Faculty Bibliography

Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat attention-deficit/hyperactivity disorder, can have rewarding and addictive effects if injected. Since methylphenidate's brain uptake is much faster after intravenous than oral intake, we hypothesize that the speed of dopamine increases in the striatum in addition to its amplitude underly drug reward. To test this we use simulations and PET data of [¹¹C]raclopride's binding displacement with oral and intravenous methylphenidate challenges in 20 healthy controls. Simulations suggest that the time-varying difference in standardized uptake value ratios for [¹¹C]raclopride between placebo and methylphenidate conditions is a proxy for the time-varying dopamine increases induced by methylphenidate. Here we show that the dopamine increase induced by intravenous methylphenidate (0.25 mg/kg) in the striatum is significantly faster than that by oral methylphenidate (60 mg), and its time-to-peak is strongly associated with the intensity of the self-report of "high". We show for the first time that the "high" is associated with the fast dopamine increases induced by methylphenidate.

The human dopamine transporter gene SLC6A3 has been consistently implicated in several neuropsychiatric diseases but the disease mechanism remains elusive. In this risk synthesis, we have concluded that SLC6A3 represents an increasingly recognized risk with a growing number of familial mutants associated with neuropsychiatric and neurological disorders. At least five loci were related to common and severe diseases including alcohol use disorder (high activity variant), attention-deficit/hyperactivity disorder (low activity variant), autism (familial proteins with mutated networking) and movement disorders (both regulatory variants and familial mutations). Association signals depended on genetic markers used as well as ethnicity examined. Strong haplotype selection and gene-wide epistases support multimarker assessment of functional variations and phenotype associations. Inclusion of its promoter region's functional markers such as DNPi (rs67175440) and 5'VNTR (rs70957367) may help delineate condensate-based risk action, testing a locus-pathway-phenotype hypothesis for one gene-multidisease etiology.

Poverty, as assessed by several socioeconomic (SES) factors, has been linked to worse cognitive performance and reduced cortical brain volumes in children. However, the relative contributions of the various SES factors on brain development and the mediating effects between cognition and brain morphometry have not been investigated. Here we used cross-sectional data from the ABCD Study to evaluate associations among various SES and demographic factors, brain morphometrics, and cognition and their reproducibility in two independent subsamples of 3892 children. Among the SES factors, family income (FI) best explained individual differences in cognitive test scores (stronger for crystallized than for fluid cognition), cortical volume (CV), and thickness (CT). Other SES factors that showed significant associations with cognition and brain morphometrics included parental education and neighborhood deprivation, but when controlling for FI, their effect sizes were negligible and their regional brain patterns were not reproducible. Mediation analyses showed that cognitive scores, which we used as surrogate markers of the children's level of cognitive stimulation, partially mediated the association of FI and CT, whereas the mediations of brain morphometrics on the association of FI and cognition were not significant. These results suggest that lack of supportive/educational stimulation in children from low-income families might drive the reduced CV and CT. Thus, strategies to enhance parental supportive stimulation and the quality of education for children in low-income families could help counteract the negative effects of poverty on children's brain development.

Binge drinking is associated with disease and death, and developing tools to identify risky drinkers could mitigate its damage. Brain processes underlie risky drinking, so we examined whether neural and psychosocial markers could identify binge drinkers. Reward is the most widely studied neural process in addiction, but processes such as emotion, social cognition, and self-regulation are also involved. Here we examined whether neural processes apart from reward contribute to predicting risky drinking behaviors. From the Human Connectome Project, we identified 177 young adults who binged weekly and 309 nonbingers. We divided the sample into a training and a testing set and used machine-learning algorithms to classify participants based on psychosocial, neural, or both (neuropsychosocial) data. We also developed separate models for each of the seven fMRI tasks used in the study. An ensemble model developed in the training dataset was then applied to the testing dataset. Model performance was assessed by the area under the receiver operating characteristic curve (AUC) and differences between models were assessed using DeLong's test. The three models performed better than chance in the test sample with the neuropsychosocial (AUC = 0.86) and psychosocial (AUC = 0.84) performing better than the neural model (AUC = 0.64). Two fMRI-based models predicted binge drinking status better than chance, corresponding to the social and language tasks. Models developed with psychosocial and neural variables could contribute as diagnostic tools to help classify risky drinkers. Since social and language fMRI tasks performed best among the neural discriminators (including those from gambling and emotion tasks), it suggests the involvement of a broader range of brain processes than those traditionally associated with binge drinking in young adults.

Morbidity and mortality from opioid use disorders (OUD) and other substance use disorders (SUD) is a major public health crisis, yet there are few medications to treat them. There is an urgency to accelerate SUD medication development. We present an integrated drug repurposing strategy that combines computational prediction, clinical corroboration using electronic health records (EHRs) of over 72.9 million patients and mechanisms of action analysis. Among top-ranked repurposed candidate drugs, tramadol, olanzapine, mirtazapine, bupropion, and atomoxetine were associated with increased odds of OUD remission (adjusted odds ratio: 1.51 [1.38-1.66], 1.90 [1.66-2.18], 1.38 [1.31-1.46], 1.37 [1.29-1.46], 1.48 [1.25-1.76], p value < 0.001, respectively). Genetic and functional analyses showed these five candidate drugs directly target multiple OUD-associated genes including BDNF, CYP2D6, OPRD1, OPRK1, OPRM1, HTR1B, POMC, SLC6A4 and OUD-associated pathways, including opioid signaling, G-protein activation, serotonin receptors, and GPCR signaling. In summary, we developed an integrated drug repurposing approach and identified five repurposed candidate drugs that might be of value for treating OUD patients, including those suffering from comorbid conditions.

Individuals with alcohol use disorder (AUD) show elevated brain metabolism of acetate at the expense of glucose. We hypothesized that a shift in energy substrates during withdrawal may contribute to withdrawal severity and neurotoxicity in AUD and that a ketogenic diet (KD) may mitigate these effects. We found that inpatients with AUD randomized to receive KD (n = 19) required fewer benzodiazepines during the first week of detoxification, in comparison to those receiving a standard American (SA) diet (n = 14). Over a 3-week treatment, KD compared to SA showed lower "wanting" and increased dorsal anterior cingulate cortex (dACC) reactivity to alcohol cues and altered dACC bioenergetics (i.e., elevated ketones and glutamate and lower neuroinflammatory markers). In a rat model of alcohol dependence, a history of KD reduced alcohol consumption. We provide clinical and preclinical evidence for beneficial effects of KD on managing alcohol withdrawal and on reducing alcohol drinking.

Visual presentation of appetitive and negative cues triggers fast responses in the human brain. Here we assessed functional MRI (fMRI) responses to food, cocaine, and neutral cues presented at a subliminal ("unconscious", 33 ms) and supraliminal ("conscious", 750 and 3000 ms) level in healthy, cocaine naïve volunteers. Because there is evidence of circadian variability in reward sensitivity, our second aim was to assess diurnal variability in the brain's reactivity to cues. Sixteen participants completed two randomly ordered fMRI sessions (once 9-11 AM and another 5-7 PM). in which food, cocaine, and neutral cues were presented for 33, 750 and 3000 ms. Participants rated food cues as positive and "wanted" (more so in evenings than mornings), and cocaine cues as negative (no diurnal differences). fMRI showed occipital cortex activation for food>neutral, cocaine>neutral and cocaine>food; dorsolateral prefrontal cortex for cocaine>neutral and cocaine>food, and midbrain for cocaine>food (all p_FWE < 0.05). When comparing unconscious (33 ms) > conscious (750 and 3000 ms) presentations, we observed significant differences for cocaine>neutral and cocaine>food in occipital cortex, for cocaine>neutral in the insula/temporal lobe, and for food>neutral in the middle temporal gyrus (p_FWE < 0.05). No diurnal differences for brain activations were observed. We interpret these findings to suggest that negative items (e.g., cocaine) might be perceived at a faster speed than positive ones (e.g., food), although we cannot rule out that the higher saliency of cocaine cues, which would be novel to non-drug using individuals, contributed to the faster speed of detection.

The current opioid epidemic is one of the most severe public health crisis in US history. Responding to it has been difficult due to its rapidly changing nature and the severity of its associated outcomes. This review examines the origin and evolution of the crisis, the pharmacological properties of opioids, the neurobiology of opioid use and opioid use disorder (OUD), medications for opioid use disorder (MOUD), and existing and promising approaches to prevention. The results of the review indicate that the opioid epidemic is a complex, evolving phenomenon that involves neurobiological vulnerabilities and social determinants of health. Successfully addressing the epidemic will require advances in basic science, development of more acceptable and effective treatments, and implementation of public health approaches, including prevention. The advances achieved in addressing the current crisis should also serve to advance the science and treatment of other substance use disorders.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.