Role of lateral habenula in methamphetamine TAAR1-mediated synaptic plasticity and aversion

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PROJECT SUMMARY Considerable research has focused on drug use disorders as motivational disorders involving inherent or drug- induced reward pathway function. However, the focus of this application is on opposing aversive effects of methamphetamine (MA) that may curb its use, which have been little studied. The Richards (Phillips) laboratory identified the trace amine associated receptor 1 (TAAR1) as a critical target impacting MA-induced aversion. TAAR1 is an intracellularly located G protein-coupled receptor. MA gains access to TAAR1 only if it is transported into the cell. This occurs via extracellular membrane transporters, such as dopamine and serotonin transporters, DAT and SERT, respectively. We propose that TAAR1 activation by MA in dopamine and serotonin neurons is responsible for MA-induced aversion and that monoaminergic circuit interactions with the lateral habenula (LHb) are of particular importance. The overarching goal of the studies proposed in this application is to understand the monoaminergic neuron-LHb interactions responsible for the experience of MA- induced aversion via TAAR1 that may reduce risk for MA use. Our preliminary data show that MA activates lateral habenula (LHb) neurons, specifically in mice with functional TAAR1. The studies in Aim 1 will use slice electrophysiology to examine the TAAR1-dependent effects of MA in ventral tegmental area dopamine and dorsal raphe serotonin neurons, comparing slices from wildtype and CRISPRed knock-in mice, mice that have functional vs. nonfunctional TAAR1, respectively. Aim 1 studies will also use optogenetic stimulation to examine the effects of MA on glutamatergic synapses from the LHb. Based on our published findings, functional behavioral studies in this aim will examine the role of a glutamate receptor subunit, GluN2B, on MA aversion and intake. Aim 2 will perform behavioral studies focused on the LHb, which has been shown to mediate other types of aversion, has not been studied for MA aversion. We will ablate the LHb in mice with and without functional TAAR1 and study the impact on MA aversion and intake. Finally, Aim 3 studies will use a retrograde tracer to identify the LHb neurons that project to either the ventral tegmentum or dorsal raphe. Electrophysiological studies will determine whether dopamine or serotonin modulate MA activation of LHb neurons and determine whether MA activation of TAAR1 in presynaptic terminals of ventral tegmental area dopamine neurons or dorsal raphe serotonin neurons regulate the effects of MA using slices from mice with and without functional TAAR1. Thus, this proposal utilizes genetic tools, circuit analysis via electrophysiology and behavioral analysis to identify how MA engages LHb neurons in a TAAR1-dependent manner, whether LHb circuits are necessary for MA-induced aversion behaviors, and whether they inhibit MA intake. This strategy could be used to study effects of MA on TAAR1 signaling in other regions. The study of mechanisms underlying sensitivity to MA-induced aversion could lead to the identification of a new class of therapeutics.