University of Sussex
Robertson, Johnathan.pdf (6.96 MB)

Genetic investigation of a4-containing GABAA receptors’ different roles in alcohol consumption and conditioned behaviours influenced by cocaine

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posted on 2023-06-09, 14:11 authored by Johnathan Robertson
The GABAA a4-subunit is found co-assembled with d subunits in extrasynaptic GABAA receptors (a4-GABAARs). Within the striatum a4-GABAARs are most highly expressed in the Nucleus Accumbens (NAc) where they mediate tonic inhibition thought to control the excitability of accumbal medium spiny neurons (MSNs). Experiments presented in this thesis use genetic techniques in mice to investigate the role of a4-GABAARs in modulating binge-like ethanol consumption and the potentiation of locomotor behaviours by cocaine. We have generated several transgenic mouse lines in which the Gabra4 gene, encoding the a4 subunit, has been deleted either constitutively or within specific neural populations expressing D1 or D2 type dopamine receptors via cre/loxp recombination. Using quantitative rt-PCR and in-situ-hybridisation methods to compare Gabra4 mRNA levels in brain sections from each genotype we confirmed that the a4 subunit was deleted either globally or in the expected cell type within conditional knockouts. We also generated an Adeno Associated Virus (AAV) carrying Cre-recombinase to knockdown a4 locally by infusing it into in specific brain regions of ‘floxed’-a4 mice. Deletion of the a4 subunit in mice significantly reduced alcohol consumption in a pre-clinical model of binge-drinking, known as drinking in the dark (DID). Moreover, targeted deletion of Gabra4 in the NAc was sufficient to mediate this effect. We did not observe any effects on alcohol consumption in mice where a4 was deleted conditionally in D1 or D2 type neurons. This data indicates that a4- GABAARs in the NAc are an important mediator of alcohol consumption. Deletion of GABAAR a4-subunits from dopamine D1-expressing neurons facilitated cocaine’s ability to potentiate locomotor activity and operant responding for natural rewards. Deletion of GABAAR a4-subunits from dopamine D2-expressing neurons had no such effects. Deletion of GABAAR a4-subunits from dopamine D1- expressing neurons also accelerated the acquisition of behavioural sensitisation to cocaine. This effect was associated with increased cFos expression in the NAc core following acute cocaine, whilst in cocaine-sensitised mice it was associated with increased cFos in both the NAc Core and Shell. A similar altered pattern of cFos expression was observed in mice with a global knockout of a4 subunits however they showed no behavioural effects. This may imply that a balance of a4-GABAARmediated inhibition in D1 and D2 neurons is required for normal behavioural sensitisation to cocaine. The data presented within this thesis indicate that a4- GABAAR-mediated inhibition of D1- and D2-expressing neurons plays an important physiological role in controlling behavioural responses to cocaine.


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