Effects of Genotype on Resting State Connectivity During Methamphetamine Administration
- Conditions
- Methamphetamine-dependence
- Interventions
- Behavioral: Magnetic resonance imaging (MRI)Drug: Placebo oral tablet
- Registration Number
- NCT03973489
- Lead Sponsor
- Oregon Health and Science University
- Brief 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 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 69
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Wild Type (WT) MUD Group Methamphetamine Hydrochloride Tablets Wild Type (WT) Group: individuals who are WT for the TAAR1 gene Common Variant (CV) MUD Group Methamphetamine Hydrochloride Tablets Common Variant (CV) Group: individuals who are hetero-or homozygous for the valine codon occurring at amino acid position 288, designated V288V, SNP on the TAAR1 gene Wild Type (WT) Healthy Control Group Methamphetamine Hydrochloride Tablets Wild Type (WT) Group: individuals who are WT for the TAAR1 gene Wild Type (WT) MUD Group Magnetic resonance imaging (MRI) Wild Type (WT) Group: individuals who are WT for the TAAR1 gene Wild Type (WT) MUD Group Placebo oral tablet Wild Type (WT) Group: individuals who are WT for the TAAR1 gene Common Variant (CV) MUD Group Magnetic resonance imaging (MRI) Common Variant (CV) Group: individuals who are hetero-or homozygous for the valine codon occurring at amino acid position 288, designated V288V, SNP on the TAAR1 gene Common Variant (CV) MUD Group Placebo oral tablet Common Variant (CV) Group: individuals who are hetero-or homozygous for the valine codon occurring at amino acid position 288, designated V288V, SNP on the TAAR1 gene Wild Type (WT) Healthy Control Group Magnetic resonance imaging (MRI) Wild Type (WT) Group: individuals who are WT for the TAAR1 gene Wild Type (WT) Healthy Control Group Placebo oral tablet Wild Type (WT) Group: individuals who are WT for the TAAR1 gene Common Variant (CV) Healthy Control Group Magnetic resonance imaging (MRI) Common Variant (CV) Group: individuals who are hetero-or homozygous for the V288V SNP on the TAAR1 gene Common Variant (CV) Healthy Control Group Methamphetamine Hydrochloride Tablets Common Variant (CV) Group: individuals who are hetero-or homozygous for the V288V SNP on the TAAR1 gene Common Variant (CV) Healthy Control Group Placebo oral tablet Common Variant (CV) Group: individuals who are hetero-or homozygous for the V288V SNP on the TAAR1 gene
- Primary Outcome Measures
Name Time Method Functional Connectivity During Resting State Magnetic Resonance Imaging (MRI) 1 hour prior to and 1.5 hours post study drug administration on visits 2 and visit 3 (randomized to placebo or methamphetamine; washout period between visit 2 and 3 was at least 3 days) Pearson correlation coefficient (r) was used to calculate cortico-striatal and intra-striatal functional connectivity during resting state. These r values were then converted into Fisher's Z-scores using the transformation: z = arctanh(r) = 0.5\*ln((1+r)/(1-r)). Fisher's Z-transformation linearizes Pearson correlations and allows for statistical analysis. The Z-scores represent the strength and direction of functional connectivity between brain regions. A Z-score of 0 represents the population mean for functional connectivity between brain regions. Larger Z-scores indicate stronger connectivity (potentially indicating greater activation or association), while smaller (negative) Z-scores indicate weaker connectivity, which could suggest reduced synchronization or disrupted brain function. Z-scores above or below ±1 standard deviation from the mean may indicate notable deviations from the expected connectivity patterns in the population.
Euphoria Effects of Study Drug 2.5 hours prior to and between 1-4 hours post study drug administration on visits 2 and visit 3 (randomized to placebo or methamphetamine; washout period between visit 2 and 3 was at least 3 days) The Morphine Benzedrine group (MBG) scale is a subscale of the Addiction Research Center Inventory (ARCI-49), a 49 item questionnaire consisting of true/false items, which measures the euphoric effects of the study drug. The MBG scale ranges from 0-16 with higher numbers indicating more euphoria. The questionnaire was administered every hour for four hours following study drug administration and the highest score during this time is considered the post drug administration score.
Craving Assessed With the Stimulant Craving Questionnaire (STCQ) 2 hours prior to and 3 hours post study drug administration on visits 2 and visit 3 (randomized to placebo or methamphetamine; washout period between visit 2 and 3 was at least 3 days) Current craving for methamphetamine was assessed using the Stimulant Craving Questionnaire (STCQ), which is a 10-item self-report measure that uses a seven-point scale, with answers ranging from 0 ("strongly disagree") to 6 ("strongly agree"). A composite score was computed by averaging the responses for all 10 items after reverse scoring items 4 and 7. Scores range from 0 to 6 with higher scores representing higher craving for methamphetamine.
Cognitive Function 2 hours prior to and 3 hours post study drug administration on visits 2 and visit 3 (randomized to placebo or methamphetamine; washout period between visit 2 and 3 was at least 3 days) Two computer tests were administered to measure how each medication intervention effects cognitive functioning. The tests administered included the Rapid Visual Information Processing Task (RVIPT), a 6 minute test of sustained attention in which participants are requested to detect target sequences of digits and the Digit Symbol Substitution Task (DSST), a 2 minute test of psychomotor speed and sustained attention consisting of digit-symbol pairs followed by a list of digits where the subject identifies the symbol that corresponds to each digit as fast as possible. The number of correct responses within the allowed time is measured. Higher scores on both tasks indicate better performance.
- Secondary Outcome Measures
Name Time Method Methamphetamine Concentration in Saliva (ng/ml) 2.5 hours prior to and 3 hours post study drug administration on visits 2 and visit 3 (randomized to placebo or methamphetamine; washout period between visit 2 and 3 was at least 3 days) Saliva samples were acquired to test concentration of methamphetamine levels
Trial Locations
- Locations (2)
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Portland VA Medical Center
🇺🇸Portland, Oregon, United States