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Genetic and pharmacological investigation of a4-containing GABAA receptors in conditioned behaviours influenced by cocaine

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posted on 2023-06-08, 16:44 authored by Tom MacPherson
a4-subunit containing GABAA receptors (a4-GABAARs) are often found co-assembled with d-subunits in extrasynaptic locations on nucleus accumbens (NAc) medium spiny neurons (MSNs), were they mediate a tonic form of inhibition thought to control the excitability of the neuron. This thesis combines genetic and pharmacological techniques to explore the role of a4-GABAARs in locomotor and reward-conditioned behaviours. Activation of a4-GABAARs by systemic or intra-accumbal administration of THIP, a GABAAR agonist with a preference for d-subunits, was able to reduce cocainepotentiated locomotor activity in wildtype but not GABAAR a4-subunit knockout mice. Similarly, the ability of repeated cocaine to induce behavioural sensitisation was unaffected in GABAAR a4-subunit knockout mice, but systemic THIP was able to reduce the sensitised increase in locomotor activity in wildtype but not knockout mice. a4-GABAARs are also able to modulate behavioural responses to reward-conditioned stimuli and their enhancement by cocaine. Deletion of GABAAR a4-subunits from dopamine D1-expressing neurons facilitated cocaine-CPP, and activation of a4- GABAARs on NAc D1-MSNs was able to attenuate cocaine-enhancement of cocaine CPP. Conversely, deletion of GABAAR a4-subunits from dopamine D2-expressing neurons increased CRf responding, and activation of a4-GABAARs on NAc D2-MSNs was able to attenuate cocaine-potentiation of CRf responding. These data also indicate that there is a dissociation in the NAc MSNs mediating cocaine-CPP and CRf responding. This may be explained by the different glutamatergic inputs needed to provide information about conditioned cues important for these behaviours. 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 conditioned cues. Furthermore, NAc a4ßd GABAARs may provide a potential therapeutic target by which to limit the enhancement of locomotor and conditioned-behaviours by cocaine.

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  • Published version

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237.0

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  • Psychology Theses

Qualification level

  • doctoral

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  • phd

Language

  • eng

Institution

University of Sussex

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  • Yes

Legacy Posted Date

2014-02-28

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