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

Doctoral thesis English OPEN
MacPherson, Tom (2014)
  • Subject: BF0207

α4-subunit containing GABAA receptors (α4-GABAARs) are often found co-assembled\ud with δ-subunits in extrasynaptic locations on nucleus accumbens (NAc) medium spiny\ud neurons (MSNs), were they mediate a tonic form of inhibition thought to control the\ud excitability of the neuron. This thesis combines genetic and pharmacological techniques\ud to explore the role of α4-GABAARs in locomotor and reward-conditioned behaviours.\ud \ud Activation of α4-GABAARs by systemic or intra-accumbal administration of THIP, a\ud GABAAR agonist with a preference for δ-subunits, was able to reduce cocainepotentiated\ud locomotor activity in wildtype but not GABAAR α4-subunit knockout mice.\ud Similarly, the ability of repeated cocaine to induce behavioural sensitisation was\ud unaffected in GABAAR α4-subunit knockout mice, but systemic THIP was able to\ud reduce the sensitised increase in locomotor activity in wildtype but not knockout mice.\ud α4-GABAARs are also able to modulate behavioural responses to reward-conditioned\ud stimuli and their enhancement by cocaine. Deletion of GABAAR α4-subunits from\ud dopamine D1-expressing neurons facilitated cocaine-CPP, and activation of α4-\ud GABAARs on NAc D1-MSNs was able to attenuate cocaine-enhancement of cocaine\ud CPP. Conversely, deletion of GABAAR α4-subunits from dopamine D2-expressing\ud neurons increased CRf responding, and activation of α4-GABAARs on NAc D2-MSNs\ud was able to attenuate cocaine-potentiation of CRf responding. These data also indicate\ud that there is a dissociation in the NAc MSNs mediating cocaine-CPP and CRf\ud responding. This may be explained by the different glutamatergic inputs needed to\ud provide information about conditioned cues important for these behaviours.\ud \ud The data presented within this thesis indicate that α4-GABAAR-mediated inhibition of\ud D1- and D2-expressing neurons plays an important physiological role in controlling\ud behavioural responses to conditioned cues. Furthermore, NAc α4βδ GABAARs may\ud provide a potential therapeutic target by which to limit the enhancement of locomotor\ud and conditioned-behaviours by cocaine.
  • References (115)
    115 references, page 1 of 12

    1.5.4. GABAARs and psychostimulant self-administration ------------ 30

    1.5.5. GABAAR pharmacogenetics of psychostimulant abuse -------- 31

    1.5.6. Summary -------------------------------------------------------------- 32 1.6. A role for α4-GABAARs in mediating addiction-related behaviours ------ 33 1.7. Strategies for exploring the role for α4-GABAARs in mediating addictionrelated behaviours -----------------------------------------------------------------------34

    1.7.1. Genetic strategies for targeting α4-GABAARs ------------------ 34

    1.7.2. Targeting extrasynaptic α4βδ GABAARs pharmacologically -38 1.8. Aims and structure of thesis ------------------------------------------------------ 40

    1.7.1. Chapter 2 ------------------------------------------------------------- 40

    1.7.2. Chapter 3 ------------------------------------------------------------- 40

    1.7.3. Chapter 4 ------------------------------------------------------------- 41

    1.7.4. Chapter 5 ------------------------------------------------------------- 41 Activity in a Novel Environment ----------------------- 84

    3.2.5. Behavioural Sensitisation to Cocaine with Intraperitoneal THIP

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