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α4-containing GABAA receptors on dopamine D2 receptor-expressing neurons mediate instrumental responding for conditioned reinforcers, and its potentiation by cocaine

Tom Macpherson, Claire I Dixon, Patricia H. Janak, Delia Belelli, Jeremy J. Lambert, David N. Stephens, Sarah King
doi: https://doi.org/10.1101/055822
Tom Macpherson
aSchool of Psychology, University of Sussex, Brighton, BN1 9QG, United Kingdom
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Claire I Dixon
aSchool of Psychology, University of Sussex, Brighton, BN1 9QG, United Kingdom
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Patricia H. Janak
cErnest Gallo Clinic and Research Center, University of California, Emeryville, CA 94608, USA
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Delia Belelli
bDivision of Neuroscience, Medical Research Institute, Ninewells Hospital & Medical School, University of Dundee, Dundee, DD1 9SY, United Kingdom
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Jeremy J. Lambert
bDivision of Neuroscience, Medical Research Institute, Ninewells Hospital & Medical School, University of Dundee, Dundee, DD1 9SY, United Kingdom
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David N. Stephens
aSchool of Psychology, University of Sussex, Brighton, BN1 9QG, United Kingdom
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Sarah King
aSchool of Psychology, University of Sussex, Brighton, BN1 9QG, United Kingdom
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Abstract:

Extrasynaptic GABAA receptors (GABAARs) composed of α4, β and δ subunits mediate GABAergic tonic inhibition and are pertinent molecular targets in the modulation of behavioural responses to drugs of abuse, including ethanol and cocaine. These GABAARs are highly expressed within the nucleus accumbens (NAc) where they influence the excitability of the medium spiny neurons (MSNs). Here we explore their role in modulating behavioural responses to reward-conditioned cues and the behaviour-potentiating effects of cocaine. α4-subunit constitutive knockout mice (α4-/-) showed higher rates of instrumental responding for reward-paired stimuli in a test of conditioned reinforcement (CRf). A similar effect was seen following viral knockdown of GABAAR α4 subunits within the NAc. Local infusion of the δ-GABAAR-preferring agonist, THIP, into the NAc had no effect on responding when given alone, but reduced cocaine potentiation of responding for conditioned reinforcers in wildtype but not α4-/- mice. Finally, specific deletion of α4-subunits from dopamine D2-, but not D1-receptor-expressing neurons, mimicked the phenotype of the constitutive knockout, potentiating CRf responding and blocking intra-accumbal THIP attenuation of cocaine-potentiated CRf responding. These data demonstrate that α4-GABAAR mediated inhibition of dopamine D2 receptor-expressing neurons reduces instrumental-responding for a conditioned reinforcer, and its potentiation by cocaine, and emphasise the potential importance of GABAergic signalling within the NAc in mediating cocaine’s effects.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 27, 2016.
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α4-containing GABAA receptors on dopamine D2 receptor-expressing neurons mediate instrumental responding for conditioned reinforcers, and its potentiation by cocaine
Tom Macpherson, Claire I Dixon, Patricia H. Janak, Delia Belelli, Jeremy J. Lambert, David N. Stephens, Sarah King
bioRxiv 055822; doi: https://doi.org/10.1101/055822
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α4-containing GABAA receptors on dopamine D2 receptor-expressing neurons mediate instrumental responding for conditioned reinforcers, and its potentiation by cocaine
Tom Macpherson, Claire I Dixon, Patricia H. Janak, Delia Belelli, Jeremy J. Lambert, David N. Stephens, Sarah King
bioRxiv 055822; doi: https://doi.org/10.1101/055822

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