It is hypothesized that higher DA bio-availability conferred by the Met allele underlies this Met associated neurocognitive ‘advantage’ in healthy adults. However, we have previously demonstrated that in chronic METH users , whose PFC is repeatedly exposed to excessive levels of DA, the Met/Met genotype is no longer associated with better executive function and may in fact confer risk for executive dysfunction . Although these findings suggest that the Met/Met genotype confers disproportionate risk to METH-related neurocognitive dysfunction, it remains unclear whether COMT genotype similarly modulates the effects of METH on biomarkers that directly measure the DAergic system. Thus, the present study evaluated cerebrospinal fluid levels of DA and its metabolite, homovanillic acid , among a cohort of adult men stratified by METH dependence and COMT genotype. Additionally, relationships between CSF DA and executive function were assessed to examine the role of CSF DA as an intermediary linking the interactive effects of METH and COMT on neurocognitive function. Participants were 75 METH-dependent and 47 METH-non-using comparison men enrolled in the University of California, San Diego’s Translational Methamphetamine AIDS Research Center , a NIDA-funded cohort study focusing on the CNS effects of HIV and METH. All participants gave written informed consent as approved by the UCSD Institutional Review Board. COMT genotyping in the parent study was restricted to male participants due to potential sexually-dimorphic effects of COMTand inadequate numbers of female participants to support sex-stratified analyses. Exclusion criteria were: 1) DSM-IV diagnosis of other substance use dependence within the last 5 years, or alcohol dependence within the last 12 months; 2) abuse of any substances other than METH within the last 12 months; 3) evidence of very recent METH use by positive urine toxicology results; 4) history of psychotic or mood disorder with psychotic features, neurological, or medical condition that may confound neuropsychological test results.
To our knowledge,vertical farming solutions the present study is among the first to examine how the interaction of these genetic and environmental factors impacts levels of DA and its metabolite, HVA, in the CNS. METH was associated with lower DA levels, accompanied by higher HVA/DA ratios, only among Met/Met individuals, suggesting that COMT genotype may underlie inter individual differences in vulnerability to METH effects on DAergic tone. Among METH individuals, Met/Met genotype exhibited significant or trend-level medium-to-large effects on higher DA levels and small-to-medium effects on lower HVA/DA ratios , consistent with the known functional effects of the COMT enzyme . However, this Met/Met-related DAergic ‘advantage’ disappeared in METH+ individuals, which parallels our prior findings demonstrating the absence of an executive function ‘advantage’ in METH+ Met/Met individuals . Notably, the strongest associations between DA and executive function occurred within METH- Met/Met individuals, who, on average, exhibited the highest levels of DA. Our findings highlight the conditional influence of COMT on neurobiological and behavioral markers of PFC function in METH use, particularly in the context of HIV, with potential relevance to other neuropsychiatric conditions characterized by DA and PFC dysfunction. The discordant COMT genotype/DA endophenotype profile in METH+ individuals suggests that genetically-driven metabolism of synaptic DA can alter the extent to which chronic METH exposure disrupts DAergic activity. Preclinical data demonstrate that the repeated over stimulation of DA release into the synaptic cleft due to serial METH exposure results in the auto-oxidation of DA and subsequent production of reactive oxygen species that are toxic to monoaminergic terminals in the PFC, striatum, and hippocampus . In an examination of DA biomarkers in post-mortem brain tissues, Kish et al. found 50–61% reductions in striatal DA levels in chronic METH users compared to age-matched controls, yet did not observe any group differences in brain concentrations of DA metabolites, including HVA .
The preservation of DA metabolites in the context of low DA suggests that although complete DA neuronal death is unlikely in METH use, compared to the severe loss of DA neurons in Parkinson’s disease, other mechanisms such as compromised storage of vesicular DA may explain why METH reduces DA but not HVA levels . Although we did not observe a main effect of METH on DA biomarkers, these postmortem results agree with our findings in METH+ Met/Met individuals, who exhibited substantially lower CSF DA and higher CSF HVA/DA ratios compared to METH- Met/Met individuals. Our results extend our previous finding that the typically-observed positive effect of the Met allele on executive function is absent among METH users . Specifically, COMT and METH use related to CSF DA levels, which in turn related to executive function. As such, this study helps to bridge the gap in the numerous neuropsychological studies that used COMT as a proxy for DA levels, which may be particularly complex in medical and neuropsychiatric conditions associated with DA dysregulation such as HIV. Interestingly, it was only in the group with the highest levels of DA, the METH- Met/Met group, that we observed a strong association between higher DA levels and better executive function. Associations between DA levels and cortical function are typically interpreted within the framework of the inverted-U hypothesis. DA levels at the peak of the curve are optimal for PFC-dependent neurocognition, whereas DA levels that are supraoptimal or suboptimal lead to poorer performance on these tasks . Our findings are in line with previous findings in the general population that the Met/Met genotype and resulting higher levels of DA are optimal for PFC-dependent neurocognition and, even within this genotype group, higher DA levels are advantageous for PFC-dependent neurocognition. However, lower DA levels that result from the Val allele in METH- individuals and from stimulant-induced injury in METH+ individuals, may be too far left of the curve to detect neurocognitive benefits of higher DA.
Taken together, this pattern of results may suggest a threshold effect whereby the neurocognitive benefits of DA are only observed when DA levels reach a certain level and DA levels in METH users fall below this threshold. It is important to consider our results and their interpretation in the context of our sample, which partially consisted of individuals with comorbid conditions that can impact the DAergic system . The majority of our sample was HIV+ . HIV is known to cause DA dysregulation though the release of neurotoxic viral proteins on DA neurons , and this DA dysregulation is associated with neurocognitive deficits . Thus, METH use can be particularly detrimental to brain and neurocognitive health in HIV+ individuals due to the compounding effects of METH and HIV on the DAergic system and the related mechanisms of oxidative stress, neuroinflammation, and blood brain barrier permeability . Consistent with our own findings in METH- individuals without HIV disease , previous studies reported a positive effect of the Met allele on PFC-dependent neurocognition in HIV+ individuals ; however, this effect was absent in HIV+ men with METH dependence . Interestingly, our AIC regression analysis did not identify HIV serostatus or other comorbidities as relevant predictors of DA in this sample, suggesting that METH use and COMT genotype are more salient modulators of the DAergic system in our study sample. Nevertheless, it is possible that the background of DA dysfunction that occurs with HIV disease and other comorbid conditions in our sample can shift the inverted-U curve and, thereby, influence the effects of COMT and METH on neurocognitive function. For example, neuroinflammatory mediated dampening of DAergic signaling in cortico-striatal circuitry is a putative pathogenic mechanism of depression ,vertical farming system which may partially underlie the higher levels of depressive symptoms in the METH+ group. These DAergic driven depressive symptoms including apathy and anhedonia may also exhibit a reciprocal relationship with addictive behaviors , particularly in METH+ individuals with extensive histories of polysubstance use . With respect to other factors, accounting for time of lumbar puncture significantly improved overall model fit but did not attenuate the effects of COMT and METH on DA and HVA/DA ratios. This is consistent with the literature examining diurnal fluctuations in CSF and plasma markers of catecholaminergic function and the influence of DAergic circuitry on clock gene expression . Given the potential for time of CSF sampling to influence catecholamine levels, it is important that studies aim to standardize the time of CSF collection across participants and/or adjust for time of collection in analyses. We acknowledge several limitations to these data. Cell sizes were small for a gene by environment interaction analysis, which precluded correction for multiple comparisons. Accordingly, these data should be considered preliminary and require independent confirmation. Nevertheless, our sample size was sufficient to model each COMT allelic variant independently and the large magnitude of effects yielded statistically significant COMT by METH group differences in CSF DA. Our neurocognitive analyses also limited multiple comparisons by conservatively focusing on the domain of executive function; importantly, our findings were consistent with prior studies that used the same well-validated tests of executive function. DA biomarkers in CSF provide a novel in vivo window into DA function in the CNS, yet they only represent a global measurement of DA and cannot formally test hypotheses about DA function in specific brain regions. Thus, future PET imaging studies are warranted to determine regional susceptibilities to the impact of COMT on METH-related DAergic injury.
Understanding genetic risk for prefrontal dysfunction is of clinical relevance for our study sample of predominantly HIV+ men, who are at risk for developing CNS complications and neuropsychiatric disorders. However, our results may not generalize to women given previously reported sexually dimorphic effects of COMT genotype on COMT enzymatic activity and risk of psychiatric disorders, as well as the reciprocal relationship between the regulation of COMT and estrogens . Thus, future studies should replicate our analyses in other clinical and non-clinical samples with adequate representation of women. Similarly, the absence of genetic ancestry markers is a limitation and studies that incorporate these markers in sufficiently sized samples to allow for stratified analyses within ethnic groups would increase confidence in these findings. From a clinical perspective, our findings bear relevance for the treatment of METH dependence. DA agonists have been considered as a means of stabilizing DA function and promoting abstinence from METH use . In a clinical trial examining the incremental efficacy of modafinil in treating METH-dependence, on top of contingency management and cognitive behavioral therapy, relapse rates were lower in modafinil vs. placebo in Val/Val homozygotes, yet modafinil did not reduce relapse rates in Met-carriers . Additionally, low baseline D2 receptor availability and blunted striatal DA release in response to methylphenidate predicts future relapse in METH users . Thus, the combination of chronic METH exposure and the Met allele may result in enough DAergic injury to render treatment-seeking METH users non-responsive to the pharmacological effects of DA agonists. Given the putative contribution of DAergic deficits to relapse even after the most effective psychosocial interventions , approaches that target the endogenous production of DA may confer neurobehavioral benefits and inform precision treatments for Met-carriers who are non-responsive to pharmacotherapy. Taken together, the present study highlights the influence of genetically-driven differences in DA metabolism on the effects of chronic METH use on DA and DA-related executive function. Our observation of lower, albeit statistically non-significant, levels of CSF DA and significantly higher CSF HVA/DA ratios in METH+ Met/Met individuals compared to METH+ Val/Met individuals challenges the widely-held assumption that the Met-allele translates into higher levels of bio-available DA. Such an assumption may be more appropriate in healthier samples, which is supported by the stair-step pattern of higher CSF DA with each additional Met allele in the METH- group; however, careful consideration should be given when forming hypotheses and interpreting data regarding the role of COMT in clinical populations that are characterized by DA dysfunction . This conditional relationship between COMT, METH, and DAergic activity may help explain why some studies have failed to find consistent independent effects of COMT and METH on neuro behavioral outcomes. Individuals experiencing homeless in the United States have high lifetime rates of incarceration, with estimates ranging from 20 to 70%.Homelessness and incarceration share many risk factors, both health-related and economic . Individuals experiencing homelessness have an increased risk of police citations related to survival behaviors , heightened visibility to law enforcement, and decreased ability to adhere to conditions of parole or pay citations, increasing the risk of arrest.