Effects of Genotype on Resting State Connectivity During Methamphetamine Administration
Condition: Methamphetamine-dependence
Study type: Interventional
Phase: Phase 4

Summary: 
      Addiction to methamphetamine (MA) is a serious health problem in the United States. Right
      now, there are no medically approved treatments for MA dependence. More research is needed to
      understand how MA affects the brain and to eventually develop medical interventions for MA
      addiction. The purpose of the study is to learn more about how MA use affects the brain by
      investigating a receptor in the brain called trace amine-associated receptor 1 (TAAR1). The
      investigators are hoping to find out if individuals with certain versions of the brain
      receptor react differently when given MA. The TAAR1 receptor has two prevalent genetic
      variations due to a single nucleotide polymorphism. These are the wild type (WT) and a common
      variant (CV). Preliminary studies have shown that these variants produce different
      connectivity (resting state functional connectivity or RSFC) in the brains of individuals
      with MA use disorder (MUD), specifically that individuals with the CV genotype exhibit lower
      RSFC than WT. In this study, MA will be administered to individuals with MA use disorder and
      healthy controls in order to:

        1. Determine the influence of CV vs. WT genotype on RSFC and craving in individuals with
           chronic MUD and healthy controls.

        2. Determine the effect of acute methamphetamine or placebo administration on the
           interaction of CV vs WT genotype on RSFC, craving, cognitive control, attention and
           subjective experience in MUD and healthy controls.
    

Detailed description: 
      This proposal will determine the effect of a common variant (CV) synonymous single nucleotide
      polymorphism (SNP) of the gene for the human trace amine associated receptor 1 (TAAR1) on the
      neural and behavioral response of subjects with methamphetamine (MA) use disorder (MUD) and
      healthy control subjects to acute MA administration. The SNP (rs8192620 on human [GRCh38.p7]
      chromosome 6 at 132,645,140 bp in htaar1, allelic frequency 22%) results from a change of
      adenine to guanine in a valine codon at amino acid 288 (v288v). MA is a potent agonist at the
      TAAR1 receptor, in addition to its actions at the dopamine transporter and the vesicular
      monoamine transporter. In rodents, a decrease in TAAR1 expression or non-functional TAAR1
      receptor is associated with an increase in striatal dopamine (DA) signaling.

      The scientific premise of this project is based on 1) preliminary findings that support a
      model that the CV alters RSFC of the striatum, a dopaminergic terminal region, and associated
      behavior in chronic MUD, 2) published reports that delineate the effect of TAAR1 on DA
      signaling and 3) preclinical evidence that TAAR1 influences sensitivity to rewarding and
      aversive effects of MA.

      Furthermore, this proposal will address questions that have important implications for
      understanding and treating patients with MUD, as the TAAR1 receptor is implicated in MA
      self-administration. As an allele of the murine TAAR1 gene associated with an inactive
      receptor leads to increased MA intake in homozygotes, it is critically important to study the
      feasibility of exploiting human variant htaar1.

      The investigators propose a model based on this premise that makes testable predictions about
      the interaction of the CV with chronic and acute MA administration in MUD. The investigators'
      preliminary data show that the CV causes over-expression of TAAR1 in cell culture.
      Stimulation of the TAAR1 receptor decreases dopaminergic signaling in mesocorticolimbic and
      corticostriatal networks. The investigators propose that this effect in conjunction with
      chronic MA use causes neuroadaptations that result in the increased striato- and
      corticolimbic RSFC as well as increased drug craving observed in MUD subjects with the CV.
      The investigators can indirectly test the hypothesis of decreased DA release due to
      ever-expression via MA administration. The effect of acute MA administration on RSFC in
      humans is not known but acute administration of S-amphetamine and methylphenidate reduce RSFC
      in salience attribution and default mode networks presumably via increased DA release.
      Stimulation of over-expressed TAAR1 should blunt this effect in CV carrying individuals
      compared to WT. There are no published reports on neural effects of the interaction between
      either chronic or acute MA administration and htaar1 genotype in humans, therefore this
      proposal represents a unique opportunity to determine whether the RSFC response to acute MA
      administration in humans is mediated by genotype.
    

Intervention name(s): Magnetic resonance imaging (MRI); Methamphetamine Hydrochloride Tablets; Placebo oral tablet
Intervention type(s): Behavioral; Drug; Drug
Intervention description(s): On visits 2 and 3, subjects will undergo a baseline MRI scan approximately 1 hour after the start of each visit followed by drug administration (placebo or MA) and a second scan 1.5 hours after that.; Study participants will receive an oral dose of methamphetamine hydrochloride on one of two scan days and an identical looking placebo in tablet form on the other scan day. Drug type will be randomized between the two visits. Participants will receive the following doses of methamphetamine hydrochloride in accordance with their weight: if weight is between 50-60 kg, 15 mg dose of methamphetamine hydrochloride will be administered. Similarly, for 60-80 kg, 20 mg dose; 80-100 kg, 25 mg dose; and 100+ kg, 30 mg dose.; Study participants will receive an oral dose of methamphetamine hydrochloride on one of two scan days and an identical looking placebo in tablet form on the other scan day. Drug type will be randomized between the two visits.
Other intervention name(s): Desoxyn
Intervention MeSH terms: Methamphetamine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Diagnostic
Keywords: Methamphetamine