Cholinrergic excitation of dopamine neurons in the ventral tegmental area

Zhang, Lei (2004) Cholinrergic excitation of dopamine neurons in the ventral tegmental area. Masters thesis, Memorial University of Newfoundland.

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Abstract

Ventral tegmental area dopaminergic neurons are critically involved in brain mechanisms of reward, motivation, and emotional arousal. The natural cholinergic agonist nicotine is highly addictive and believed to cause addiction through activating the central dopamine system. In this thesis, we used perforated patch-clamp recording to examine the effects of the cholinergic agonist carbachol on the excitability of dopamine neurons in brain slices. Results from these experiments revealed that bath application of carbachol (20 μM) for 1-2 min excited most cells in the VTA regardless of their membrane characteristics and neurochemical identities. Muscarinic and nicotinic receptors appeared to contribute equally to carbachol-induced excitation. A majority of cells putatively identified as dopaminergic based on the expression of hyperpolarization-activated current and dopamine-induced autoinhibition, responded to carbachol with depolarization and an increased rate of firing. Of these cells, 13% responded to the carbachol with a switching of firing pattern from tonic firing to bursting. Carbachol-induced excitation and bursting were all reversible and could be prevented by combined muscarinic and nicotinic antagonism. -- The synaptic blocker cocktail containing 100 μM APV (NMDA receptor blocker), 10 μM CNQX (AMPA receptor blocker) and 100 μM picotoxin (GABAA receptor blocker) did not alter carbachol's effect on neuronal excitability and bursting. In addition, a small proportion of dopamine cells were spontaneously bursting in the slice. The characteristics of these bursts were very similar to those induced by carbachol. Both spontaneous and carbachol-induced bursting could be blocked by the non-selective Ca²⁺ channel blocker cadmium and the L-type Ca²⁺ channel blocker nifedipine, while blocking the T-type Ca²⁺ channels did not have any effect on bursting. Spontaneous and induced bursting occurred on a slow, large amplitude membrane oscillation or hump potential which was dependent on Ca²⁺ entry through voltage-gated Ca²⁺ channels, and more specifically through the L-type Ca²⁺ channels. -- In summary, the present investigation provides evidence that cholinergic excitation of dopamine cells is mainly postsynaptic. More importantly, cholinergic activation can serve as a trigger that switches the firing mode of dopamine cells and promotes burst firing. Burst firing induced as such is dependent on Ca²⁺ entry through the L-type Ca²⁺ channels, suggesting a new target for modulating the central dopamine system.

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