The bed nucleus of the stria terminalis (BST), especially its oval (ov) subregion, receives a robust dopaminergic input from the periaqueducal, retrorubral, and ventral tegmental midbrain areas (Hasue & Shammah-Lagnado, 2002). Given the critical role of dopamine in motivated behaviors, we combined behavioral testing of operant responding towards natural and pharmacological rewards, and brain slices patch-clamp electrophysiology to identify specific alterations in dopaminergic regulation of inhibitory synaptic transmission within the ovBST as a result of chronic cocaine self-administration. In drug naïve rats we observed that DA dose-dependently decreased GABAA-inhibitory post-synaptic currents (IPSC) through the actions of pre-synaptic D2 receptors. However in rats maintaining cocaine self-administration, DA (1µM) increased the amplitude of GABAA-IPSC and this increase resulted from a loss of functional pre-synaptic D2 receptors and the de novo addition of D1 receptors. Furthermore, direct activation of D1 receptors only in rats maintaining cocaine self-administration resulted in a sustained increase of GABAA-IPSC (LTPGABA). The D1-induced LTPGABA was blocked by intracellular application of a Src-tyrosine kinase antagonist in the recording pipette. Based on this observation we concluded that the D1 receptor was located post-synaptically. However, the measured LTPGABA was associated with modifications in the coefficient of variation and paired pulse ratio of evoked GABAA IPSCs, suggesting that it is maintained by persistently increased GABA release from pre-synaptic terminals. Therefore to explain this apparent contradiction we propose the existence of a currently unknown retrograde messenger that is released from the post-synaptic neuron, upon D1 receptor activation, and travels backward to increase GABA release from presynaptic terminals. Moreover, application of a D2 agonist blocked the D1-induced LTPGABA, and co-application of a G-protein antagonist in the intracellular pipette prevented this D2 mediated inhibition, suggesting that due to maintenance of cocaine self-administration there was an emergence of a new post-synaptic D2 component whose functional role seems to inhibit the D1 receptor increase of GABAA-IPSCs. Importantly, modulation of synaptic transmission by dopamine was identical to drug-naïve conditions when intravenous cocaine administration was not contingent upon operant responding (yoked), before the maintenance phase of cocaine self-administration (acquisition), or in rats maintaining operant responding for sucrose under the same reinforcement schedule. All together we identified robust alterations in the effects of dopamine on inhibitory synaptic transmission following voluntary cocaine self-administration, these results represent to our knowledge, the first evidence of a change in dopaminergic regulation of synaptic transmission specific to voluntary drug intake. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2011-05-04 14:58:56.775
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OKQ.1974/6501 |
| Date | 05 May 2011 |
| Creators | KRAWCZYK, MICHAL |
| Contributors | Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.)) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Rights | This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner. |
| Relation | Canadian theses |
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