Investigating the control of striatal dopamine neurotransmission by axonal calcium channels and by striatal neuromodulators: Insights for Parkinson's disease

Thesis

Dopamine (DA) is a key striatal neuromodulator which is central to processes including action selection and reward-related learning. DA dysfunction is associated with a number of psychomotor disorders, most notably of which is Parkinson's disease (PD). This thesis uses fast-scan cyclic voltammetry in acute mouse striatal slices to detect DA release at carbon fibre microelectrodes with subsecond temporal resolution, to investigate factors affecting the presynaptic control of DA release.

In this thesis, I have investigated the roles of voltage dependent calcium channels (VDCCs) and the neuromodulator, substance P (SP), in the presynaptic control of DA, in the presence of nicotinic acetylcholine receptor (nAChR) blockade. This is because ACh has profound modulatory and driving effects on DA release, via activation of nAChRs on DA terminals.

In CPu, blockers for N-, P/Q-, T- or L-type VDCCs (ω-Conotoxin GVIA, ω-Agatoxin IVA, NNC 55-0396, isradipine) reduced DA release to varying degrees (N>P/Q>T>L). Furthermore, L-type function was eliminated by α-synuclein knockout. In NAc, only N and P/Q-blockers modified DA release (N>P/Q) and more weakly than in CPu. Frequency-specific effects of some VGCCs were reproduced by changes to extracellular Ca2+ or release probability, consistent with Ca2+ entry governing the relationship between DA release probability and its short-term plasticity. Finally I have shown that SP can directly modulate striatal DA 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 of the striosome-matrix division of the striatum.

Authors: Brimblecombe, K; Katherine Brimblecombe

• Publication date: 2014
• DOI: 10.5287/ora-r88vkxaeg
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Substance P; Calcium channels; Parkinson's disease; voltammetry; Dopamine
• Subjects: Physiology and anatomy