Negative affectivity drivers of impulsivity in opioid use disorder
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Childhood family environment and μ-opioid receptor availability in vivo in adulthood
Animal studies have reported associations of early maternal separation with altered μ-opioid receptor function but data on humans are scarce. We now investigated whether childhood family environment is related to μ-opioid receptor availability in the human brain in adulthood. Healthy participants (n = 37–39 in the analyses) were recruited from the prospective population-based Young Finns Study (YFS) that started in 1980. Childhood family environment was evaluated in 1980, including scores for stress-prone life events, disadvantageous emotional family atmosphere, and adverse socioeconomic environment. We used positron emission tomography (PET) with radioligand [11C]carfentanil to measure μ–opioid receptor availability in adulthood. Age- and sex-adjusted analyses showed that exposure to stress-prone life events in childhood was related to lower μ-opioid receptor binding in the orbitofrontal cortex, hippocampus, putamen, amygdala, insula, thalamus, anterior cingulate cortex, and dorsal caudate in adulthood (when compared to participants not exposed to stress-prone life events). Unfavorable socioeconomic family environment or disadvantageous emotional family atmosphere was not associated with μ-opioid receptor availability in adulthood. In conclusion, exposure to environmental instability (i.e., to stress-prone life events below traumatic threshold) during early development is associated with dysregulation of the u-opioid receptor transmission in adulthood. The findings increase understanding of the neurobiological mechanisms involved in the associations between childhood adversities and adulthood mental disorders.
Outpatient tapering of buprenorphine in opioid use disorder pregnancies may improve neonatal outcomes
The main objective of the study was to compare neonatal outcomes: the incidence of NOWS, length of hospital stay (LOS), admission to neonatal intensive care (NICU), birth weight, treatment with morphine, and head circumference between newborns of mothers who had tapering of buprenorphine (T group) during pregnancy to non-tapering of buprenorphine (NT group).
Validation of L-type calcium channel blocker amlodipine as a novel ADHD treatment through cross-species analysis, drug-target Mendelian randomization, and clinical evidence from medical records
ADHD is a chronic neurodevelopmental disorder that significantly affects life outcomes, and current treatments often have adverse side effects, high abuse potential, and a 25% non-response rate, highlighting the need for new therapeutics. This study investigates amlodipine, an L-type calcium channel blocker, as a potential foundation for developing a novel ADHD treatment by integrating findings from animal models and human genetic data. Amlodipine reduced hyperactivity in SHR rats and decreased both hyperactivity and impulsivity in adgrl3.1−/− zebrafish. It also crosses the blood-brain barrier, reducing telencephalic activation. Crucially, Mendelian Randomization analysis linked ADHD to genetic variations in L-type calcium channel subunits (α1-C; CACNA1C, β1; CACNB1, α2δ3; CACNA2D3) targeted by amlodipine, while polygenic risk score analysis showed symptom mitigation in individuals with high ADHD genetic liability. With its well-tolerated profile and efficacy across species, supported by genetic evidence, amlodipine shows potential to be refined and developed into a novel treatment for ADHD.
The dopaminergic effects of esketamine are mediated by a dual mechanism involving glutamate and opioid receptors
Esketamine represents a new class of drugs for treating mood disorders. Unlike traditional monoaminergic-based therapies, esketamine primarily targets N-methyl-D-aspartate receptors (NMDAR). However, esketamine is a complex drug with low affinity for NMDAR and can also bind to other targets, such as opioid receptors. Its precise mechanism of action for its antidepressant properties remains debated, as does its potential for misuse. A key component at the intersection of mood and reward processing is the dopaminergic system. In this study, we evaluated the effects of esketamine in locomotion, anxiety tests and operant responding and we used in vivo fiber photometry to explore the neurochemical effects of esketamine in the nucleus accumbens of mice. Our findings demonstrated multifaceted effects of esketamine on neurotransmitter dynamics. In freely behaving mice, esketamine increased locomotion and increased extracellular dopamine tone -by impairing dopamine clearance rather than promoting dopamine release- while decreasing glutamatergic activity. However, it decreased dopamine spontaneous release event frequency and impaired reward-evoked dopamine release, leading to a reduction in operant responding rates. These dopaminergic effects were partially, and conditionally, blocked by the opioid antagonist naloxone and required glutamatergic input. In summary, our study reveals a complex interaction between neurotransmitter systems, suggesting that the neurochemical effects of esketamine are both circuit- and state-dependent.
The impact of ovulation-suppressing contraceptives on behavioral and functional difficulties in borderline personality disorder
Borderline Personality Disorder (BPD) is characterized by rapidly shifting emotional, interpersonal, and behavioral symptoms, often co-morbid with mood and anxiety disorders. Females are more likely to be diagnosed with BPD than males and exhibit greater functional impairment. Hormonal fluctuations may influence the manifestation of BPD symptoms. Here, we investigated the influence of ovulation-suppressing contraceptives on behavioral and functional difficulties in BPD. The sample included 348 females ages 18-50 undergoing residential treatment for psychiatric disorders, with 131 having a BPD diagnosis. Patients were categorized by their contraceptive method: Ovulation-suppressing contraceptives (N = 145) and naturally cycling (N = 203). Interaction models tested the impact of ovulation-suppressing contraceptives on the relationship between BPD diagnosis and behavioral and functional difficulties at admission and discharge, assessed by the four Behavior and Symptom Identification Scale (BASIS-32) domains: difficulties in relationships, daily living, depression/anxiety, and impulsivity. Females with a BPD diagnosis were more likely to use ovulation-suppressing contraceptives compared to those without BPD (p = 0.04). However, ovulation-suppressing contraceptive use was not associated with behavioral and functional difficulties at admission, discharge, or over time. Ovulation-suppressing contraceptives moderated the association between BPD diagnosis and difficulties in relationships (p = 0.004), difficulties in daily living (p = 0.01), and depression/anxiety symptoms (p = 0.004). Specifically, patients with BPD experienced more behavioral and functional difficulties only if naturally cycling, whereas patients without BPD showed higher symptom severity only if using ovulation-suppressing contraceptives. Our findings suggest that the impact of ovulation-suppressing contraceptives on behavioral and functional difficulties varies depending on BPD diagnosis and underscores the need for further clinical studies.
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