Effects of Genotype on Resting State Connectivity During Methamphetamine Administration

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.

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 Genome Reference Consortium Human Build 38 patch release 7 chromosome 6 at 132,645,140 bp in htaar1, allelic frequency 22%) results from a change of adenine to guanine in a valine codon occurring at amino acid position 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.

Eligibility Criteria:
Criteria for Inclusion:

\[All groups\]

* 18 to 55 years old
* Homozygous or heterozygous for the human TAAR1 (hTAAR1) V288V genotype or wild type for hTAAR1 (determined during screening visit "Visit 1")

\[Meth use group\]

* Subjects must have a positive urine drug screen for methamphetamine during visit one
* Meets current criteria for methamphetamine use disorder
* Subjects should have been using at least 100mg of methamphetamine (not prescribed), 5 days per week for at least one year
* Abstinent from methamphetamine for 24 hours on days of scans

\[Healthy volunteer group\]

- At least one exposure to a stimulant, either recreational or prescribed

Criteria for Exclusion:

\[All groups\]

* Allergies to stimulants or hypersensitivity to taking a stimulant in the past
* Diagnosis of a psychotic or mood disorder
* Self-reported claustrophobia
* Women who are pregnant or breast-feeding
* Intoxicated on study days
* Clinically significant neurological, cardiovascular, endocrine, renal, hepatic or systemic disease that could compromise safe participation or confound outcomes (including hepatitis C, HIV, severe anemia, or liver disease)
* History of glaucoma
* Metal in the body which is contraindicated for MRI or would compromise image quality
* Current prescription use of stimulants, anti-psychotic drugs or anti-Parkinson's drugs
* Use of monoamine oxidase inhibitors within 14 days
* Use of serotonin reuptake inhibiters, serotonin norepinephrine reuptake inhibiters, triptans, tricyclic antidepressants, Fentanyl, lithium, tramadol, tryptophan, buspirone , St. John's Wort, insulin, phenothiazines, guanethidine, acidifying/alkalinizing agents, CYP2D6 inhibitors, proton pump inhibitors

\[Meth use group\]

* Positive urine drug screen at any point during the study (except for meth or marijuana)
* History of any severe substance use disorders within the last 5 years, except for methamphetamine use disorder or tobacco use disorder

\[Healthy volunteer group\]

* History of any severe substance use disorders within the last 5 years except tobacco use disorder
* Positive urine drug screen at any point in the study (except for marijuana or for verified medical reasons)