Genetic and pharmacological investigation of α4-containing GABAA receptors in conditioned behaviours influenced by cocaine

MacPherson, Tom (2014) Genetic and pharmacological investigation of α4-containing GABAA receptors in conditioned behaviours influenced by cocaine. Doctoral thesis (PhD), University of Sussex.

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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.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Psychology > Psychology
Subjects: B Philosophy. Psychology. Religion > BF Psychology > BF0207 Psychotropic drugs and other substances
Depositing User: Library Cataloguing
Date Deposited: 28 Feb 2014 15:34
Last Modified: 18 Sep 2015 13:30

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