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Investigating the control of striatal dopamine neurotransmission by axonal Ca2+ channels and by striatal neuromodulators : insights for Parkinson's disease

Dopamine (OA) is a key striatal neuromodulator which is central to processes including action selection and reward-related learning. OA dysfunction is associated with a number of psychomotor disorders, most notably of which is Parkinson's disease (PO). This thesis uses fastscan cyclic voltammetry in acute mouse striatal slices to detect OA release at carbon fibre microelectrodes with subsecond temporal resolution, to investigate factors affecting the presynaptic control of OA release. In this thesis, I have investigated the roles of voltage dependent calcium channels (VOCCs) and the neuromodulator, substance P (SP), in the presynaptic control of OA, in the presence of nicotinic acetylcholine receptor (nAChR) blockade. This is because ACh has profound modulatory and driving effects on OA release, via activation of nAChRs on OA terminals. In CPu, blockers for N-, P/Q-, T- or L-type VOCCs (w-Conotoxin GVIA, w-Agatoxin IVA, NNC 55- 0396, isradipine) reduced OA release to varying degrees (N)P/Q>T>L). Furthermore, L-type function was eliminated by a~synuclein knockout. In NAc, only Nand P/Q-blockers modified OA 1 release (N)P/Q) and more weakly than in CPu. Frequency-specific effects of some VGCCs were reproduced by changes to extracellular Ca 2 + or release probability, consistent with Ca 2 + entry governing the relationship between OA release probability and its short-term plasticity. Finally I have shown that SP can directly modulate striatal OA release in a manner that depends on striosome-matrix location. To date there is much conflict in the literature on the role of SP in a number of striatal processes, this finding may help to resolve these conflicts and shed light on the little understood role ofthe striosome-matrix division of the striatum.
Date January 2013
CreatorsBrimblecombe, Katherine
PublisherUniversity of Oxford
Source SetsEthos UK
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation

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