Ignite Creation Date:
2024-05-06 @ 1:15 PM
Last Modification Date:
2024-10-26 @ 1:11 PM
Study NCT ID:
NCT03973489
Status:
COMPLETED
Last Update Posted:
2023-11-18
First Post:
2019-05-31
Brief Title:
Effects of Genotype on Resting State Connectivity During Methamphetamine Administration
Sponsor:
Oregon Health and Science University
Organization:
Oregon Health and Science University
Study Overview
Official Title:
Effects of Genotype on Resting State Connectivity During Methamphetamine Administration
Status:
COMPLETED
Status Verified Date:
2023-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
MATAAR
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
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 GRCh38p7 chromosome 6 at 132645140 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
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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None