Co-targeting the kappa opioid receptor and dopamine transporter reduces motivation to self-administer cocaine and partially reverses dopamine system dysregulation.

Cocaine disrupts dopamine (DA) and kappa opioid receptor (KOR) system activity, with long-term exposure reducing inhibiton of DA uptake by cocaine and increasing KOR system function. Single treatment therapies have not been successful for cocaine use disorder; therefore, this study focuses on a combination therapy targeting the dopamine transporter (DAT) and KOR. Sprague Dawley rats self-administered 5 days of cocaine (1.5 mg/kg/inf, max 40 inf/day, FR1), followed by 14 days on a progressive ratio (PR) schedule (0.19 mg/kg/infusion). Behavioral effects of individual and combined administration of phenmetrazine and nBNI were then examined using PR. Additionally, ex vivo fast scan cyclic voltammetry was then used to assess alterations in DA and KOR system activity in the nucleus accumbens before and after treatments. Chronic administration of phenmetrazine as well as the combination of phenmetrazine and nBNI-but not nBNI alone-significantly reduced PR breakpoints. In addition, the combination of phenmetrazine and nBNI partially reversed cocaine-induced neurodysregulations of the KOR and DA systems, indicating therapeutic benefits of targeting the DA and KOR systems in tandem. These data highlight the potential benefits of the DAT and KOR as dual-cellular targets to reduce motivation to administer cocaine and reverse cocaine-induced alterations of the DA system.

Nicotine modifies cocaine responding in a concurrent self-administration model.

BACKGROUND: Preclinical models of cocaine use disorder (CUD) have not yielded any FDA-approved pharmacotherapies, potentially due to a focus on cocaine use in isolation, which may not fully translate to real-world drug taking patterns. Cocaine and nicotine are commonly used together, and clinical research suggests that nicotine may increase the potency and reinforcing strength of cocaine. In this study, we sought to determine whether and how the addition of nicotine would alter ongoing intravenous cocaine self-administration and motivation to take cocaine in rats. METHODS: Male Sprague-Dawley rats self-administered cocaine alone on a long access, Fixed Ratio one (FR1) schedule, and then switched to a combination of cocaine and nicotine. Finally, rats responded on a Progressive Ratio (PR) schedule for several doses of cocaine alone and in combination with a single dose of nicotine. RESULTS: Under long access conditions, rats co-self-administering cocaine and nicotine responded less and with decreased response rates than for cocaine alone and did not escalate responding. However, under PR conditions that test motivation to take drugs, the dose response curve for the combination was shifted upwards relative to cocaine alone. CONCLUSIONS: Together, these results suggest that nicotine may enhance the reinforcing strength of cocaine, increasing PR responding for cocaine across the dose response curve.

Cocaine self-administration augments kappa opioid receptor system-mediated inhibition of dopamine activity in the mesolimbic dopamine system.

Prior studies examining the effects of cocaine on the dynorphin/kappa opioid receptor (Dyn/KOR) system primarily focus on non-contingent cocaine exposure, but the effects of self-administration, which more closely reflects human drug-taking behaviors, are not well studied. In this study we characterized the effects of escalated intravenous cocaine self-administration on the functional state of the Dyn/KOR system and its interaction with mesolimbic dopamine signaling. Rats self-administered cocaine in an extended access, limited intake cocaine procedure, in which animals obtained 40 infusions per day (1.5 mg/kg/inf) for 5 consecutive days to ensure comparable consumption levels. Following single day tests of cue reactivity and progressive ratio responding, quantitative real-time polymerase chain reaction was used to measure levels of Oprk and Pdyn transcripts in the ventral tegmental area and nucleus accumbens. Additionally, after self-administration, ex vivo fast-scan cyclic voltammetry in the NAc was used to examine the ability of the KOR agonist U50,488 to inhibit dopamine release. We found that KOR-induced inhibition of dopamine release was enhanced in animals that self-administered cocaine compared to controls, suggesting upregulated Dyn/KOR activity after cocaine self-administration. Furthermore, expression levels of Pdyn in the nucleus accumbens and ventral tegmental area, and Oprk in the nucleus accumbens, were elevated in cocaine animals compared to controls. Additionally, Pdyn expression in the nucleus accumbens was negatively correlated with progressive ratio breakpoints, a measure of motivation to self-administer cocaine. Overall, these data suggest that cocaine self-administration elevates KOR/Dyn system activity in the mesolimbic dopamine pathway.

Mechanisms of mindfulness in patients with migraine: Results of a qualitative study.

OBJECTIVE: To understand the mechanisms of mindfulness' impact on migraine. BACKGROUND: Promising mindfulness research demonstrates potential benefit in migraine, but no data-driven model exists from the lived experiences of patients that explains the mechanisms of mindfulness in migraine. METHODS: Semi-structured qualitative interviews were conducted with adults with migraine who participated in two mindfulness-based stress reduction (MBSR) clinical trials (n = 43). Interviews were audio-recorded, transcribed, and summarized into a framework matrix with development of a master codebook. Constructivist grounded theory approach was used to identify themes/subthemes. RESULTS: Participants who learned mindfulness techniques through MBSR experienced altered pain perception, altered response to migraine attacks and disease, increased awareness of external and internal experiences, improved overall well-being, and group benefits. Mindfulness resulted in earlier stress-body awareness and increased interoceptive awareness resulting in earlier attack recognition, leading to earlier and more effective management. Interictal factors of self-blame, guilt, and stigma decreased while migraine acceptance, hope, empowerment, self-efficacy, and self-compassion increased. Improved emotion regulation resulted in decreased fear of migraine, pain catastrophizing, anticipatory anxiety, and pain reactivity. Although taught as prevention, mindfulness was used both acutely and prophylactically. We created a conceptual model hypothesizing that MBSR skills led to an infusion of mindfulness in daily life, resulting in altered pain perception and experience, ultimately leading to improvement in overall well-being, which may positively feed back to the infusion of mindfulness in daily life. The therapeutic benefit of learning mindfulness in a group setting may moderate these effects. CONCLUSIONS: This study identified several new potential mechanisms of mindfulness' effect on migraine. After learning MBSR skills, participants reported altered pain and migraine perception and experiences. Increased stress-body and interoceptive awareness resulted in earlier migraine awareness and treatment. Mindfulness may target important interictal factors that affect disease burden such as fear of migraine, pain catastrophizing, and anticipatory anxiety. This is the first data-driven study to help elucidate the mechanisms of mindfulness on migraine from patient voices and can help direct future research endeavors.

KOR Control over Addiction Processing: An Exploration of the Mesolimbic Dopamine Pathway.

Drug addiction is a complex, persistent, and chronically relapsing neurological disorder exacerbated by acute and chronic stress. It is well known that the dynorphin/kappa opioid receptor (KOR) system regulates stress perception and responsivity, while the mesolimbic dopamine system plays a role in reward and reinforcement associated with alcohol and substance use disorders. Interestingly, the dopamine and dynorphin/KOR systems are highly integrated in mesolimbic areas, with KOR activation leading to inhibition of dopamine release, further altering the perception of reinforcing and aversive stimuli. Chronic or repeated exposure to stress or drugs potentiates KOR function ultimately contributing to a hypodopaminergic state. This hypodopaminergic state is one of the hallmarks of hyperkatifeia, defined as the hypersensitivity to emotional distress that is exacerbated during drug withdrawal and abstinence. The relationship between stress and drug addiction is bidirectional; repeated/chronic stress promotes pro-addictive behaviors, and repeated cycles of drug exposure and withdrawal, across various drug classes, produces stress. Neuroadaptations driven by this bidirectional relationship ultimately influence the perception of the reinforcing value of rewarding stimuli. In this chapter, we address the involvement of the dopamine and dynorphin/KOR systems and their interactions in shaping reinforcement value processing after drug and stress exposure, as well as a combinatorial impact of both drugs and stress.

Online Mindfulness May Target Psychological Distress and Mental Health during COVID-19.

BACKGROUND: The COVID-19 pandemic has dramatically affected mental health, creating an urgent need for convenient and safe interventions to improve well-being. Online mindfulness interventions show promise for improving depression, anxiety, and general well-being. OBJECTIVE: To assess: 1) the impact of online mindfulness on psychological distress, 2) altruistic efforts, and 3) the quantity, quality, and availability of online mindfulness resources during the COVID-19 pandemic. METHODS: 233 participants (203 U.S.; 20 international; 10 unknown) participated in this prospective, single-arm, non-randomized clinical trial of a single online mindfulness meditation session with pre- and post-surveys. MAIN OUTCOME MEASURES: (a) Mindfulness session helpfulness, online platform effectiveness, and immediate pre- to post-session changes in momentary stress, anxiety, and COVID-19 concern; (b) qualitative themes representing how people are helping others during the pandemic; (c) absolute changes in quantity of mindfulness-oriented web content and free online mindfulness resource availability from May to August 2020. RESULTS: Most participants felt the online mindfulness session was helpful and the electronic platform effective for practicing mindfulness (89%, 95% CI: [82 to 93%]), with decreased momentary anxiety (76%; 95% CI: [69 to 83%]), stress (80%; [72 to 86%]), and COVID-19 concern (55%; [46 to 63%]), (p < 0.001 for each measure). Participants reported helping others in a variety of ways during the pandemic, including following public health guidelines, conducting acts of service and connection, and helping oneself in hopes of helping others. "Mindfulness + COVID" search results increased by 52% from May to August 2020. Most (73%) Academic Consortium for Integrative Medicine and Health member websites offer free online mindfulness resources. CONCLUSIONS: Virtual mindfulness is an increasingly accessible intervention available world-wide that may reduce psychological distress during this isolating public health crisis. Kindness and altruism are being demonstrated during the pandemic. The consolidated online mindfulness resources provided may help guide clinicians and patients.

Opioid stewardship training during the transition to residency to prepare medical students to recognize and treat opioid use disorder.

Background: With a drastic shortage of addiction medicine specialists-and an ever-growing number of patients with opioid use disorder (OUD)-there is a dire need for more clinicians to feel confident in prevention and management of OUD and obtain a DEA-X waiver to prescribe medications to treat OUD. Here we determine if it is feasible to certify 4th year medical students with DEA-X waiver training as a component of the PROUD (Prevent and Reduce Opioid Use Disorder) curriculum, and if PROUD enhanced preparedness for medical students to manage OUD as interns. Methods: We implemented a sequential mixed-methods IRB approved study to assess feasibility (completing all required components of DEA-X waiver training) and impact of PROUD (measured by knowledge growth, enhancement for residency, and utilization of training during internship). Students completed 11 hours of required OUD training. Quantitative data included pre-/post- knowledge and curriculum satisfaction assessments as well as long-term impact with follow up survey as interns. Qualitative data was collected by survey and semi-structured focus groups. Results: All 120 graduating medical students completed the required components of the curriculum. Knowledge improved on the Provider Clinical Support Services (12.9-17.3, p < 0.0001) and Brief Opioid Overdose Knowledge assessments (10.15-10.81, p < 0.0001). Course satisfaction was high: 90% recommended online modules; 85% recommended training overall. Six qualitative themes emerged: (1) curriculum content was practical, (2) online modules allowed flexibility, (3) in-person seminars ensured authenticity, (4) timing at the transition to residency was optimal, (5) curriculum enhanced awareness and confidence, and (6) training was applicable to future careers. At 3 months, 60% reported using their training during internship; 64% felt more prepared to treat OUD than peers. Conclusions: PROUD trained 4th year medical students in opioid stewardship. As interns, students felt ready to serve as change agents to prevent, diagnose, and treat OUD.

Learning the full impact of migraine through patient voices: A qualitative study.

OBJECTIVE: To better characterize the ways that migraine affects multiple domains of life. BACKGROUND: Further understanding of migraine burden is needed. METHODS: Adults with migraine randomized to mindfulness-based stress reduction or headache education arms (n = 81) in two separate randomized clinical trials participated in semistructured in-person qualitative interviews conducted after the interventions. Interviews queried participants on migraine impact on life and were audio-recorded, transcribed, and summarized into a framework matrix. A master codebook was created until meaning saturation was reached and magnitude coding established code frequency. Themes and subthemes were identified using a constructivist grounded theory approach. RESULTS: Despite most participants being treated with acute and/or prophylactic medications, 90% (73/81) reported migraine had a negative impact on overall life, with 68% (55/81) endorsing specific domains of life impacted and 52% (42/81) describing impact on emotional health. Six main themes of migraine impact emerged: (1) global negative impact on overall life; (2) impact on emotional health; (3) impact on cognitive function; (4) impact on specific domains of life (work/career, family, social); (5) fear and avoidance (pain catastrophizing and anticipatory anxiety); and (6) internalized and externalized stigma. Participants reported how migraine (a) controls life, (b) makes life difficult, and (c) causes disability during attacks, with participants (d) experiencing a lack of control and/or (e) attempting to push through despite migraine. Emotional health was affected through (a) isolation, (b) anxiety, (c) frustration/anger, (d) guilt, (e) mood changes/irritability, and (f) depression/hopelessness. Cognitive function was affected through concentration and communication difficulties. CONCLUSIONS: Migraine has a global negative impact on overall life, cognitive and emotional health, work, family, and social life. Migraine contributes to isolation, frustration, guilt, fear, avoidance behavior, and stigma. A greater understanding of the deep burden of this chronic neurological disease is needed to effectively target and treat what is most important to those living with migraine.

Detrimental effects of flame retardant, PBB153, exposure on sperm and future generations.

In 1973, the Velsicol Chemical Company, which manufactured FireMaster, a brominated flame retardant, and NutriMaster, a nutritional supplement, mistakenly shipped hundreds of pounds of FireMaster to grain mills around Michigan where it was incorporated into animal feed and then into the food chain across the state. An estimated 6.5 million Michigan residents consumed polybrominated biphenyl (PBB)-laced animal products leading to one of the largest agricultural accidents in U.S. history. To date, there have been no studies investigating the effects of PBB on epigenetic regulation in sperm, which could explain some of the endocrine-related health effects observed among children of PBB-exposed parents. Fusing epidemiological approaches with a novel in vitro model of human spermatogenesis, we demonstrate that exposure to PBB153, the primary component of FireMaster, alters the epigenome in human spermatogenic cells. Using our novel stem cell-based spermatogenesis model, we show that PBB153 exposure decreases DNA methylation at regulatory elements controlling imprinted genes. Furthermore, PBB153 affects DNA methylation by reducing de novo DNA methyltransferase activity at increasing PBB153 concentrations as well as reducing maintenance DNA methyltransferase activity at the lowest tested PBB153 concentration. Additionally, PBB153 exposure alters the expression of genes critical to proper human development. Taken together, these results suggest that PBB153 exposure alters the epigenome by disrupting methyltransferase activity leading to defects in imprint establishment causing altered gene expression, which could contribute to health concerns in the children of men exposed to PBB153. While this chemical is toxic to those directly exposed, the results from this study indicate that the epigenetic repercussions may be detrimental to future generations. Above all, this model may be expanded to model a multitude of environmental exposures to elucidate the effect of various chemicals on germline epigenetics and how paternal exposure may impact the health of future generations.

Measurement of Dopamine Using Fast Scan Cyclic Voltammetry in Rodent Brain Slices.

Fast scan cyclic voltammetry (FSCV) is an electrochemical technique that allows sub-second detection of oxidizable chemical species, including monoamine neurotransmitters such as dopamine, norepinephrine, and serotonin. This technique has been used to record the physiological dynamics of these neurotransmitters in brain tissue, including their rates of release and reuptake as well as the activity of neuromodulators that regulate such processes. This protocol will focus on the use of ex vivo FSCV for the detection of dopamine within the nucleus accumbens in slices obtained from rodents. We have included all necessary materials, reagents, recipes, procedures, and analyses in order to successfully perform this technique in the laboratory setting. Additionally, we have also included cautionary points that we believe will be helpful for those who are novices in the field.