Mechanism of TAAR1 modulation of response to MA administration

William Hoffman, M.D., Ph.D., Principal Investigator
Damien Fair, Ph.D., Co-Investigator

Methamphetamine (MA) use disorder (MUD) is a chronic illness problem with increasing global prevalence that crosses socioeconomic boundaries and causes substantial medical morbidity and economic burden. The relapse rate during the first year of treatment exceeds 60%. This project investigates a human amine associated receptor, TAAR1, synonymous single nucleotide polymorphism (SNP; V288V) that is associated with both increased craving (a predictor of relapse) and increased striato-limbic and cortico-striatal resting state functional connectivity (RSFC) in MA users. We hypothesize that MA, a potent agonist at the intracellular TAAR1 receptor, interacts with altered expression resulting from the V288V SNP to change network connectivity in chronic MUD. Specifically, we hypothesize that differences in degree of TAAR1 function will alter network connectivity in downstream targets of the mesocorticolimbic dopamine (DA) projection that originates in the ventral tegmental area SA1). As a result of this alteration of RSFC, we expect to find differences in neural response to a craving task (SA2), between wild type (WT) and V288V MA groups. TAAR1 regulates DA signaling in VTA targets and we expect individuals in the two genetic groups to perform differently on the Monetary Incentive Delay task, a procedure sensitive to changes in DA signaling (SA3). We use acute oral administration of MA to both controls (CS) and MA subjects to amplify any effect of genotype on DA signaling.

  • Aim 1: Determine how TAAR1 WT vs V288V common variant genotype modulates the effect of acute MA administration on RSFC networks in CS and chronic active MA users.
  • Aim 2: Elucidate how TAAR1 genotype modulates the effect of MA administration on the neural correlates of craving and hedonic response.
  • Aim 3: Evaluate the genotypic modulation of acute MA administration on measures sensitive to DA signaling using the Monetary Incentive Delay task.

This project will consent and enroll up to 250 subjects in four groups: CS-WT, CS-V288V, MA-WT and MA-V288V. Subjects will be administered MA and placebo in a blinded, randomized manner over two visits and evaluated with resting state fMRI, task-based fMRI (Drug-Preference Task and the Monetary Incentive Delay Task), subjective effects and behavioral tasks. P002 will test the hypothesis that TAAR1 affects VTA dopaminergic neurons (hence the network of VTA targets) via regulation of glutamate signaling in the VTA, while P003 will investigate murine Taar1 modulation of incubation of craving via assessment of synaptic plasticity in VTA neurons and their striatal and cortical targets. Finally, P004 will investigate RSFC in the mouse and rat models in P002 and P003 for direct comparison with human results from this component.