BACKGROUND: Alcohol's ability to potentiate the activity of γ-aminobutyric acid (GABA) at GABAA receptors has been implicated as a key mechanism underlying the behavioral effects of alcohol. The complex molecular biology of these receptors raises the possibility that particular receptor subtypes may play unique roles in alcohol's abuse-related effects and that subtype-selective ligands with therapeutic specificity against alcohol might be developed. This study evaluated the capacity of α5GABAA receptor ligands to alter selectively the reinforcing effects of alcohol. METHODS: Two groups of rhesus monkeys were trained to orally self-administer alcohol or sucrose under fixed-ratio schedules and limited daily access conditions. In addition, following daily self-administration sessions, the behavior of each monkey was scored for both species-typical and drug-induced behaviors. RESULTS: Concentrations of 1 to 6% alcohol maintained self-administration above water levels, engendered pharmacologically relevant blood alcohol levels ranging from 90 to 160 mg/dl, and produced changes in behavior typical of alcohol intoxication. Concentrations of 0.3 to 3% sucrose also reliably maintained self-administration. The α5GABAA receptor agonist QH-ii-066 enhanced and the α5GABAA receptor inverse agonist L-655,708 inhibited alcohol, but not sucrose drinking. The changes in alcohol drinking could be reversed with the α5GABAA receptor antagonist XLi-093. However, L-655,708 increased yawning in both alcohol and sucrose drinkers, possibly indicative of an anxiogenic effect. CONCLUSIONS: These findings suggest a prominent and specific role for α5GABAA receptor mechanisms in the reinforcing effects of alcohol. Moreover, these results suggest that α5GABAA receptors may represent a novel pharmacological target for the development of medications to reduce drinking. Of ligands modulating this receptor, α5GABAA receptor inverse agonists may hold the most promise as alcohol pharmacotherapies.
BACKGROUND:Alcohol's ability to potentiate the activity of γ-aminobutyric acid (GABA) at GABAA receptors has been implicated as a key mechanism underlying the behavioral effects of alcohol. The complex molecular biology of these receptors raises the possibility that particular receptor subtypes may play unique roles in alcohol's abuse-related effects and that subtype-selective ligands with therapeutic specificity against alcohol might be developed. This study evaluated the capacity of α5GABAA receptor ligands to alter selectively the reinforcing effects of alcohol. METHODS: Two groups of rhesus monkeys were trained to orally self-administer alcohol or sucrose under fixed-ratio schedules and limited daily access conditions. In addition, following daily self-administration sessions, the behavior of each monkey was scored for both species-typical and drug-induced behaviors. RESULTS: Concentrations of 1 to 6% alcohol maintained self-administration above water levels, engendered pharmacologically relevant blood alcohol levels ranging from 90 to 160 mg/dl, and produced changes in behavior typical of alcohol intoxication. Concentrations of 0.3 to 3% sucrose also reliably maintained self-administration. The α5GABAA receptor agonist QH-ii-066 enhanced and the α5GABAA receptor inverse agonist L-655,708 inhibited alcohol, but not sucrose drinking. The changes in alcohol drinking could be reversed with the α5GABAA receptor antagonist XLi-093. However, L-655,708 increased yawning in both alcohol and sucrose drinkers, possibly indicative of an anxiogenic effect. CONCLUSIONS: These findings suggest a prominent and specific role for α5GABAA receptor mechanisms in the reinforcing effects of alcohol. Moreover, these results suggest that α5GABAA receptors may represent a novel pharmacological target for the development of medications to reduce drinking. Of ligands modulating this receptor, α5GABAA receptor inverse agonists may hold the most promise as alcohol pharmacotherapies.
Authors: Donna M Platt; James K Rowlett; Roger D Spealman; James Cook; Chunrong Ma Journal: Psychopharmacology (Berl) Date: 2002-09-04 Impact factor: 4.530
Authors: H L June; S C Harvey; K L Foster; P F McKay; R Cummings; M Garcia; D Mason; C Grey; S McCane; L S Williams; T B Johnson; X He; S Rock; J M Cook Journal: J Neurosci Date: 2001-03-15 Impact factor: 6.167
Authors: Cassie M Chandler; Jaren Reeves-Darby; Sherman A Jones; J Abigail McDonald; Guanguan Li; Md T Rahman; James M Cook; Donna M Platt Journal: Psychopharmacology (Berl) Date: 2019-01-12 Impact factor: 4.530
Authors: Eileen K Sawyer; Casey Moran; Madelynn H Sirbu; Melissa Szafir; Michael Van Linn; Ojas Namjoshi; V V N Phani Babu Tiruveedhula; James M Cook; Donna M Platt Journal: Alcohol Clin Exp Res Date: 2013-12-13 Impact factor: 3.455
Authors: Lais F Berro; Daniela Rüedi-Bettschen; Jemma E Cook; Lalit K Golani; Guanguan Li; Rajwana Jahan; Farjana Rashid; James M Cook; James K Rowlett; Donna M Platt Journal: Alcohol Clin Exp Res Date: 2019-04-08 Impact factor: 3.455
Authors: Angela N Duke; Zhiqiang Meng; Donna M Platt; John R Atack; Gerard R Dawson; David S Reynolds; V V N Phani Babu Tiruveedhula; Guanguan Li; Michael Rajesh Stephen; Werner Sieghart; James M Cook; James K Rowlett Journal: J Pharmacol Exp Ther Date: 2018-05-02 Impact factor: 4.030
Authors: Zhiqiang Meng; Lais F Berro; Eileen K Sawyer; Daniela Rüedi-Bettschen; Jemma E Cook; Guanguan Li; Donna M Platt; James M Cook; James K Rowlett Journal: J Psychopharmacol Date: 2019-10-31 Impact factor: 4.153
Authors: S L Huskinson; D M Platt; M Brasfield; M E Follett; T E Prisinzano; B E Blough; K B Freeman Journal: Psychopharmacology (Berl) Date: 2020-05-06 Impact factor: 4.530