Neuropsychological Performance and Functional Capacity Following Mild Traumatic Brain Injury in Veterans.

OBJECTIVE: To examine the relationship between neuropsychological functioning and performance-based functional capacity in veterans with a history of mild traumatic brain injury (mTBI), as well as the moderating effects of age and psychiatric symptoms on this relationship. SETTING: Three Veterans Affairs medical centers. PARTICIPANTS: One hundred nineteen Iraq/Afghanistan veterans with a history of mTBI and self-reported cognitive difficulties. DESIGN: Cross-sectional, secondary data analysis of baseline measures in a randomized controlled trial. MAIN MEASURES: The main outcome measure, functional capacity, was assessed using the objective and performance-based University of California San Diego Performance-based Skills Assessment-Brief. A global deficit score (GDS) was created as a composite score for performance on a battery of neuropsychological measures assessing domains of attention, processing speed, executive functioning, and verbal memory performance. Posttraumatic stress disorder (PTSD) symptom severity was assessed using the PTSD Checklist-Military Version, and depressive symptom severity was assessed using the Beck Depression Inventory, Second Edition. RESULTS: Bivariate analyses indicated that worse neuropsychological performance (ie, higher GDS) and greater PTSD symptom severity were associated with worse communication abilities and worse overall functional capacity. Multiple linear regressions demonstrated that GDS and PTSD symptom severity explained 9% of the variance in communication and 10% of the variance in overall functional capacity; however, GDS emerged as the only significant predictor in both regressions. Age, PTSD, and depressive symptom severity did not moderate the relationship between GDS and overall functional capacity. Performance in the verbal learning and memory domain emerged as the strongest neuropsychological predictor of communication and overall functional capacity. CONCLUSIONS: Worse neuropsychological functioning was moderately associated with worse performance-based functional capacity, even when accounting for PTSD symptom severity. Verbal learning and memory was the primary neuropsychological domain driving the relationship with functional capacity; improvement in verbal learning and memory may translate into improved functional capacity.

Change in Learning and Memory Partially Mediates Effects of Compensatory Cognitive Training on Self-Reported Cognitive Symptoms.

OBJECTIVE: To examine associations among compensatory cognitive training (CCT), objective cognitive functioning, and self-reported cognitive symptoms. We examined whether change in objective cognitive functioning associated with participation in CCT at 10-week follow-up mediates change in self-reported cognitive symptoms associated with CCT at 15-week follow-up. SETTING: Three VA outpatient mental health clinics. PARTICIPANTS: Veterans with a history of mild traumatic brain injury who reported cognitive deficits. DESIGN: Randomized controlled trial post hoc causal mediation analysis. MAIN MEASURES: Self-reported cognitive symptoms were measured by the Prospective-Retrospective Memory Questionnaire and the Multiple Sclerosis Neuropsychological Screening Questionnaire. Objective cognitive functioning was measured using a battery of neuropsychological tests. RESULTS: Improvement on the Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall test mediated the association between participation in CCT and decrease in the Prospective-Retrospective Memory Questionnaire total score. Improvement on the HVLT-R Total Recall and HVLT-R Delayed Recall tests both meditated the association between participation in CCT and decrease in the Multiple Sclerosis Neuropsychological Screening Questionnaire total score. No other measures of objective cognitive functioning were significant mediators. CONCLUSION: Patients' perceptions of cognitive symptom improvement due to CCT are partially mediated by learning and memory, though these subjective improvements occur regardless of other changes in objective cognitive functioning associated with CCT.

Predictors of Intervention Adherence in Compensatory Cognitive Training for Veterans With a History of Mild Traumatic Brain Injury.

OBJECTIVE: The purpose of this study was to determine modifiable predictors of intervention adherence in a study of group-based Compensatory Cognitive Training (CCT) for Iraq/Afghanistan War veterans with a history of mild traumatic brain injury (mTBI). METHODS: One hundred twenty-three veterans enrolled in a randomized controlled trial of a 10-week CCT intervention (54 assigned to CCT) and were evaluated at baseline, 5 weeks, 10 weeks, and 15 weeks. CCT adherence was determined by the number of CCT sessions attended, with more sessions indicative of greater adherence. Baseline demographic and clinical characteristics, and subjective and objective neuropsychological performance, were examined in relation to CCT session attendance. RESULTS: Older age and worse attention performance at baseline were associated with higher CCT attendance rates. CONCLUSIONS: This study generates preliminary evidence for potential modifiable neuropsychological factors that may improve engagement in CCT interventions.

Functional MRI and delay discounting in patients infected with hepatitis C.

Hepatitis C virus-infected (HCV+) adults evidence increased rates of psychiatric and cognitive difficulties. This is the first study to use functional magnetic resonance imaging (fMRI) to examine brain activation in untreated HCV+ adults. To determine whether, relative to non-infected controls (CTLs), HCV+ adults exhibit differences in brain activation during a delay discounting task (DDT), a measure of one's tendency to choose smaller immediate rewards over larger delayed rewards-one aspect of impulsivity. Twenty adults with HCV and 26 CTLs completed an fMRI protocol during the DDT. Mixed effects regression analyses of hard versus easy trials of the DDT showed that, compared with CTLs, the HCV+ group exhibited less activation in the left lateral occipital gyrus, precuneus, and superior frontal gyrus. There were also significant interactive effects for hard-easy contrasts in the bilateral medial frontal gyrus, left insula, left precuneus, left inferior parietal lobule, and right temporal occipital gyrus; the CTL group evidenced a positive relationship between impulsivity and activation, while the HCV+ group exhibited a negative relationship. Within the HCV+ group, those with high viral load chose immediate rewards more often than those with low viral load, regardless of choice difficulty; those with low viral load chose immediate rewards more often on hard choices relative to easy choices. Results show that HCV+ patients exhibit greater impulsive behavior when presented with difficult choices, and impulsivity is negatively related to activation in regions important for cognitive control. Thus, interventions that decrease impulsive choice may be warranted with some HCV+ patients.

Parallel Effects of Methamphetamine on Anxiety and CCL3 in Humans and a Genetic Mouse Model of High Methamphetamine Intake.

BACKGROUND: Methamphetamine (MA) abuse causes immune dysfunction and neuropsychiatric impairment. The mechanisms underlying these deficits remain unidentified. METHODS: The effects of MA on anxiety-like behavior and immune function were investigated in mice selectively bred to voluntarily consume high amounts of MA [i.e., MA high drinking (MAHDR) mice]. MA (or saline) was administered to mice using a chronic (14-day), binge-like model. Performance in the elevated zero maze (EZM) was determined 5 days after the last MA dose to examine anxiety-like behavior. Cytokine and chemokine expressions were measured in the hippocampus using quantitative polymerase chain reaction (qPCR). Human studies were also conducted to evaluate symptoms of anxiety using the General Anxiety Disorder-7 Scale in adults with and without a history of MA dependence. Plasma samples collected from human research participants were used for confirmatory analysis of murine qPCR results using an enzyme-linked immunosorbent assay. RESULTS: During early remission from MA, MAHDR mice exhibited increased anxiety-like behavior on the EZM and reduced expression of chemokine (C-C motif) ligand 3 (ccl3) in the hippocampus relative to saline-treated mice. Human adults actively dependent on MA and those in early remission had elevated symptoms of anxiety as well as reductions in plasma levels of CCL3, relative to adults with no history of MA abuse. CONCLUSIONS: The results highlight the complex effects of MA on immune and behavioral function and suggest that alterations in CCL3 signaling may contribute to the mood impairments observed during remission from MA addiction.

Mental Health Does Not Moderate Compensatory Cognitive Training Efficacy for Veterans With a History of Mild Traumatic Brain Injury.

OBJECTIVE: To examine the potential moderating effects of mental health symptoms on the efficacy of compensatory cognitive training (CCT) for Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn veterans with a history of mild traumatic brain injury (mTBI). DESIGN: Secondary analysis of a randomized controlled trial of CCT. Posttraumatic stress disorder, depression, and substance dependence symptom severity were examined as potential moderators of CCT efficacy for subjective cognitive complaints, use of cognitive strategies, and objective neurocognitive performance. SETTING: Three Veterans Affairs medical centers. PARTICIPANTS: Participants included veterans with history of mTBI (N=119): 50 participated in CCT and 69 received usual care (UC). INTERVENTION: CCT is a 10-week group-based (90 minutes per session) manualized cognitive rehabilitation intervention. MAIN OUTCOME MEASURES: Objective (neuropsychological functioning) and subjective (self-report) cognitive functioning and use of cognitive strategies. RESULTS: Baseline mental health symptoms did not moderate CCT efficacy: veterans who received CCT reported significantly greater improvement in cognitive difficulties and use of cognitive strategies compared with the UC group, regardless of baseline mental health symptom severity. The CCT group also demonstrated significant improvements on neuropsychological measures of attention, learning, and executive functioning compared with the UC group, regardless of baseline mental health symptom severity. CONCLUSIONS: CCT is efficacious for improving objective cognitive functioning and compensatory strategy use for veterans with a history of mTBI, regardless of the severity of comorbid psychiatric symptoms.

Compensatory Cognitive Training for Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn Veterans With Mild Traumatic Brain Injury.

OBJECTIVE: The purpose of the study was to evaluate the efficacy of group-based compensatory cognitive training (CCT) for Operation Enduring Freedom (OEF)/Operation Iraqi Freedom(OIF)/Operation New Dawn (OND) Veterans with a history of mild traumatic brain injury. METHOD: One hundred nineteen OEF/OIF/OND Veterans with history of mild traumatic brain injury participated at 3 sites, and 50 of the Veterans were randomized to CCT group, while 69 Veterans were randomized to the usual care control group. The CCT group participated in 10 weeks of CCT. Both CCT and usual care groups were assessed at baseline, 5 weeks (midway through CCT), 10 weeks (immediately following CCT), and 15 weeks (5-week follow-up) on measures of subjective cognitive complaints, use of cognitive strategies, psychological functioning, and objective cognitive performance. RESULTS: Veterans who participated in CCT reported significantly fewer cognitive and memory difficulties and greater use of cognitive strategies. They also demonstrated significant improvements on neurocognitive tests of attention, learning, and executive functioning, which were 3 of the cognitive domains targeted in CCT. CONCLUSIONS: Findings indicate that training in compensatory cognitive strategies facilitates behavioral change (ie, use of cognitive strategies) as well as both subjective and objective improvements in targeted cognitive domains.

Everyday problems with executive dysfunction and impulsivity in adults recovering from methamphetamine addiction.

OBJECTIVES: Compared with non-addicted controls (CTLs), adults in remission from methamphetamine addiction (MA-REM) evidence impairments on objective measures of executive functioning and impulsivity. METHODS: To evaluate the impact of these impairments in MA-REM adults, demographically matched groups (MA-REM, n=30; CTLs, n=24) completed objective and self-report measures of executive functioning and impulsivity. RESULTS: MA-REM adults demonstrated significantly (p < 0.050) greater objective and subjective problems with executive functioning and impulsivity. CONCLUSIONS: These results suggest that adults in MA-REM are aware of their deficits and that these deficits have significant impact in everyday life.

Comparing the Neuropsychological Test Performance of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans with and without Blast Exposure, Mild Traumatic Brain Injury, and Posttraumatic Stress Symptoms.

To compare neuropsychological test performance of Veterans with and without mild traumatic brain injury (MTBI), blast exposure, and posttraumatic stress disorder (PTSD) symptoms. We compared the neuropsychological test performance of 49 Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans diagnosed with MTBI resulting from combat blast-exposure to that of 20 blast-exposed OEF/OIF Veterans without history of MTBI, 23 OEF/OIF Veterans with no blast exposure or MTBI history, and 40 matched civilian controls. Comparison of neuropsychological test performance across all four participant groups showed a complex pattern of mixed significant and mostly nonsignificant results, with omnibus tests significant for measures of attention, spatial abilities, and executive function. The most consistent pattern was the absence of significant differences between blast-exposed Veterans with MTBI history and blast-exposed Veterans without MTBI history. When blast-exposed Veteran groups with and without MTBI history were aggregated and compared to non-blast-exposed Veterans, there were significant differences for some measures of learning and memory, spatial abilities, and executive function. However, covariation for severity of PTSD symptoms eliminated all significant omnibus neuropsychological differences between Veteran groups. Our results suggest that, although some mild neurocognitive effects were associated with blast exposure, these neurocognitive effects might be better explained by PTSD symptom severity rather than blast exposure or MTBI history alone.

Protective effects of higher cognitive reserve for neuropsychological and daily functioning among individuals infected with hepatitis C.

Higher levels of cognitive reserve (CR) can be protective against the neuropsychological manifestation of neural injury across a variety of clinical disorders. However, the role of CR in the expression of neurocognitive deficits among persons infected with the hepatitis C virus (HCV) is not well understood. Thirty-nine HCV-infected participants were classified as having either high (n = 19) or low (n = 20) CR based on educational attainment, oral word reading, and IQ scores. A sample of 40 demographically comparable healthy adults (HA) was also included. All participants completed the Neuropsychological Assessment Battery, Delis-Kaplan Executive Function System, and Behavioral Rating Inventory of Executive Function, Adult Version (BRIEF-A). Linear regression analyses, controlling for gender, depression, and lifetime substance use disorders, found significant effects of HCV/CR group on verbal fluency, executive functions, and daily functioning T scores, but not in learning or the BRIEF-A. Pairwise comparisons revealed that the HCV group with low CR performed significantly below the HCV high CR and HA cohorts, who did not differ from one another. Findings indicate that higher levels of CR may be a protective factor in the neurocognitive and real-world manifestation of neural injury commonly associated with HCV infection.

Efficacy of cognitive rehabilitation therapies for mild cognitive impairment (MCI) in older adults: working toward a theoretical model and evidence-based interventions.

To evaluate the efficacy of cognitive rehabilitation therapies (CRTs) for mild cognitive impairment (MCI). Our review revealed a need for evidence-based treatments for MCI and a lack of a theoretical rehabilitation model to guide the development and evaluation of these interventions. We have thus proposed a theoretical rehabilitation model of MCI that yields key intervention targets-cognitive compromise, functional compromise, neuropsychiatric symptoms, and modifiable risk and protective factors known to be associated with MCI and dementia. Our model additionally defines specific cognitive rehabilitation approaches that may directly or indirectly target key outcomes-restorative cognitive training, compensatory cognitive training, lifestyle interventions, and psychotherapeutic techniques. Fourteen randomized controlled trials met inclusion criteria and were reviewed. Studies markedly varied in terms of intervention approaches and selected outcome measures and were frequently hampered by design limitations. The bulk of the evidence suggested that CRTs can change targeted behaviors in individuals with MCI and that CRTs are associated with improvements in objective cognitive performance, but the pattern of effects on specific cognitive domains was inconsistent across studies. Other important outcomes (i.e., daily functioning, quality of life, neuropsychiatric symptom severity) were infrequently assessed across studies. Few studies evaluated long-term outcomes or the impact of CRTs on conversion rates from MCI to dementia or normal cognition. Overall, results from trials are promising but inconclusive. Additional well-designed and adequately powered trials are warranted and required before CRTs for MCI can be considered evidence-based.

Cognition during active methamphetamine use versus remission.

OBJECTIVE: To evaluate whether cognitive performance in adults with active methamphetamine use (MA-ACT) differs from cognitive performance in adults in remission from MA use disorder (MA-REM) and adults without a history of substance use disorder (CTLs). METHOD: MA-ACT (n = 36), MA-REM (n = 48), and CTLs (n = 62) completed the Neuropsychological Assessment Battery (NAB). RESULTS: The MA-ACT group did not perform significantly worse than CTLs on any NAB Index. The MA-REM group performed significantly (p < 0.050) worse than CTLs on the NAB Memory Index. The MA-ACT group performed significantly better than CTLs and the MA-REM group on the Executive Functions Index. CONCLUSIONS: Some cognitive deficits are apparent during remission from MA use, but not during active use; this may result in clinical challenges for adults attempting to maintain recovery and continue with treatment.

Global and local morphometric differences in recently abstinent methamphetamine-dependent individuals.

Methamphetamine (MA) is associated with behavioral and cognitive deficits that may be related to macrostructural abnormalities. Quantitative anatomical comparisons between controls and methamphetamine-dependent individuals have produced conflicting results. We examined local and global differences in brain structure in 61 abstinent methamphetamine-dependent individuals and 44 controls with voxel-based morphometry and tissue segmentation. We related regional differences in gray matter density and whole brain segmentation volumes to performance on a behavioral measure of impulsivity and group membership using multiple linear regression. Within the MA group, we related cortical and subcortical gray matter density to length of abstinence. Controls had greater density relative to MA in bilateral insula and left middle frontal gyrus. Impulsivity was higher in the MA group and, within all subjects, impulsivity was positively correlated with gray matter density in posterior cingulate cortex and ventral striatum and negatively correlated in left superior frontal gyrus. Length of abstinence from MA was associated with greater amygdalar density. Earlier age of first use of MA (in subjects who initiated use before age 21) was associated with smaller intracranial volume. The findings are consistent with multiple possible mechanisms including neuroadaptations due to addictive behavior, neuroinflammation as well as dopaminergic and serotonergic neurotoxicity.

Neuroimmune mechanisms of cytokine-induced depression: current theories and novel treatment strategies.

The relationships between immune and neural function are an increasingly important area of study for neuropsychiatric disorders, in particular depression. This is exemplified by the growing number of publications on cytokines and depression during the last 10 years, as compared to earlier decades. This review summarizes the current theories and novel treatment strategies for depression, with a focus on cytokine-induced depression. Neuroimmune mechanisms are now viewed as central to the development of depressive symptoms and emerging evidence is beginning to identify the neural circuits involved in cytokine-induced depression. The current diagnostic categories for depression, as defined by the Diagnostic and Statistical Manual of Mental Disorders, however, are not etiologically or biologically derived, and it has been proposed that "depression", likely reflects multiple pathogeneses leading to varying symptom constellations. As we move toward a better biological understanding of depression-related symptom constellations or syndromes, the term "depression" may prove inadequately broad, and an integration of interdisciplinary literatures will increase in importance. Future research should aim to characterize these depression-related symptom constellations or syndromes better with the goal of optimizing treatment strategies.

Partial MHC/neuroantigen peptide constructs attenuate methamphetamine-seeking and brain chemokine (C-C motif) ligand 2 levels in rats.

There are no medications that target the neurotoxic effects or reduce the use of methamphetamine. Recombinant T-cell receptor ligand (RTL) 1000 [a partial major histocompatibility complex (pMHC) class II construct with a tethered myelin peptide], addresses the neuroimmune effects of methamphetamine addiction by competitively inhibiting the disease-promoting activity of macrophage migration inhibitory factor to CD74, a key pathway involved in several chronic inflammatory conditions, including substance use disorders. We previously reported that RTL constructs improve learning and memory impairments and central nervous system (CNS) inflammation induced by methamphetamine in mouse models. The present study in Lewis rats evaluated the effects of RTL1000 on maintenance of self-administration and cue-induced reinstatement using operant behavioral methods. Post-mortem brain and serum samples were evaluated for the levels of inflammatory factors. Rats treated with RTL1000 displayed significantly fewer presses on the active lever as compared to rats treated with vehicle during the initial extinction session, indicating more rapid extinction in the presence of RTL1000. Immunoblotting of rat brain sections revealed reduced levels of the pro-inflammatory chemokine (C-C motif) ligand 2 (CCL2) in the frontal cortex of rats treated with RTL1000, as compared to vehicle. Post hoc analysis identified a positive association between the levels of CCL2 detected in the frontal cortex and the number of lever presses during the first extinction session. Taken together, results suggest that RTL1000 may block downstream inflammatory effects of methamphetamine exposure and facilitate reduced drug seeking-potentially offering a new strategy for the treatment of methamphetamine-induced CNS injury and neuropsychiatric impairments.

Methamphetamine use alters human plasma extracellular vesicles and their microRNA cargo: An exploratory study.

Methamphetamine (MA) is the largest drug threat across the globe, with health effects including neurotoxicity and cardiovascular disease. Recent studies have begun to link microRNAs (miRNAs) to the processes related to MA use and addiction. Our studies are the first to analyse plasma EVs and their miRNA cargo in humans actively using MA (MA-ACT) and control participants (CTL). In this cohort we also assessed the effects of tobacco use on plasma EVs. We used vesicle flow cytometry to show that the MA-ACT group had an increased abundance of EV tetraspanin markers (CD9, CD63, CD81), but not pro-coagulant, platelet-, and red blood cell-derived EVs. We also found that of the 169 plasma EV miRNAs, eight were of interest in MA-ACT based on multiple statistical criteria. In smokers, we identified 15 miRNAs of interest, two that overlapped with the eight MA-ACT miRNAs. Three of the MA-ACT miRNAs significantly correlated with clinical features of MA use and target prediction with these miRNAs identified pathways implicated in MA use, including cardiovascular disease and neuroinflammation. Together our findings indicate that MA use regulates EVs and their miRNA cargo, and support that further studies are warranted to investigate their mechanistic role in addiction, recovery, and recidivism.

Randomized controlled trial protocol for project BRIDGE: A telephone-administered motivational interviewing intervention targeting risky sexual behavior in older people living with HIV.

PURPOSE: By 2020, 70% of people living with HIV in the United States will be greater than 50 years of age. As many as 37% of sexually active older people living with HIV (OPLWH) engage in HIV transmission sexual behaviors. In spite of repeated calls for secondary prevention interventions to reduce condomless sex in OPLWH, no age-appropriate, evidence-based secondary prevention interventions exist for this group. Furthermore, many OPLWH face barriers to engaging in face-to-face secondary prevention services because of HIV- and age-related stigma, comorbid mental and physical health conditions that complicate travel, or geographic isolation. High rates of depression in OPLWH may further complicate engagement in interventions intended to reduce HIV transmissions. Telephone-administered motivational interviewing may be a feasible and efficacious intervention for this population. METHODS: This randomized controlled trial will test the efficacy of a 5-session telephone-administered motivational interviewing plus behavioral skills training (teleMI+BST) intervention versus a 5-session telephone-administered coping effectiveness training (teleCET) control intervention to reduce condomless sex in OPLWH. A diverse sample of 336 OPLWH will be recruited across the U.S. The primary analysis will test the efficacy of teleMI+BST to reduce occasions of non-condom protected anal and vaginal intercourse with HIV serodiscordant sex partners. Secondary analyses will examine the efficacy of teleMI+BST to reduce depressive symptoms in mildly depressed OPLWH. CONCLUSION: This is the first large-scale RCT intended to reduce HIV sexual transmission risk behavior in OPLWH and will add to the literature on secondary prevention telehealth interventions for people living with HIV. ClinicalTrials.gov Identifier: NCT03004170. This trial has been conducted by the approval of the Institutional Review Board. Participants provided verbal consent to participate in this trial.

The cognitive effects of hepatitis C in the presence and absence of a history of substance use disorder.

The aim of the study was to determine whether infection with the hepatitis C virus (HCV) is associated with cognitive impairment beyond the effects of prevalent comorbidities and a history of substance use disorder (SUD). Adult veterans were recruited from the Portland Veterans Affairs Medical Center into three groups: (1) HCV+/SUD+ (n = 39), (2) HCV+/SUD- (n = 24), and (3) HCV-/SUD- (n = 56). SUD+ participants were in remission for > or =90 days, while SUD- participants had no history of SUD. Groups did not significantly differ in terms of rates of psychiatric or medical comorbidities. Procedures included clinical interviews, medical record reviews, and neuropsychological testing. Significant group differences were found in the domains of Verbal Memory, Auditory Attention, Speeded Visual Information Processing, and Reasoning/Mental Flexibility (p

Neuroinflammation in addiction: A review of neuroimaging studies and potential immunotherapies.

Addiction is a worldwide public health problem and this article reviews scientific advances in identifying the role of neuroinflammation in the genesis, maintenance, and treatment of substance use disorders. With an emphasis on neuroimaging techniques, this review examines human studies of addiction using positron emission tomography to identify binding of translocator protein (TSPO), which is upregulated in reactive glial cells and activated microglia during pathological states. High TSPO levels have been shown in methamphetamine use but exhibits variable patterns in cocaine use. Alcohol and nicotine use, however, are associated with lower TSPO levels. We discuss how mechanistic differences at the neurotransmitter and circuit level in the neural effects of these agents and subsequent immune response may explain these observations. Finally, we review the potential of anti-inflammatory drugs, including ibudilast, minocycline, and pioglitazone, to ameliorate the behavioral and cognitive consequences of addiction.

Trace amine-associated receptor gene polymorphism increases drug craving in individuals with methamphetamine dependence.

BACKGROUND: Methamphetamine (MA) is a potent agonist at the trace amine-associated receptor 1 (TAAR1). This study evaluated a common variant (CV) in the human TAAR1 gene, synonymous single nucleotide polymorphism (SNP) V288V, to determine the involvement of TAAR1 in MA dependence. METHODS: Participants (n = 106) with active MA dependence (MA-ACT), in remission from MA dependence (MA-REM), with active polysubstance dependence, in remission from polysubstance dependence, and with no history of substance dependence completed neuropsychiatric symptom questionnaires and provided blood samples. In vitro expression and function of CV and wild type TAAR1 receptors were also measured. RESULTS: The V288V polymorphism demonstrated a 40% increase in TAAR1 protein expression in cell culture, but message sequence and protein function were unchanged, suggesting an increase in translation efficiency. Principal components analysis resolved neuropsychiatric symptoms into four components, PC1 (depression, anxiety, memory, and fatigue), PC2 (pain), PC3 (drug and alcohol craving), and PC4 (sleep disturbances). Analyses of study group and TAAR1 genotype revealed a significant interaction for PC3 (craving response) (p = 0.003). The control group showed no difference in PC3 associated with TAAR1, while adjusted mean craving for the MA-ACT and MA-REM groups, among those with at least one copy of V288V, was estimated to be, respectively, 1.55 (p = 0.036) and 1.77 (p = 0.071) times the adjusted mean craving for those without the TAAR1 SNP. CONCLUSIONS: Neuroadaptation to chronic MA use may be altered by TAAR1 genotype and result in increased dopamine signaling and craving in individuals with the V288V genotype.