Model summarizing nicotinic effects on glutamate terminals in the DRN Model summarizing nicotinic effects on glutamate terminals in the DRN. A, In physiological conditions, the cholinergic tone is regulating the excitatory glutamatergic input to the DRN 5-HT neurons through the activation of α4β2 nAChRs, located at glutamate ... Model summarizing nicotinic effects on glutamate terminals in the DRN. A, In physiological conditions, the cholinergic tone is regulating the excitatory glutamatergic input to the DRN 5-HT neurons through the activation of α4β2 nAChRs, located at glutamate terminals. Released ACh is quickly metabolized by the enzyme acetylcholinesterase. As a result, the Ca2+ influx into the glutamate terminals and glutamate release will be maintained at low levels. B, When nicotine is present (for example, in smokers), more α4β2 nAChRs will be activated, because nicotine cannot be degraded in the synaptic cleft. This will enhance Ca2+ entry, followed by depolarization of glutamate terminals and activation of VGCCs. This, in turn, will increase even more intracellular calcium and produce CICR from the endoplasmic reticulum (ER) through the activation of ryanodine receptors (RyR). This last event generates a long-term potentiation of glutamate release. Julieta Garduño et al. J. Neurosci. 2012;32:15148-15157 ©2012 by Society for Neuroscience