α5GABAA subunit-containing receptors and sweetened alcohol cue-induced reinstatement and active sweetened alcohol self-administration in male rats
- 15 Downloads
GABAA receptors containing the α5 subunit (i.e., α5GABAA receptors) appear to be critically involved in the reinforcing and subjective effects of alcohol. Their role in alcohol relapse remains unknown.
Pharmacological approaches were used to probe the role of α5GABAA receptors in alcohol seeking induced by re-exposure to a sweetened alcohol-paired cue, as well as in alcohol + sucrose vs. sucrose self-administration.
For reinstatement studies, rats were trained to self-administer alcohol under a fixed-ratio schedule in which responding was maintained by alcohol + sucrose deliveries and an alcohol-paired stimulus. Sweetened alcohol seeking was extinguished by eliminating solution deliveries and the sweetened alcohol-paired stimulus. During reinstatement tests, animals received pretreatments of an α5GABAA inverse agonist (L-655,708) or an agonist (QH-ii-066) prior to sessions in which presentation of the sweetened alcohol-paired stimulus was restored, but no solution was delivered. For self-administration studies, rats were trained to self-administer alcohol + sucrose or sucrose under a fixed-ratio schedule. Once stable, animals received pretreatments of QH-ii-066, L-655,708, the inverse agonist RY-023, or naltrexone.
L-655,708 attenuated reinstatement of sweetened alcohol seeking by alcohol + sucrose-paired cues; whereas sweetened alcohol-seeking behavior was augmented by QH-ii-066, albeit at different doses in different rats. Both L-655,708 and RY-023 selectively reduced alcohol + sucrose vs. sucrose self-administration. In contrast, naltrexone reduced both alcohol + sucrose and sucrose self-administration; whereas QH-ii-066 enhanced sucrose self-administration only.
α5GABAA receptors play a key role in the modulation of sweetened alcohol cue-induced reinstatement, as well as in alcohol + sucrose but not sucrose self-administration. Inverse agonist activity at α5GABAA receptors may offer a novel strategy for both the reduction of problematic drinking and the prevention of relapse.
KeywordsAlcohol Ethanol Reinstatement Self-administration GABAA receptors
We would like to thank Dr. Joyce Besheer (UNC-Chapel Hill) for invaluable advice regarding alcohol self-administration in rats; Dr. Kevin Freeman (UMMC) for use of his operant conditioning chambers, and Dr. Sally Huskinson for her Med State programming expertise. We also would like to thank the Shimadzu Analytical Laboratory of Southeastern Wisconsin.
Compliance with ethical standards
All animals were maintained and experiments were conducted in accordance with the University of Mississippi Medical Center’s Institutional Animal Care and Use Committee and were in accordance with the National Research Council’s Guide for Care and Use of Laboratory Animals (eighth edition, 2011).
Conflict of interest
The authors declare that they have no conflict of interest.
- Casula MA, Bromidge FA, Pillai GV, Wingrove PB, Martin K, Maubach K, Seabrook GR, Whiting PJ, Hadingham KL (2001) Identification of amino acid residues responsible for the alpha-5 subunit binding selectivity of L-655,708, a benzodiazepine binding site ligand at the GABA-A receptor. J Neurochem 77:445–451CrossRefGoogle Scholar
- Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C, Smith A, Otu FM, Howell O, Atack JR, McKernan RM, Seabrook GR, Dawson GR, Whiting PJ, Rosahl TW (2002) Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci 22:5572–5580CrossRefGoogle Scholar
- Cook JB, Foster KL, Eiler WJ 2nd, McKay PF, Woods J 2nd, Harvey SC, Garcia M, Grey C, McCane S, Mason D, Cummings R, Li X, Cook JM, June HL (2005) Selective GABAA alpha5 benzodiazepine inverse agonist antagonizes the neurobehavioral actions of alcohol. Alcohol Clin Exp Res 29:1390–1401CrossRefGoogle Scholar
- Grant BF, Chou SP, Saha TD, Pickering RP, Kerridge BT, Ruan WJ, Huang B, Jung J, Zhang H, Fan A, Hasin DS (2017) Prevalence of 12-month alcohol use, high-risk drinking, and DSM-IV Alcohol Use Disorder in the United States, 2001-2002 to 2012-2013: results from the National Epidemiologic Survey on Alcohol and Related Conditions. JAMA Psychiatry 74:911–923CrossRefGoogle Scholar
- Huang Q, Zhang W, Liu R, McKernan RM, Cook JM (1996) Benzo-fused benzodiazepines as topological probes for the study of benzodiazepine receptor subtypes. Med Chem Res 6:384–391Google Scholar
- Jin Z, Bazov I, Kononenko O, Korpi ER, Bakalkin G, Birnir B (2012) Selective changes of GABAA channel subunit mRNAs in the hippocampus and orbitofrontal cortex but not in prefrontal cortex of human alcoholics. Front Cell Neurosci 5:30. https://doi.org/10.3389/fncel.2011.00030
- June HL, Harvey SC, Foster KL, McKay PF, Cummings R, Garcia M, Mason D, Grey C, McCane S, Williams LS, Johnson TB, He X, Rock S, Cook JM (2001) GABAA receptors containing α5 subunits in the CA1 and CA3 hippocampal fields regulate ethanol-motivated behaviors: an extended ethanol reward circuitry. J Neurosci 21:2166–2177CrossRefGoogle Scholar
- Knust H, Achermann G, Ballard T, Buettelmann B, Gasser R, Fischer H, Hernandez MC, Knoflach F, Koblet A, Stadler H, Thomas AW, Trube G, Waldmeier P (2009) The discovery and unique pharmacological profile of RO4938581 and RO4882224 as potent and selective GABAA alpha5 inverse agonists for the treatment of cognitive dysfunction. Bioorg Med Chem Lett 19:5940–5944CrossRefGoogle Scholar
- Möhler H, Rudolph U (2017) Disinhibition, an emerging pharmacology of learning and memory. F1000Res. https://doi.org/10.12688/f1000research.9947.1
- Redrobe JP, Elster L, Frederiksen K, Bundgaard C, de Jong IE, Smith GP, Bruun AT, Larsen PH, Didriksen M (2012) Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats. Psychopharmacology 221:451–468CrossRefGoogle Scholar
- Song J, Koller DL, Foroud T, Carr K, Zhao J, Rice J, Nurnberger JI Jr, Begleiter H, Porjesz B, Smith TL, Schuckit MA, Edenberg HJ (2003) Association of GABAA receptors and alcohol dependence and the effects of genetic imprinting. Am J Med Genet B Neuropsychiatr Genet 117B:39–45CrossRefGoogle Scholar
- Weiss F (2010) Advances in animal models of relapse for addiction research. In: Kuhn CM, Koob GF (eds) Advances in the neuroscience of addiction, 2nd edn. CRC Press/Taylor & Francis, Boca Raton Chapter 1Google Scholar