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Title: Examining the local regulation of extracellular hippocampal GABA concentrations using microdialysis
Author: Rowley, Samuel C. S.
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2011
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Anatomical evidence describes both extensive serotonergic input and local GABAergic modulation in the hippocampus and synaptic GABA release is modulated by 5-HT in vitro. The majority of extracellular GABA mediating tonic inhibition originates from synaptic spillover suggesting serotonergic modulation of GABA output will have concomitant effects upon tonic inhibition. Therefore, microdialysis coupled to electrochemical detection was utilised to measure extracellular concentrations of 5-HT, 5-HlAA and GABA to examine hippocampal regulation of tonic inhibition. The augmentation of hippocampal 5-HT transmission by the infusion of the selective serotonin reuptake inhibitor citalopram revealed a negative modulation upon ambient GABA levels. Subsequently, local infusion of selective pharmacological compounds was used to examine the receptors mediating this effect. Infusions of the 5-HT1A receptor agonist, 8-0H- DPAT and the 5-HT1A receptor antagonist, WAY 100,635, demonstrated that the citalopram- induced suppression of GABA was dependent upon 5-HT1A receptor activation and its activation evoked comparable decreases. Conversely, activation of hippocampal 5-HT 2A receptors by TCB-2 infusion caused transient increases in detected GABA. No GABA alterations were seen in response to local activation of 5-HT2C or 5-HT3 receptors and no tonic serotonergic modulation was revealed via suppressions of 5-HT in response to the 5-HT1B agonist CP 93,129. Hippocampal endocannabinoids function as inhibitory retrograde messengers suppressing synaptic GABAergic transmission via activation of CB1 receptors in response to postsynaptic triggers. However, the current examination of the influence of CB1 receptor activation upon hippocampal extracellular GABA levels revealed a complex biphasic effect. During drug infusions, both exogenous and endogenous activation of CB1 receptors induced increases in extracellular GABA concentrations which were subsequently followed by long-term suppressions. Hippocampal tonic inhibition is implicated in apt behavioural and neuronal responding, cognition and mood. Therefore, the current demonstration of novel, local modulatory roles for 5-HT and the endocannabinoids upon tonic inhibition is both physiologically important and pathologically relevant.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available