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Title: Genetic and pharmacological investigation of α4-containing GABAA receptors in conditioned behaviours influenced by cocaine
Author: MacPherson, Tom
ISNI:       0000 0004 5349 5174
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2014
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α4-subunit containing GABAA receptors (α4-GABAARs) are often found co-assembled with δ-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 α4-GABAARs in locomotor and reward-conditioned behaviours. Activation of α4-GABAARs by systemic or intra-accumbal administration of THIP, a GABAAR agonist with a preference for δ-subunits, was able to reduce cocainepotentiated locomotor activity in wildtype but not GABAAR α4-subunit knockout mice. Similarly, the ability of repeated cocaine to induce behavioural sensitisation was unaffected in GABAAR α4-subunit knockout mice, but systemic THIP was able to reduce the sensitised increase in locomotor activity in wildtype but not knockout mice. α4-GABAARs are also able to modulate behavioural responses to reward-conditioned stimuli and their enhancement by cocaine. Deletion of GABAAR α4-subunits from dopamine D1-expressing neurons facilitated cocaine-CPP, and activation of α4- GABAARs on NAc D1-MSNs was able to attenuate cocaine-enhancement of cocaine CPP. Conversely, deletion of GABAAR α4-subunits from dopamine D2-expressing neurons increased CRf responding, and activation of α4-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 α4-GABAAR-mediated inhibition of D1- and D2-expressing neurons plays an important physiological role in controlling behavioural responses to conditioned cues. Furthermore, NAc α4βδ GABAARs may provide a potential therapeutic target by which to limit the enhancement of locomotor and conditioned-behaviours by cocaine.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: BF0207 Psychotropic drugs and other substances