Parkin regulates drug-taking behavior in rat model of methamphetamine use disorder.
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ABSTRACT:
SUBMITTER: Sharma A
PROVIDER: S-EPMC8129108 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
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Parkin regulates drug-taking behavior in rat model of methamphetamine use disorder.
Sharma Akhil A Harutyunyan Arman A Schneider Bernard L BL Moszczynska Anna A
Translational psychiatry 20210517 1
There is no FDA-approved medication for methamphetamine (METH) use disorder. New therapeutic approaches are needed, especially for people who use METH heavily and are at high risk for overdose. This study used genetically engineered rats to evaluate PARKIN as a potential target for METH use disorder. PARKIN knockout, PARKIN-overexpressing, and wild-type young adult male Long Evans rats were trained to self-administer high doses of METH using an extended-access METH self-administration paradigm. ...[more]
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Project description:In recent years, methamphetamine (METH) misuse in the US has been rapidly increasing, and there is no FDA-approved pharmacotherapy for METH use disorder (MUD). We previously determined that ubiquitin-protein ligase parkin is involved in the regulation of METH addictive behaviors in rat models of MUD. Parkin is not yet a “druggable” drug target; therefore, this study aimed to determine which biological processes, pathways, and proteins downstream of parkin are likely drug targets against MUD. Employing young adult Long Evans male rats with parkin deficit or excess in the nucleus accumbens (NAc), label-free proteomics, and molecular biology, we determined that the pathways downstream of parkin that are candidates for regulating METH addictive behaviors in young adult male rats are mitochondrial respiration, oxidative stress, AMPA receptor trafficking, GABAergic neurotransmission, and actin cytoskeleton dynamics.
2025-08-04 | PXD065059 | Pride
Project description:People with methamphetamine use disorder (MUD) struggle to shift their behaviour from methamphetamine-orientated habits to goal-oriented choices. The model-based/model-free framework is well suited to understand this difficulty by unpacking the computational mechanisms that support experienced-based (model-free) and goal-directed (model-based) choices. We aimed to examine whether 1) participants with MUD differed from controls on behavioural proxies and/or computational mechanisms of model-based/model-free choices; 2) model-based/model-free decision-making correlated with MUD symptoms; and 3) model-based/model-free deficits improved over six weeks in the group with MUD. Participants with MUD and controls with similar age, IQ and socioeconomic status completed the Two-Step Task at treatment commencement (MUD n = 30, Controls n = 31) and six weeks later (MUD n = 23, Controls n = 26). We examined behavioural proxies of model-based/model-free decisions using mixed logistic regression, and their underlying mechanisms using computational modelling. At a behavioural level, participants with MUD were more likely to switch their choices following rewarded actions, although this pattern improved at follow up. At a computational level, groups were similar in their use of model-based mechanisms, but participants with MUD were less likely to apply model-free mechanisms and less likely to repeat rewarded actions. We did not find evidence that individual differences in model-based or model-free parameters were associated with greater severity of methamphetamine dependence, nor did we find that group differences in computational parameters changed between baseline and follow-up assessment. Decision-making challenges in people with MUD are likely related to difficulties in pursuing choices previously associated with positive outcomes.
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Project description:Research has supported an association between suicidal thoughts/behaviors and risk taking, which may be particularly strong during adolescence when risk taking is known to increase. However, extant research has focused on individual risk-taking behaviors (e.g., alcohol use), limiting our ability to evaluate the unique association between different risk-taking behaviors and suicidal thoughts/behaviors. The current study aimed to fill this gap by examining the simultaneous influence of multiple risk-taking behaviors (i.e., risky sexual behavior, tobacco/alcohol use, illicit drug use, delinquent behavior, violent behavior) on adolescent suicidal thoughts/behaviors. Data from the National Longitudinal Study of Adolescent Health was utilized. The sample consisted of 4,834 adolescents who completed home interviews at two time points. At the first time point, participants' mean age was 15.15, with 48% (n = 2,315) identifying as male. Participants provided information about suicidal thoughts/behaviors and multiple risk-taking behaviors at an initial interview and at a second interview, approximately 11 months later. When independently examined, nearly all assessed risk-taking behaviors were independently associated with suicidal ideation concurrently and prospectively, and with suicide attempts concurrently. When all risk-taking behaviors were examined simultaneously, illicit drug use was the only significant concurrent and significant prospective, albeit negative, predictor of suicidal thoughts and only concurrent predictor of suicidal behavior. The current findings suggest that illicit drug use may have a stronger association with suicidal thoughts and behaviors than other risk-taking behavior. These findings have implications for prevention and intervention programs for adolescents.
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Project description:ImportanceMortality associated with methamphetamine use has increased markedly in the US. Understanding patterns of methamphetamine use may help inform related prevention and treatment.ObjectiveTo assess the national trends in and correlates of past-year methamphetamine use, methamphetamine use disorder (MUD), injection, frequent use, and associated overdose mortality from 2015 to 2019.Design, setting, and participantsThis cross-sectional study analyzed methamphetamine use, MUD, injection, and frequent use data from participants in the 2015 to 2019 National Surveys on Drug Use and Health (NSDUH). Mortality data were obtained from the 2015 to 2019 National Vital Statistics System Multiple Cause of Death files.ExposuresMethamphetamine use.Main outcomes and measuresMethamphetamine use, MUD, injection, frequent use, and overdose deaths.ResultsOf 195 711 NSDUH respondents aged 18 to 64 years, 104 408 were women (weighted percentage, 50.9%), 35 686 were Hispanic individuals (weighted percentage, 18.0%), 25 389 were non-Hispanic Black (hereafter, Black) individuals (weighted percentage, 12.6%), and 114 248 were non-Hispanic White (hereafter, White) individuals (weighted percentage, 60.6%). From 2015 to 2019, overdose deaths involving psychostimulants other than cocaine (largely methamphetamine) increased 180% (from 5526 to 15 489; P for trend <.001); methamphetamine use increased 43% (from 1.4 million [95% CI, 1.2-1.6 million] to 2.0 million [95% CI, 1.7-2.3 million]; P for trend = .002); frequent methamphetamine use increased 66% (from 615 000 [95% CI, 512 000-717 000] to 1 021 000 [95% CI, 860 000-1 183 000]; P for trend = .002); methamphetamine and cocaine use increased 60% (from 402 000 [95% CI, 306 000-499 000] to 645 000 [95% CI, 477 000-813 000]; P for trend = .001); and MUD without injection increased 105% (from 397 000 [95% CI, 299 000-496 000] to 815 000 [95% CI, 598 000-1 033 000]; P for trend = .006). The prevalence of MUD or injection surpassed the prevalence of methamphetamine use without MUD or injection in each year from 2017 to 2019 (60% to 67% vs 37% to 40%; P for trend ≤.001). Adults with MUD or using injection were more likely to use methamphetamine frequently (52.68%-53.84% vs 32.59%; adjusted risk ratio, 1.62-1.65; 95% CI, 1.35-1.94). From 2015 to 2019, the adjusted prevalence of MUD without injection more than tripled among heterosexual women (from 0.24% to 0.74%; P < .001) and lesbian or bisexual women (from 0.21% to 0.71%; P < .001) and more than doubled among heterosexual men (from 0.29% to 0.79%; P < .001) and homosexual or bisexual men (from 0.29% to 0.80%; P = .007). It increased over 10-fold among Black individuals (from 0.06% to 0.64%; P < .001), nearly tripled among White individuals (from 0.28% to 0.78%; P < .001), and more than doubled among Hispanic individuals (from 0.39% to 0.82%; P < .001). Risk factors for methamphetamine use, MUD, injection, and frequent use included lower educational attainment, lower annual household income, lack of insurance, housing instability, criminal justice involvement, comorbidities (eg, HIV/AIDS, hepatitis B or C virus, depression), suicidal ideation, and polysubstance use.Conclusions and relevanceThis cross-sectional study found consistent upward trends in overdose mortality, greater risk patterns of methamphetamine use, and populations at higher risk for MUD diversifying rapidly, particularly those with socioeconomic risk factors and comorbidities. Evidence-based prevention and treatment interventions are needed to address surges in methamphetamine use and MUD.
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Project description:Methamphetamine (METH) use disorder (MUD) is often accompanied by psychotic symptoms, cognitive deficits, and pathological changes in the brains of users. Animals that experimenters injected with drugs also show neurodegenerative changes in their brains. Recently, we have been investigating METH-induced molecular and biochemical consequences in animals that had infused themselves with METH using the drug self-administration (SA) paradigm. In that model, footshocks administered contingently help to separate rats that had already escalated their METH intake into resilient-to-drug (shock-sensitive, SS) or compulsive (shock-resistant, SR) METH takers. Herein, we used that model to test the idea that compulsive METH takers might show evidence of drug-induced autophagic changes in their brains. There were significant increases in mRNA levels of autophagy-related genes including Atg2a, Atg5, Atg14, and Atg16L1 in the rat dorsal striatum. Levels of two autophagy biomarkers, autophagy activating kinase (ULK1) and phospho-Beclin1, were also increased. In addition, we found increased p53 but decreased Bcl-2 protein levels. Moreover, the expression of cleaved initiator caspase-9 and effector caspase-6 was higher in compulsive METH takers in comparison to shock-sensitive rats. When taken together, these results suggest that the striata of rats that had escalated and continue to take METH compulsively the presence of adverse consequences exhibit some pathological changes similar to those reported in post-mortem human striatal tissues. These results provide supporting evidence that compulsive METH taking is neurotoxic. Our observations also support the notion of developing neuro-regenerative agents to add to the therapeutic armamentarium against METH addiction.
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Project description:Methamphetamine (MA) is a highly addictive stimulant with recent upward trends in prevalence and associated public health problems. Drug demand, as assessed by hypothetical purchasing tasks, has been useful in addictions research and may help our understanding of the factors influencing MA use. However, no studies have assessed MA demand using current models of demand. The purpose of the current study was to assess demand for MA using a hypothetical drug purchasing task. Given high rates of cigarette smoking among MA users, it was of interest also to assess and compare demand for MA relative to cigarettes. Participants consisted of non-treatment-seeking volunteers with MA use disorder (N = 18), of whom 17 reported daily smoking. Results showed the exponentiated demand model provided a good fit to consumption data. Results from Bayesian generalized linear modeling demonstrated multiple positive relationships (posterior probability ≥75%) between self-reported drug use (days MA used in the past 30 days, cigarettes smoked per day) and indices of demand for each drug (Qo, Omax, Pmax, and break point). Comparing MA to cigarettes, results from Bayesian generalized linear mixed modeling revealed greater abuse liability for MA compared to cigarettes (posterior probability ≥99%) based on α and essential value. Overall, the findings of the current study support the feasibility and validity of the exponentiated demand model for assessing demand for drugs among individuals with MA use disorder. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
| S-EPMC7508771 | biostudies-literature
Project description:To date, diagnosis of methamphetamine use disorder (MUD) is based primarily on the patient’s self-reports of drug-seeking behaviour and interviews with psychiatrists in the absence of objective biomarkers. As an effective clinical method for diagnosis of MUD is still not available, the development of potential biomarkers for more accurate diagnosis is imperative. Transcription profiling and discovery of biomarkers in the treatment and recovery periods of MUD patients can be used as scientific basis to provide a greater understanding of the disease and to facilitate decisions on whether to continue or not. In this study, RNA sequencing analysis was performed to profile transcripts from hair follicle cells of healthy controls and patients with MUD, and biomarkers were discovered at each transition states to be used to diagnose MUD. This study will present an important information to diagnose MUD using non-invasive biomarkers for human addicts and it will help to develop better pharmacological treatment of MUD in the future.
2023-05-31 | GSE227204 | GEO
Project description:Individuals who begin drug use during early adolescence experience more adverse consequences compared to those initiating later, especially if they are female. The mechanisms for these age and gender differences remain obscure, but studies in rodents suggest that psychostimulants may disrupt the normal ontogeny of dopamine and glutamate systems in the prefrontal cortex (PFC). Here, we studied Sprague-Dawley rats of both sexes who began methamphetamine (METH, i.v.) self-administration in adolescence (postnatal [P] day 41) or adulthood (P91). Rats received seven daily 2-h self-administration sessions with METH or saccharin as the reinforcer, followed by 14 daily long access (LgA; 6 h) sessions. After 7 and 14 days of abstinence, novel object (NOR) or object-in-place (OiP) recognition was assessed. PFC and nucleus accumbens were collected 7 days after the final cognitive test and NMDA receptor subunits and dopamine D1 receptor expression was measured. We found that during LgA sessions, adolescent-onset rats escalated METH intake more rapidly than adult-onset rats, with adolescent-onset females earning the most infusions. Adolescent-onset rats with a history of METH self-administration exhibited modest deficits in OiP compared to their adult-onset counterparts, but there was no sex difference and self-administration groups did not differ from naïve control rats. All rats displayed intact novel object recognition memory. We found no group differences in D1 and NMDA receptor expression, suggesting no long-lasting alteration of ontogenetic expression profiles. Our findings suggest that adolescent-onset drug use is more likely to lead to compulsive-like patterns of drug-taking and modest dysfunction in PFC-dependent cognition.
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