UC Irvine

Nicotine, the reinforcing component of tobacco and e-cigarettes, directly acts on the cholinergic system by targeting nicotinic acetylcholine receptors (nAChRs) in the brain. Activation of nAChRs leads to a multitude of immediate and long-lasting effects in specific cellular populations, thereby affecting the addictive properties of the drug. nAChRs in the ventral tegmental area (VTA) have been shown to mediate the reinforcing actions of nicotine, whereas nAChRs in the medial habenula (MHb) to interpeduncular nucleus (IPN) pathway have been shown to be involved in the aversive effects of nicotine. In addition to their important role in nicotine reinforcement behaviors, nAChRs also play a crucial role in nervous system function with important effects on cognition, attention, motivation, and learning and memory. Although we know of the function of nAChRs in these brain regions, little is known about downstream projections of these circuits or endogenous modulators that may be mediating these effects. Endogenous allosteric modulators, such as lynx1, have been shown to decrease the activity of the receptor in the presence of an agonist. This dissertation seeks to determine the role of different modulators and circuits that are mediating cholinergic processes. We found that the downstream projections of the IPN, specifically to the ventral hippocampus, is not involved in nicotine reinforcement behaviors, but surprisingly, is involved in stress coping. We also demonstrate that the negative allosteric modulator, lynx1 plays an important role in nicotine reinforcement in the VTA. Finally, we have also shown that the lynx1 is involved in cognitive and sensory processing behaviors. Taken together, this dissertation illustrates the important role of allosteric modulation and circuits in cholinergic functions.