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Ketamine, a noncompetitive NMDA receptor antagonist, has been exclusively used as an anesthetic in medicine and has led to new insights into the pathophysiology of neuropsychiatric disorders. Clinical studies have shown that low subanesthetic doses of ketamine produce antidepressant effects for individuals with depression. However, its use as a treatment for psychiatric disorders has been limited due to its reinforcing effects and high potential for diversion and misuse. Preclinical studies have focused on understanding the molecular mechanisms underlying ketamine’s antidepressant effects, but a precise mechanism had yet to be elucidated. Here we review different hypotheses for ketamine’s mechanism of action including the direct inhibition and disinhibition of NMDA receptors, AMPAR activation, and heightened activation of monoaminergic systems. The proposed mechanisms are not mutually exclusive, and their combined influence may exert the observed structural and functional neural impairments. Long term use of ketamine induces brain structural, functional impairments, and neurodevelopmental effects in both rodents and humans. Its misuse has increased rapidly in the past 20 years and is one of the most common addictive drugs used in Asia. The proposed mechanisms of action and supporting neuroimaging data allow for the development of tools to identify ‘biotypes’ of ketamine use disorder (KUD) using machine learning approaches, which could inform intervention and treatment.

Sex differences in the prevalence of dopamine-related neuropsychiatric diseases and in the sensitivity to dopamine-boosting drugs such as stimulants is well recognized. Here we assessed whether there are sex differences in the brain dopamine system in humans that could contribute to these effects. We analyzed data from two independent [11C]raclopride PET brain imaging studies that measured methylphenidate-induced dopamine increases in the striatum using different routes of administration (Cohort A = oral 60 mg; Cohort B = intravenous 0.5 mg/kg; total n = 95; 65 male, 30 female), in blinded placebo-controlled designs. Females when compared to males reported stronger feeling of “drug effects” and showed significantly greater dopamine release in the ventral striatum (where nucleus accumbens is located) to both oral and intravenous methylphenidate. In contrast, there were no significant differences in methylphenidate-induced increases in dorsal striatum for either oral or intravenous administration nor were there differences in levels of methylphenidate in plasma. The greater dopamine increases with methylphenidate in ventral but not dorsal striatum in females compared to males suggests an enhanced sensitivity specific to the dopamine reward system that might underlie sex differences in the vulnerability to substance use disorders and to attention-deficit/hyperactivity disorder (ADHD).

Side effects of medications for opioid use disorder (MOUD) such as weight gain contribute to their stigma. Substantial evidence suggests that women have a more severe side effect profile to MOUD than men, and concerns about weight gain during treatment are prevalent. However, the few studies reporting sex differences in weight gain during treatment show conflicting results and are restricted to methadone. In addition, little is known about possible sex differences in weight gain to buprenorphine, which is the most commonly prescribed MOUD in the United States.To address these issues, we performed a systematic review and meta-analysis on the few studies reporting longitudinal data on sex differences in body mass index (BMI) gain during methadone treatment (Study 1). In a separate study, we also re-analyzed data from trial CTN-0030 of the National Institute on Drug Abuse Clinical Trial Network (NIDA CTN), which involved a 12-week buprenorphine treatment regimen (Study 2; n = 360; 209 Male, 151 Female).For Study 1, across all papers reporting longitudinal data (k = 4, n = 362 OUD patients), there were BMI increases that ranged from 2.2 to 5.4 BMI after at least one year of methadone treatment, but there were no significant sex differences in BMI increases (Standardized Mean Difference, FemaleMale = 0.352, SE =0.270; 95 % CI = [-0.18 0.88]; p = .193). Study 2 showed no significant differences in weight before and after 12 weeks of buprenorphine treatment nor did it show sex differences in weight change with treatment (β = 2.34, p = .511).These analyses corroborate evidence of weight gain with methadone treatment but did not observe a sex-based disparity in weight gain with methadone or buprenorphine treatment for OUD.

Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine enhancing medication widely used to treat attention-deficit/hyperactivity disorder, has rewarding and addictive effects if injected. Since methylphenidate’s brain uptake is much faster when injected than when taken orally, we hypothesized that the amplitude and the speed of dopamine release in striatum would underly drug reward. To test this hypothesis we developed a non-invasive method to assess methylphenidate-related extracellular dopamine increases at 1-minute temporal resolution using positron emission tomography, which we validated in preclinical microdialysis data. Using a placebo-controlled double-blind within-subjects design, we show in 20 healthy controls that striatal dopamine increases induced by intravenous methylphenidate (0.25 mg/kg) were significantly faster than those induced by oral methylphenidate (60 mg) and that the time-to-peak of dopamine release was strongly associated with the intensity of self-reports of feeling “high”. With this novel approach we show for the first time in humans that stronger drug reward is associated with shorter dopamine time-to-peak after methylphenidate administration.

Low socioeconomic status (SES) in childhood is associated with deficits in executive function and changes in cortical morphology. Furthermore, rates of childhood obesity are greater among low SES children and childhood obesity is also associated with cortical alterations and impaired neurocognition, specifically in the domain of executive function. To investigate the influence of BMI on the relationships between SES and both neurocognition and brain morphology, we used data from the Adolescent Brain Cognitive Development (ABCD) study to construct multiple linear regression models and conduct mediation analyses. Overall, SES as measured by household income, highest level of parental education, and area deprivation, was associated with lower BMI, greater total and prefrontal cortical volume, and better performance on assessments of executive function. Mediation analysis indicated that BMI had a significant indirect effect on associations between area deprivation and both total and prefrontal cortical volumes. BMI also played a mediating role in the associations between area deprivation and composite neurocognitive scores, which were driven by performance on tasks of working memory and cognitive flexibility, but not cognitive control. These findings suggest that BMI should be considered in future studies investigating the relationship between low SES and poor neurodevelopmental outcomes.

Sex differences in the prevalence of dopamine-related neuropsychiatric diseases and in the sensitivity to dopamine-boosting drugs such as stimulants is well recognized. Here we assessed whether there are sex differences in the brain dopamine system in humans that could contribute to these effects. We analyzed data from two independent [

From humans to vinegar flies, exposure to diets rich in sugar and fat lowers taste sensation, changes food choices, and promotes feeding. However, how these peripheral alterations influence eating is unknown. Here we used the genetically tractable organism D. melanogaster to define the neural mechanisms through which this occurs. We characterized a population of protocerebral anterior medial dopaminergic neurons (PAM DANs) that innervates the β’2 compartment of the mushroom body and responds to sweet taste. In animals fed a high sugar diet, the response of PAM-β’2 to sweet stimuli was reduced and delayed, and sensitive to the strength of the signal transmission out of the sensory neurons. We found that PAM-β’2 DANs activity controls feeding rate and satiation: closed-loop optogenetic activation of β’2 DANs restored normal eating in animals fed high sucrose. These data argue that diet-dependent alterations in taste weaken satiation by impairing the central processing of sensory signals., eLife digest Obesity is a major health problem affecting over 650 million adults worldwide. It is typically caused by overeating high-energy foods, which often contain a lot of sugar. Consuming sugary foods triggers the production of a reward signal called dopamine in the brains of insects and mammals, which reinforces sugar-consuming behavior. The brain balances this with a process called ‘sensory-enhanced satiety’, which makes foods that provide a stronger sensation of sweetness better at reducing hunger and further eating. High-energy food was scarce for most of human evolution, but over the past century sugar has become readily available in our diet leading to an increase in obesity. Last year, a study in fruit flies reported that a sugary diet reduces the sensitivity to sweet flavors, which leads to overeating and weight gain. It appears that this sensitivity is linked to the effectiveness of sensory-enhanced satiety. However, the mechanism linking diets high in sugar and overeating is still poorly understood. One hypothesis is that fruit flies estimate the energy content of food based on the degree of dopamine released in response to the sugar. May et al. compared the responses of neurons in fruit flies fed a normal diet to those in flies fed a diet high in sugar. As expected, both groups activated the neurons involved in the dopamine reward response when they tasted sugar. However, when the flies were on a sugar-heavy diet, these neurons were less active. This was because the neurons responsible for tasting sweetness were activated less in flies fed a high-sugar diet, leading to a lowered response by the neurons that produce dopamine. The flies in these experiments were genetically engineered so that the dopamine-producing neurons could be artificially activated in response to light, a technique called optogenetics. When May et al. applied this technique to the flies on a sugar-heavy diet, they were able to stop these flies from overeating. These findings provide further evidence to support the idea that a sugary diet reduces the brain’s sensitivity to overeating. Given the significant healthcare cost of obesity to society, this improved understanding could help public health initiatives focusing on manufacturing food that is lower in sugar.