties of alcohol at the end of the nocturnal period in sP rats

et al. 2015

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Rationale Sardinian alcohol-preferring (sP) rats displayed high sensitivity to time schedule and consumed intoxicating amounts of alcohol during the last portion of the dark phase of the light/dark cycle when exposed to daily drinking sessions of one hour, with concurrent availability of multiple alcohol concentrations, and unpredictability of time of alcohol access. Objectives The present study investigated whether sensitivity of sP rats to time schedule extended to operant procedures of alcohol self-administration. Methods In Experiment 1, three different alcohol solutions (10%, 20%, and 30%, v/v) were concurrently available under a Fixed Ratio 4 schedule of reinforcement and with unpredictable time schedule; water was available uncontingently. Experiments 2 and 3 assessed the sensitivity of the motivational properties of alcohol to time schedule; rats were exposed to (a) self-administration sessions under the Progressive Ratio (PR) schedule of reinforcement and (b) sessions of alcohol seeking under the extinction responding (ER) schedule. Results In Experiment 1, number of lever-responses and amount of self-administered alcohol were positively correlated with time of alcohol access during the dark phase. When the self-administration session occurred at the first and latest hours of the dark phase, the amount of self-administered alcohol averaged 0.95–1.0 and 1.55–1.65 g/kg, respectively. In Experiments 2 and 3, values of breakpoint and ER for alcohol were approximately 50% higher when the sessions occurred at the last than first hour of the dark phase. Conclusions The reinforcing and motivational properties of alcohol were sensitive to time schedule and stronger at the end of the dark phase.

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“…The present study was designed to contribute to this new line of research, testing the effect of the two baclofen enantiomers on operant, oral alcohol self-administration in selectively bred Sardinian alcohol-preferring (sP) rats. Alcohol self-administration in sP rats has repeatedly been demonstrated to be sensitive to pharmacological manipulation of the GABA B receptor, by means of both orthosteric agonists, such as baclofen ( 24 – 26 ), and positive allosteric modulators ( 25 , 26 , 41 – 45 ). The study design included (a) a dose of (±)-baclofen (3 mg/kg) known to effectively reduce alcohol self-administration in sP rats ( 24 – 26 ), (b) doses of the more active enantiomer, R(+)-baclofen, calculated as corresponding to half of (0.75 mg/kg), equal to (1.5 mg/kg), and double (3 mg/kg) its content in the tested dose of (±)-baclofen, and (c) doses of the less active enantiomer, S(−)-baclofen, calculated as corresponding to equal to (6 mg/kg), double (12 mg/kg), and fourfold (24 mg/kg) of its content in the tested dose of (±)-baclofen.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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Inhibition of alcohol self-administration by positive allosteric modulators of the GABAB receptor in rats: lack of tolerance and potentiation of baclofen

Cited by 34 publications

References 28 publications

Anxiety-like behaviors at the end of the nocturnal period in sP rats with a “history” of unpredictable, limited access to alcohol

Anxiety-like behaviors at the end of the nocturnal period in sP rats with a “history” of unpredictable, limited access to alcohol

Elevated reinforcing and motivational properties of alcohol at the end of the nocturnal period in sP rats

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

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