Effects of Nicotine on Hindbrain Catecholamine Neurons

Stephen Joseph Page

Nicotine is an addictive drug that has broad effects throughout the brain. One site of action is the nucleus of the solitary tract (NTS), where nicotine initiates a stress response and modulates cardiovascular and gastric function through nicotinic acetylcholine receptors (nAChRs). Catecholamine neurons in the NTS (NTS-CA neurons) influence stress, and gastric and cardiovascular reflexes, making them potential mediators of nicotine’s effects. We have determined nicotine’s actions on NTS-CA neurons using patch-clamp techniques in brainslices from transgenic mice. Picospritzing nicotine induced a direct post-synaptic current and increased the frequency of spontaneous excitatory post-synaptic currents (sEPSCs); effects blocked by non-selective nAChR antagonists. The increase in sEPSC frequency was mimicked by a nAChRα7 agonist, and blocked by a nAChRα7 antagonist. In contrast, the nicotine-induced post-synaptic current was mimicked by a nAChRα4β2 agonist, and blocked by a nAChRα4β2 antagonist. Nicotine responses were larger in nicotine-dependent mice that underwent spontaneous nicotine withdrawal. These results demonstrate that 1) nicotine activates NTS-CA neurons both directly, by inducing a direct current, and indirectly by increasing glutamate inputs, and 2) NTS-CA nicotine responsiveness is altered during nicotine withdrawal. Some NTS neurons are known to be sensitive to changes in extracellular glucose concentration. We tested whether nicotine responses were dependent on changes in local glucose. Lowering bath glucose concentration from 5mM to 2mM reduced the amplitude of nicotine currents in NTS-CA neurons, and attenuated the nicotine-induced increase in sEPSC frequency. The effect of 2mM glucose on nicotine responses was mimicked by activation of intracellular low-energy sensors. Conversely, inhibition of these targets prevented the effect of 2mM glucose to reduce nicotine responses. We conclude that nicotine activation of NTS-CA neurons is dependent on glucose concentration. Finally, we investigated whether endogenous acetylcholine (ACh) neurotransmission in the NTS is also modulated by nicotine withdrawal or glucose. To test this we used an optogenetic mouse model of physiological ACh release, which allowed simultaneous recording of NTS-CA neurons and selective photo-stimulation of local cholinergic fibers. NTS-CA neurons responded to photo-stimulated acetylcholine (ACh) release with a nAChRα7-dependent increase in sEPSCs. ACh responses were subject to modulation by both glucose manipulation and nicotine withdrawal.

Effects of Nicotine on Hindbrain Catecholamine Neurons

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