Nicotinic acetylcholine receptor modulation of noradrenaline release in the rodent brain

Cognitive function in the brain is controlled by neurotransmitters whose release is tightly controlled. When normal levels are perturbed deficits in function can be observed both in humans and in animal models. The cholinergic system, acting via muscarinic or nicotinic receptors, modulates neurotransmitter release. The aim of this thesis was to investigate the identity of the nicotinic acetylcholine receptor (nAChR) subtypes involved in modulating noradrenaline (NA) release, in rodent frontal cortex (FC) and hippocampus (HC). Comparisons were made both in vitro and in vivo using pharmacological tools. In vitro, acute application of nicotinic agonists evoked release of previously loaded [3H]-NA from prisms of rat FC and HC. There was a 2000-fold more potent response to β2* selective nAChR agonist 5-iodo-A85380 in FC than HC. A greater response to choline in HC than FC, combined with a lack of response to selective α7 ligands supports α3β4* nAChRs as the main mediator of nicotinic stimulated NA release in vitro in HC. A proportion of the release in each region was mediated via a potentially excitatory action of GABA. The profile of responses was unchanged after the acute or chronic administration of nicotine in vivo. In vivo microdialysis experiments were designed to test whether the nAChR subtype differences in vitro were representative of differences in vivo. 5-iodo-A85380 administered by reverse dialysis increased NA levels to a greater extent in FC than HC, supporting differences in the nAChR composition involved in NA regulation between these two regions. Targeted stimulation of these different nAChR subtypes could allow exploitation of this disparity to improve function with novel compounds such as those described in Chapter 2. Overall the studies described in this thesis show that there are differences in the subtype of nAChRs involved in NA release from terminal fields of FC and HC both in vitro and in vivo.EThOS - Electronic Theses Online ServiceGBUnited Kingdo