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fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
MacPherson, Tom (2014)
Languages: English
Types: Doctoral thesis
Subjects: 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.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 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 3.2.4.2. Activity in a Novel Environment ----------------------- 84
    • 3.2.5. Behavioural Sensitisation to Cocaine with Intraperitoneal THIP
    • Challenge ----------------------------------------------------------------------- 84
    • 3.2.6. Statistical Analysis ----------------------------------------------------- 84
    • 4.2.6.1. Dose Response for Behavioural Sensitisation to Cocaine
    • 4.2.6.2. Conditioned Activity --------------------------------------- 85
    • 4.2.6.3. Activity in a Novel Environment ------------------------- 85
    • 4.2.6.4. Behavioural Sensitisation to Cocaine with Intraperitoneal
    • THIP Challenge ------------------------------------------------------- 85
    • 3.3. Results ---------------------------------------------------------------------------- 87
    • 3.3.1. Dose Response for Behavioural Sensitisation to Cocaine -------- 87
    • 3.3.1.1. Conditioned Activity --------------------------------------- 91
    • 3.3.1.2. Activity in a Novel Environment ------------------------- 92
    • 3.3.2. Behavioural Sensitisation to Cocaine with Intraperitoneal THIP
    • Challenge ----------------------------------------------------------------------- 92 3.4. Discussion -------------------------------------------------------------------------- 94 Chapter 4. The role of α4-containing GABAA receptors in conditioned place preference to cocaine -------------------------------------------------------------------------- 98
    • 4.1. Introduction ------------------------------------------------------------------------ 98
    • 4.2. Materials and Methods ---------------------------------------------------------- 105
    • 4.2.1. Animals ---------------------------------------------------------------- 105
    • 4.2.2. Genotyping -------------------------------------------------------------108
    • 4.2.2.1. Conditional Dopamine D1-/D2-expressing Neuron Specific
    • GABAAR α4-subunit Knockout Mice PCR ------------------------------ 108
    • 4.2.3. Quantitative Reverse Transcription PCR (qRT-PCR) mRNA
    • Analysis ----------------------------------------------------------------------- 108
    • 4.2.4. Stereotaxic Cannulation --------------------------------------------- 108
    • 4.2.5. Drugs ------------------------------------------------------------------- 109
    • 4.2.6. Apparatus -------------------------------------------------------------- 109
    • 4.2.7. Conditioned Place Preference to Cocaine ------------------------- 109
    • 4.2.8. Statistical Analysis --------------------------------------------------- 110 4.2.8.1. qRT-PCR --------------------------------------------------- 110
    • 4.2.8.2. Conditioned Place Preference to Cocaine in Wildtype and
    • GABAAR α4-subunit Knockout Mice with Intraperitoneal THIP -
    • 4.2.8.3. Conditioned Place Preference to Cocaine in Wildtype and
    • GABAAR α4-subunit Knockout Mice with Intra-accumbal THIP -
    • 4.2.8.4. Conditioned Place Preference to Cocaine in Wildtype and
    • Dopamine D1/D2-expressing neuron specific GABAAR α4-
    • subunit Knockout Mice with Intraperitoneal THIP ------------- 111 4.3. Results ----------------------------------------------------------------------------- 112
    • 4.3.1. qRT-PCR mRNA analysis in dopamine D1-/D2-expresing neuron
    • specific GABAAR α4-subunit wildtype and knockout mice ----------- 112
    • 4.3.2. Conditioned Place Preference to Cocaine in Wildtype and
    • GABAAR α4-subunit Knockout Mice with Intraperitoneal THIP ----- 115
    • 4.3.3. Conditioned Place Preference to Cocaine in Wildtype and
    • GABAAR α4-subunit Knockout Mice with Intra-accumbal THIP ----- 119
    • 4.3.4. Conditioned Place Preference to Cocaine in Wildtype and
    • Dopamine D1/D2-expressing neuron specific GABAAR α4-subunit
    • Knockout Mice with Intraperitoneal THIP ------------------------------- 123 4.4. Discussion ------------------------------------------------------------------------ 127 Chapter 5. The role of α4-containing GABAA receptors in food conditioned reinforcement and its potentiation by cocaine------------------------------------------- 133
    • 5.1. Introduction ----------------------------------------------------------------------- 133
    • 5.2. Materials and Methods ---------------------------------------------------------- 139
    • 5.2.1. Animals --------------------------------------------------------------- 139
    • 5.2.2. Stereotaxic Cannulation -------------------------------------------- 139
    • 5.2.3. Stereotaxic Viral Infusion ------------------------------------------ 139
    • 5.2.4. Immunohistochemistry --------------------------------------------- 140
    • 5.2.5. Quantitative reverse transcription PCR (qRT-PCR) RNA analysis
    • 5.2.6. Drugs ------------------------------------------------------------------ 141
    • 5.2.7. Apparatus ------------------------------------------------------------- 141 5.2.8. Pavlovian Conditioning --------------------------------------------- 141
    • 5.2.9. Conditioned Reinforcement (CRf) --------------------------------- 142
    • 5.2.9.1. Conditioned Reinforcement in Wildtype and GABAAR
    • α4-Subunit Knockout Mice with Cocaine Potentiation Dose-
    • Response ------------------------------------------------------------- 142
    • 5.2.9.2. Conditioned Reinforcement in Wildtype and GABAAR
    • α4-Subunit Knockout Mice with Cocaine Potentiation and Intra-
    • accumbal THIP ----------------------------------------------------- 142
    • 5.2.9.3. Conditioned Reinforcement in Scrambled Virus Control
    • (Ad-NSS) and α4 Adenoviral Knockdown (Ad-shα4) Mice with
    • Cocaine Potentiation and Intraperitoneal THIP ----------------- 142
    • 5.2.9.4. CRf in Wildtype and α4D1 / α4D2 Knockout Mice with
    • Cocaine Potentiation and Intra-accumbal THIP --- 143
    • 5.2.10. Statistical Analysis -------------------------------------------------- 143
    • 5.2.10.1. Conditioned Reinforcement in Wildtype and GABAAR
    • α4-Subunit Knockout Mice with Cocaine Potentiation Dose-
    • Response ------------------------------------------------------------- 143
    • 5.2.10.2. Conditioned Reinforcement in Wildtype and GABAAR
    • α4-Subunit Knockout Mice with Cocaine Potentiation and Intra-
    • accumbal THIP ------------------------------------------------------ 143
    • 5.2.10.3. RNA Analysis of Ad-shα4 Adenovirus Knockdown of
    • GABAAR α4-Subunits ---------------------------------------------- 144
    • 5.2.10.4. Conditioned Reinforcement in Scrambled Virus Control
    • (Ad-NSS) and α4 Adenoviral Knockdown (Ad-shα4) Mice with
    • Cocaine Potentiation and Intraperitoneal THIP ----------------- 144
    • 5.2.10.5. Conditioned Reinforcement in Wildtype and α4D1 / α4D2
    • THIP ------------------------------------------------------------------ 144 5.3. Results ----------------------------------------------------------------------------- 146
    • 5.3.1. Conditioned Reinforcement in Wildtype and GABAAR α4-Subunit
    • ----------------------------------------------------------------------------------- 146 5.3.2. Conditioned Reinforcement in Wildtype and GABAAR α4-Subunit
    • 5.3.3. RNA Analysis of Ad-shα4 Adenovirus Knockdown of GABAAR
    • α4-Subunits ------------------------------------------------------------------- 152
    • 5.3.4. Conditioned Reinforcement in Scrambled Virus Control (Ad-NSS)
    • and α4 Adenoviral Knockdown (Ad-shα4) Mice with Cocaine
    • Potentiation ------------------------------------------------------------------- 152
    • 5.3.5. Conditioned Reinforcement in Wildtype and α4D1 / α4D2 Knockout
    • ----------------------------------------------------------------------------------- 154 5.4. Discussion ------------------------------------------------------------------------ 157 Chapter 6. General Discussion ------------------------------------------------------------ 163
    • 6.1. α4-GABAARs in Locomotor Activity ----------------------------------------- 163
    • 6.2. α4-GABAARs in Behavioural Sensitisation to Cocaine -------------------- 164
    • 6.3. α4-GABAARs in Cocaine-CPP ------------------------------------------------ 165
    • 6.4. α4-GABAARs in CRf ------------------------------------------------------------ 166
    • 6.5. A Dissociation Between NAc MSNs Mediating Reward-Seeking in
    • Response to Contextual or Discrete Cues? ---------------------------------------- 167
    • 6.6. Does Activation of α4-GABAARs Attenuate Cocaine-Potentiation of
    • Behaviours by Inhibition of MSNs Within the NAc Shell? --------------------- 170
    • 6.7. Implications for Drug Abuse --------------------------------------------------- 171
    • 6.7.1. Compounds Acting at α4-GABAARs as a Treatment for Cocaine
    • Abuse? ------------------------------------------------------------------------- 171
    • 6.7.2. Investigation of GABRA4 Genes in Humans --------------------- 172
    • 6.8. Considerations -------------------------------------------------------------------- 173
    • 6.8.1. The Use of THIP to Target α4-GABAARs ------------------------ 173
    • 6.8.2. The Use of Mouse Behavioural Paradigms to Model Addiction-
    • Associated Behaviours ------------------------------------------------------ 174
    • 6.8.3. Genetic Limitations -------------------------------------------------- 175
    • 6.9. Future Work ---------------------------------------------------------------------- 176
    • 6.9.1. Further Investigation of the Role of α4-GABAARs in Locomotor
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