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

Alessandro Orrù, Daniele Fujani, Chiara Cassina, Mirko Conti, Angelo Di Clemente, Luigi Cervo

Research output: Contribution to journalArticle

Abstract

Rationale With its high palatability, near-beer has been successfully used in rats as a vehicle to induce ethanol oral self-Administration. Objectives The study aimed to develop an operant model of oral alcoholic beer self-Administration promoting a stable intake of pharmacologically relevant amounts of ethanol in free-feeding C57BL/6J mice. It also aimed to assess the model's predictive validity by evaluating the influence of baclofen, a GABAB agonist, and BHF177, a GABAB positive allosteric modulator, on alcoholic beer self-Administration. Methods Mice were trained to self-Administer, under a fixed ratio three schedule of reinforcement, 10 μl of beer containing increasing ethanol concentrations (0-18% v/v) in daily 30- min sessions. The effects on motor coordination (rotarod), locomotor activity (open field, automated cages) and anxiety-like behavior (elevated plus maze, EPM) were examined. Baclofen (1.25-5 mg/kg, intraperitoneal, i.p.) and BHF177 (3.75-30 mg/kg, i.p.) were used to see the effects on 9% alcoholic beer and near-beer self-Administration. Results Near-beer stably maintained operant oral selfadministration in mice. Adding ethanol to near-beer reduced the number of active lever presses, while the corresponding amount of ethanol self-Administration increased (0.8-1.0 g/ kg/session). Motor impairment was observed when more than 1.3 g/kg/session of ethanol was self-Administered with beer and slight but consistent hyperlocomotion with more than 0.9-1.0 g/kg/session. BHF177 (15 mg/kg) preferentially reduced 9% alcoholic beer self-Administration, while the higher dose (30 mg/kg)-like baclofen 5 mg/kg-Also reduced near-beer self-Administration. Conclusions The operant model of oral alcoholic beer selfadministration in C57BL/6J mice should prove useful for studying ethanol-reinforced behaviors and to identify candidate compounds for the pharmacological management of alcohol addiction.

Original languageEnglish
Pages (from-to)685-700
Number of pages16
JournalPsychopharmacology
Volume222
Issue number4
DOIs
Publication statusPublished - Aug 2012

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Self Administration
Inbred C57BL Mouse
Ethanol
Baclofen
N-(bicyclo(2.2.1)hept-2-yl)-2-methyl-5-(4-(trifluoromethyl)phenyl)-4-pyrimidinamine
Reinforcement Schedule
Locomotion
Alcoholism
Oral Administration
Anxiety

Keywords

  • Alcoholic beer
  • Baclofen
  • BHF177
  • C57BL/6J mice
  • Oral operant selfadministration

ASJC Scopus subject areas

  • Pharmacology

Cite this

Operant, oral alcoholic beer self-Administration by C57BL/6J mice : Effect of BHF177, a positive allosteric modulator of GABAB receptors. / Orrù, Alessandro; Fujani, Daniele; Cassina, Chiara; Conti, Mirko; Di Clemente, Angelo; Cervo, Luigi.

In: Psychopharmacology, Vol. 222, No. 4, 08.2012, p. 685-700.

Research output: Contribution to journalArticle

Orrù, Alessandro ; Fujani, Daniele ; Cassina, Chiara ; Conti, Mirko ; Di Clemente, Angelo ; Cervo, Luigi. / Operant, oral alcoholic beer self-Administration by C57BL/6J mice : Effect of BHF177, a positive allosteric modulator of GABAB receptors. In: Psychopharmacology. 2012 ; Vol. 222, No. 4. pp. 685-700.
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abstract = "Rationale With its high palatability, near-beer has been successfully used in rats as a vehicle to induce ethanol oral self-Administration. Objectives The study aimed to develop an operant model of oral alcoholic beer self-Administration promoting a stable intake of pharmacologically relevant amounts of ethanol in free-feeding C57BL/6J mice. It also aimed to assess the model's predictive validity by evaluating the influence of baclofen, a GABAB agonist, and BHF177, a GABAB positive allosteric modulator, on alcoholic beer self-Administration. Methods Mice were trained to self-Administer, under a fixed ratio three schedule of reinforcement, 10 μl of beer containing increasing ethanol concentrations (0-18{\%} v/v) in daily 30- min sessions. The effects on motor coordination (rotarod), locomotor activity (open field, automated cages) and anxiety-like behavior (elevated plus maze, EPM) were examined. Baclofen (1.25-5 mg/kg, intraperitoneal, i.p.) and BHF177 (3.75-30 mg/kg, i.p.) were used to see the effects on 9{\%} alcoholic beer and near-beer self-Administration. Results Near-beer stably maintained operant oral selfadministration in mice. Adding ethanol to near-beer reduced the number of active lever presses, while the corresponding amount of ethanol self-Administration increased (0.8-1.0 g/ kg/session). Motor impairment was observed when more than 1.3 g/kg/session of ethanol was self-Administered with beer and slight but consistent hyperlocomotion with more than 0.9-1.0 g/kg/session. BHF177 (15 mg/kg) preferentially reduced 9{\%} alcoholic beer self-Administration, while the higher dose (30 mg/kg)-like baclofen 5 mg/kg-Also reduced near-beer self-Administration. Conclusions The operant model of oral alcoholic beer selfadministration in C57BL/6J mice should prove useful for studying ethanol-reinforced behaviors and to identify candidate compounds for the pharmacological management of alcohol addiction.",
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AU - Fujani, Daniele

AU - Cassina, Chiara

AU - Conti, Mirko

AU - Di Clemente, Angelo

AU - Cervo, Luigi

PY - 2012/8

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N2 - Rationale With its high palatability, near-beer has been successfully used in rats as a vehicle to induce ethanol oral self-Administration. Objectives The study aimed to develop an operant model of oral alcoholic beer self-Administration promoting a stable intake of pharmacologically relevant amounts of ethanol in free-feeding C57BL/6J mice. It also aimed to assess the model's predictive validity by evaluating the influence of baclofen, a GABAB agonist, and BHF177, a GABAB positive allosteric modulator, on alcoholic beer self-Administration. Methods Mice were trained to self-Administer, under a fixed ratio three schedule of reinforcement, 10 μl of beer containing increasing ethanol concentrations (0-18% v/v) in daily 30- min sessions. The effects on motor coordination (rotarod), locomotor activity (open field, automated cages) and anxiety-like behavior (elevated plus maze, EPM) were examined. Baclofen (1.25-5 mg/kg, intraperitoneal, i.p.) and BHF177 (3.75-30 mg/kg, i.p.) were used to see the effects on 9% alcoholic beer and near-beer self-Administration. Results Near-beer stably maintained operant oral selfadministration in mice. Adding ethanol to near-beer reduced the number of active lever presses, while the corresponding amount of ethanol self-Administration increased (0.8-1.0 g/ kg/session). Motor impairment was observed when more than 1.3 g/kg/session of ethanol was self-Administered with beer and slight but consistent hyperlocomotion with more than 0.9-1.0 g/kg/session. BHF177 (15 mg/kg) preferentially reduced 9% alcoholic beer self-Administration, while the higher dose (30 mg/kg)-like baclofen 5 mg/kg-Also reduced near-beer self-Administration. Conclusions The operant model of oral alcoholic beer selfadministration in C57BL/6J mice should prove useful for studying ethanol-reinforced behaviors and to identify candidate compounds for the pharmacological management of alcohol addiction.

AB - Rationale With its high palatability, near-beer has been successfully used in rats as a vehicle to induce ethanol oral self-Administration. Objectives The study aimed to develop an operant model of oral alcoholic beer self-Administration promoting a stable intake of pharmacologically relevant amounts of ethanol in free-feeding C57BL/6J mice. It also aimed to assess the model's predictive validity by evaluating the influence of baclofen, a GABAB agonist, and BHF177, a GABAB positive allosteric modulator, on alcoholic beer self-Administration. Methods Mice were trained to self-Administer, under a fixed ratio three schedule of reinforcement, 10 μl of beer containing increasing ethanol concentrations (0-18% v/v) in daily 30- min sessions. The effects on motor coordination (rotarod), locomotor activity (open field, automated cages) and anxiety-like behavior (elevated plus maze, EPM) were examined. Baclofen (1.25-5 mg/kg, intraperitoneal, i.p.) and BHF177 (3.75-30 mg/kg, i.p.) were used to see the effects on 9% alcoholic beer and near-beer self-Administration. Results Near-beer stably maintained operant oral selfadministration in mice. Adding ethanol to near-beer reduced the number of active lever presses, while the corresponding amount of ethanol self-Administration increased (0.8-1.0 g/ kg/session). Motor impairment was observed when more than 1.3 g/kg/session of ethanol was self-Administered with beer and slight but consistent hyperlocomotion with more than 0.9-1.0 g/kg/session. BHF177 (15 mg/kg) preferentially reduced 9% alcoholic beer self-Administration, while the higher dose (30 mg/kg)-like baclofen 5 mg/kg-Also reduced near-beer self-Administration. Conclusions The operant model of oral alcoholic beer selfadministration in C57BL/6J mice should prove useful for studying ethanol-reinforced behaviors and to identify candidate compounds for the pharmacological management of alcohol addiction.

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