Activation and modulation of GABA(B) receptor systems in physiogenic and pathophysiological conditions

γ-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system. This thesis explores the actions of known or proposed agonists for the GABA type B (GABAB) receptor in isolated cells and on nerve terminals releasing dopamine in rodents. The first chapter provides the background information for the research undertaken in this thesis. In the second chapter I used whole cell patch clamp electrophysiology to explore the action of the proposed atypical GABAB receptor agonist, R-isovaline, at heterologously or natively expressed GABAB receptors in isolated cells. I found that R-isovaline did not initiate GABAB-mediated K+ currents and did not occlude or enhance the responses of other GABAB receptor agonists. Our data suggest that R-isovaline does not act as a direct agonist at GABAB receptors. In the third chapter I used fast-scan cyclic voltammetry in brain slices to explore the mechanisms behind GABAB modulation of dopamine release in the nucleus accumbens core of mice. The canonical GABAB receptor agonist, baclofen, concentration-dependently inhibited dopamine release by a direct action on dopamine neuron terminals. Baclofen-mediated inhibition of release was reduced when dopamine was released by stimulations that mimicked burst firing of dopamine neurons. Baclofen also decreased the probability of dopamine release. I also found that GABAB modulation of dopamine release was not altered by a sensitising cocaine treatment. In the fourth chapter I used fast scan cyclic voltammetry to assess whether diet induced obesity or a binge pattern of eating could alter GABAB or dopamine D2 receptor mediated regulation of dopamine release in the nucleus accumbens core in rats. The abilities of baclofen and the D2 agonist quinpirole to inhibit dopamine release were unchanged by long term access to a palatable cafeteria diet. Chapter 5 discusses the main findings of these experiments and potential future experiments.