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

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.