Alpha4 subunit-containing GABAA receptors in the accumbens shell contribute to the reinforcing effects of alcohol.
- Authors
- Rewal, Mridula; Donahue, Rachel; Gill, T Michael; Nie, Hong; Ron, Dorit; Janak, Patricia H
- Year
- 2012
- Journal
- Addiction biology
- PMID
- 21507158
- DOI
- 10.1111/j.1369-1600.2011.00333.x
- PMCID
- PMC3191302
The α4βδ gamma-aminobutyric acid A receptor (GABA(A) R) has been proposed to mediate the rewarding effects of low-to-moderate concentrations of alcohol (ethanol) that approximate those achieved by social drinking. If this is true, then this receptor should be necessary for the reinforcing effects of ethanol as assessed in an instrumental self-administration procedure in which rats are trained to lever press for oral ethanol. We used viral-mediated RNA interference to transiently reduce expression of the α4 GABA(A) R subunit in the shell region of the nucleus accumbens (NAc). We found that responding for ethanol was significantly reduced after α4 reductions in the NAc shell, but not NAc core. This reduction was specific to ethanol, as responding for sucrose was not altered. The presence of ethanol was also required as unreinforced responding for ethanol in subjects previously trained to respond for ethanol (i.e. responding during an extinction test) was not altered. In addition, responding during reinforced sessions was not altered during the initial 5 minutes of the session, but decreased after 5 minutes, following multiple reinforced responses. Together, these findings indicate that the α4 GABA(A) R subunit in the NAc shell is necessary for the instrumental reinforcing effects of oral ethanol, further supporting a role for α4-containing GABA(A) Rs in the rewarding/reinforcing effects of ethanol. Possible pharmacological and non-pharmacological explanations for these effects are considered.
Viral-mediated GABAAR α4 subunit knockdown in NAc shell decreases instrumental responding for ethanol. Rats were infused in the NAc shell with Ad-shα4 (n = 12) or Ad-NSS (n = 12) bilaterally. For panels a–c, data for Ad-shα4-treated rats are expressed as a percentage of Ad-NSS-treated rats at the same timepoint. (a) Responding on the active lever is decreased 18 days after Ad-shα4 infusion. *P < 0.05, compared to baseline (B). (b) Inactive lever responding was not affected. (c) Estimated ethanol intake (g/kg) was decreased 18 days after Ad-shα4 infusion. *P < 0.05, compared to baseline. (d, e) Time course of active lever responses (d) and estimated ethanol intake (e) over days 5–30 after virus infusion depicts the decrease in responding after Ad-shα4, followed by a recovery of responding at day 24. For all panels, ‘B’ refers to baseline, the average of last 3 days prior to virus infusion. Values depict mean +/− SEM
Decreases in instrumental responding for ethanol after GABAAR α4 subunit knockdown in the NAc shell occurs after session initiation. Within-session responding during 30-minute sessions by the same subjects depicted in Fig. 1 during the final session prior to virus infusion (a; baseline) and during day 5 (b), day 18 (c) and day 30 (d). (c) Responding by Ad-shα4-treated rats was significantly decreased on day 18 at the 5–10 and 10–15 minutes intervals (*P < 0.05, **P < 0.01, Ad-shα4 versus Ad-NSS groups) but not during the first 5 minutes of the session. There were no group differences during the baseline session or days 5 and 30 (a, b, d). Values depict mean +/− SEM of active lever responses within 5-minute bins. Data are presented as mean +/− SEM. n = 12 rats per group
Decreases in instrumental responding for ethanol after GABAAR α4 subunit knockdown in the NAc shell depend upon the concurrent experience of ethanol consumption. Two cohorts of rats were trained to lever press for ethanol and were then infused in the NAc shell with Ad-shα4 or Ad-NSS. On day 18 after viral infusion, rats underwent a single test session in which responding was (a–c) or was not (d–f) reinforced by ethanol delivery. (a) Active lever responses were decreased on day 18 when responding was reinforced (Ad-shα4 versus Ad-NSS groups, *P < 0.001). Panels b and c depict within-session responding during the 30-minute sessions by the same subjects depicted in panel a during the final session prior to virus infusion (b; baseline) and during day 18 (c). (b) There were no group differences during the baseline session. (c)There was a significant decrease in responding by Ad-shα4-treated rats on day 18 at the 5–10 and 10–15 minutes intervals (*P < 0.05, Ad-shα4 versus Ad-NSS groups) but not during the first 5 minutes of the session. (d) When responding was not reinforced on day 18, Ad-shα4-infused rats did not decrease active lever responses. (e) There were no group differences in the pattern of responding during the 30-minute baseline session. (f)There were no group differences in the pattern of responding during the 30-minute session on day 18 when responding was not reinforced. Data are presented as mean +/− SEM. n = 8 rats per group
Viral-mediated GABAAR α4 subunit knockdown in the NAc core does not affect instrumental responding for ethanol. Rats were infused in the NAc core with Ad-shα4 (n = 12) or Ad-NSS (n = 12) bilaterally. For panels a–c, data for Ad-shα4-treated rats are expressed as a percentage of Ad-NSS-treated rats at the same timepoint. (a) Responding on the active lever was not altered after Ad-shα4 infusion. (b) Inactive lever responding was not altered. (c) Estimated ethanol intake (g/kg) was not altered.‘B’ refers to baseline, the average of 3 days prior to virus infusion. Data presented as mean +/− SEM
Viral-mediated GABAAR α4 subunit knockdown in NAc shell does not affect instrumental responding for sucrose. Rats were infused in the NAc shell with Ad-shα4 (n = 11) or Ad-NSS (n = 11) bilaterally. For panels a–c, data for Ad-shα4-treated rats are expressed as a percentage of Ad-NSS-treated rats at the same timepoint. (a) Responding on the active lever for 2% sucrose was not altered after Ad-shα4 infusion. (b) Inactive lever responding was not altered. (c) Estimated sucrose intake (g/kg) was not altered.‘B’ refers to baseline, the average of 3 days prior to virus infusion. Data presented as mean +/− SEM
Viral-mediated GABAAR α4 subunit knockdown in NAc shell does not affect motor activity. Rats were infused in the NAc shell with Ad-shα4 (n = 10) or Ad-NSS (n = 10) bilaterally. (a) Distance traveled in an open field for Ad-shα4 and Ad-NSS-treated rats prior to viral infusion (baseline) and on day 18 after viral infusion. (b) Latency to fall from the rotarod for Ad-shα4 and Ad-NSS-treated rats prior to viral infusion (baseline) and on day 18 after viral infusion. Data presented as mean +/− SEM
| Name | Type |
|---|---|
| active lever presses local | phenotype |
| active lever responding local | phenotype |
| Active lever responding local | phenotype |
| active lever responses local | phenotype |
| adenovirus local | drug |
| Adeno-X Virus Purification Kit local | drug |
| Ad-NSS local | cohort |
| Ad-NSS local | drug |
| Ad-NSS group local | cohort |
| Ad-NSS virus local | drug |
| Ad-sh4-1 virus local | drug |
| Ad-shα4 local | drug |
| Ad-shα4-1 local | cohort |
| Ad-shα4-1 local | drug |
| Ad-shα4-1 group local | cohort |
| Ad-shα4-1 virus local | drug |
| Ad-shα4 virus local | drug |
| alcohol | phenotype |
| Alcohol seeking | phenotype |
| alcohol self-administration | phenotype |
| amphetamine | drug |
| baseline operant responding local | phenotype |
| bicuculline | drug |
| blood ethanol concentration | phenotype |
| Blood ethanol level | phenotype |
| Chow intake local | phenotype |
| Clontech | drug |
| cocaine | phenotype |
| Conditioned Reinforcing Properties of Ethanol local | phenotype |
| control group | cohort |
| control rats | cohort |
| control virus | drug |
| control virus group local | cohort |
| coordination | phenotype |
| core | anatomy |
| dorsal medial prefrontal cortex | anatomy |
| Estimated g/kg ethanol dose local | phenotype |
| ethanol consumption | phenotype |
| ethanol preference | phenotype |
| Ethanol-reinforced cohort local | cohort |
| ethanol reinforcement | phenotype |
| Ethanol reinforcing and rewarding effects local | phenotype |
| EtOH | drug |
| experimental group | cohort |
| GABA | phenotype |
| GABAA receptor | drug |
| Gabra1 | gene |
| GABRA2 | gene |
| GABRA3 | gene |
| Gabra4 | gene |
| GABRA5 | gene |
| GABRA6 | gene |
| GABRB | gene |
| GABRB1 | gene |
| Gabrb2 | gene |
| Gabrb3 | gene |
| Gabrd | gene |
| GABRE | gene |
| Gabrg1 | gene |
| Gabrg2 | gene |
| Gabrg3 | gene |
| GABRP | gene |
| GABRQ | gene |
| Gamma-aminobutyric acid A receptor local | drug |
| glutamate | drug |
| HEK293 cells local | drug |
| hippocampus | anatomy |
| Home cage ethanol intake local | phenotype |
| inactive lever responding local | phenotype |
| Inactive lever responding local | phenotype |
| inactive lever responses local | phenotype |
| Instrumental responding for oral ethanol local | phenotype |
| Invitrogen | drug |
| isoflurane | drug |
| Latency to fall | phenotype |
| lateral hypothalamus | anatomy |
| Lever-press responding for ethanol local | phenotype |
| Lipofectamine 2000 | drug |
| locomotor activity | phenotype |
| Long Evans rats local | cohort |
| medial prefrontal cortex | anatomy |
| mice | cohort |
| motor activity | phenotype |
| muscimol | drug |
| NAc core | anatomy |
| NAc shell | anatomy |
| negative siRNA control local | drug |
| non-reinforced group local | cohort |
| nucleus accumbens | anatomy |
| nucleus accumbens core | anatomy |
| nucleus accumbens shell | anatomy |
| Open field test | phenotype |
| percent change measure local | phenotype |
| rats | cohort |
| Rats with GABRA4 reduction local | cohort |
| reinforced group local | cohort |
| Rewarding properties of ethanol | phenotype |
| Rotarod performance | phenotype |
| Satiation local | phenotype |
| self-administration sessions local | phenotype |
| serotonin | drug |
| shell | anatomy |
| shRNA | drug |
| siRNA | drug |
| SR 95531 local | drug |
| standard rat chow local | drug |
| sucrose | drug |
| Sucrose intake | phenotype |
| Sucrose-reinforced responding local | phenotype |
| target mRNAs local | gene |
| taste reactivity | phenotype |
| Taste Reactivity to Ethanol local | phenotype |
| transient behavioral effects local | phenotype |
| Treatment virus local | drug |
| treatment virus group local | cohort |
| trichloroacetic acid | drug |
| Unreinforced cohort local | cohort |
| unreinforced responding for ethanol local | phenotype |
| ventral medial prefrontal cortex | anatomy |
| ventral pallidum | anatomy |
| viral infusion local | drug |
| Viral infusion local | drug |
| Virus local | drug |
| virus infusion local | drug |
| Virus infusion local | drug |
| virus treatment local | drug |
| voluntary alcohol consumption | phenotype |
| water | drug |
| α4-1 siRNA local | drug |
| α4βδ GABAAR local | drug |
| α4βδ GABA_A receptor local | drug |
| Δ9THC local | drug |
No uploaded files.
In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Neurosteroid Modulation of Synaptic and Extrasynaptic GABA<sub>A</sub> Receptors of the Mouse Nucleus Accumbens. | Mitchell SJ et al. | — | 2024 | → |
| Aging in nucleus accumbens and its impact on alcohol use disorders. | Konar-Nié M et al. | — | 2023 | → |
| GABA tone regulation and its cognitive functions in the brain. | Koh W et al. | — | 2023 | → |
| Early postnatal allopregnanolone levels alteration and adult behavioral disruption in rats: Implication for drug abuse. | Bartolomé I et al. | — | 2020 | → |
| Molecular tools to elucidate factors regulating alcohol use. | Logrip ML | — | 2019 | → |
| Nucleus Accumbens Shell Orexin-1 Receptors Are Critical Mediators of Binge Intake in Excessive-Drinking Individuals. | Lei K et al. | — | 2019 | → |
| Using human stem cells as a model system to understand the neural mechanisms of alcohol use disorders: Current status and outlook. | Scarnati MS et al. | — | 2019 | → |
| An Emerging Circuit Pharmacology of GABA<sub>A</sub> Receptors. | Engin E et al. | — | 2018 | → |
| Dynamic Adaptation in Neurosteroid Networks in Response to Alcohol. | Finn DA et al. | — | 2018 | → |
| GABA<sub>A</sub> Receptor Subtype Mechanisms and the Abuse-Related Effects of Ethanol: Genetic and Pharmacological Evidence. | Chandler CM et al. | — | 2018 | → |
| Protein complexes as psychiatric and neurological drug targets. | Kato AS et al. | — | 2018 | → |
| The Cerebellar GABA<sub>A</sub>R System as a Potential Target for Treating Alcohol Use Disorder. | Rossi DJ et al. | — | 2018 | → |
| Alcohol and basal ganglia circuitry: Animal models. | Lovinger DM et al. | — | 2017 | → |
| Effects of neonatal and adolescent neuroactive steroid manipulation on locomotor activity induced by ethanol in male wistar rats. | Bartolomé I et al. | — | 2017 | → |
| GABA<sub>A</sub> receptor subtype involvement in addictive behaviour. | Stephens DN et al. | — | 2017 | → |
| Ethanol-induced GABAA receptor alpha4 subunit plasticity involves phosphorylation and neuroactive steroids. | Werner DF et al. | — | 2016 | → |
| Habitual Alcohol Seeking: Neural Bases and Possible Relations to Alcohol Use Disorders. | Corbit LH et al. | — | 2016 | → |
| Nucleus Accumbens Shell and mPFC but Not Insula Orexin-1 Receptors Promote Excessive Alcohol Drinking. | Lei K et al. | — | 2016 | → |
| α4-containing GABA<sub>A</sub>receptors on dopamine D2 receptor-expressing neurons mediate instrumental responding for conditioned reinforcers, and its potentiation by cocaine | Macpherson T et al. | — | 2016 | — |
| Effect of nucleus accumbens shell infusions of ganaxolone or gaboxadol on ethanol consumption in mice. | Ramaker MJ et al. | — | 2015 | → |
| Alcohol use disorders and current pharmacological therapies: the role of GABA(A) receptors. | Liang J et al. | — | 2014 | → |
| Plasticity of GABA(A) receptor-mediated neurotransmission in the nucleus accumbens of alcohol-dependent rats. | Liang J et al. | — | 2014 | → |
| Role of GABA-active neurosteroids in the efficacy of metyrapone against cocaine addiction. | Schmoutz CD et al. | — | 2014 | → |
| Tonic inhibition of accumbal spiny neurons by extrasynaptic α4βδ GABAA receptors modulates the actions of psychostimulants. | Maguire EP et al. | — | 2014 | → |
| Ethanol-induced alterations of amino acids measured by in vivo microdialysis in rats: a meta-analysis. | Fliegel S et al. | — | 2013 | → |
| Effect of ganaxolone and THIP on operant and limited-access ethanol self-administration. | Ramaker MJ et al. | — | 2012 | → |
| Effects of alcohol on the membrane excitability and synaptic transmission of medium spiny neurons in the nucleus accumbens. | Marty VN et al. | — | 2012 | → |
| The genetics of alcohol dependence: advancing towards systems-based approaches. | Palmer RH et al. | — | 2012 | → |