A novel cholinergic projection from the lateral parabrachial nucleus and its role in methamphetamine-primed...

Drug relapse is a big clinical challenge in the treatment of addiction, but its neural circuit mechanism is far from being fully understood. Here, we identified a novel cholinergic pathway from choline acetyltransferase-positive neurons in the external lateral parabrachial nucleus (eLPB^ChAT) to the GABAergic neurons in the central nucleus of the amygdala (CeA^GABA) and explored its role in methamphetamine priming-induced reinstatement of conditioned place preference. The anatomical structure and functional innervation of the eLPB^ChAT-CeA^GABA pathway were investigated by various methods such as fluorescent micro-optical sectioning tomography, virus-based neural tracing, fibre photometry, patch-clamp and designer receptor exclusively activated by a designer drug. The role of the eLPB^ChAT-CeA^GABA pathway in methamphetamine relapse was assessed using methamphetamine priming-induced reinstatement of conditioned place preference behaviours in male mice. We found that the eLPB^ChAT neurons mainly projected to the central nucleus of the amygdala. A chemogenetic activation of the eLPB^ChAT neurons in vitro or in vivo triggered the excitabilities of the CeA^GABA neurons, which is at least in part mediated via the cholinergic receptor system. Most importantly, the chemogenetic activation of either the eLPB^ChAT neurons or the eLPB^ChAT neurons that project onto the central nucleus of the amygdala decreased the methamphetamine priming-induced reinstatement of conditioned place preference in mice. Our findings revealed a previously undiscovered cholinergic pathway of the eLPB^ChAT-CeA^GABA and showed that the activation of this pathway decreased the methamphetamine priming-induced reinstatement of conditioned place preference.