Neurobiology of Drug Reward and Addiction

National Institute On Alcohol Abuse And Alcoholism

Investigators

Linked publications, trials & patents

Abstract

We recruited and screened 75 participants into NIAAA Screening protocol #14-AA-0181. We enrolled 32 participants into protocol 17-AA-0114. During FY22 we pre-screened 358 subjects (n=314 with OUD), 225 of whom (n=215 with OUD) continued to complete the phone screening process and 122 (n=112 with OUD) who passed the phone screening process. We completed a total of 62 PET, 28 MRI, and 1 PET/MR scan in FY22. This resulted in a total of 17 subjects completing the procedures on the 17AA0114 protocol and 1 subject completing the procedures on the 17AA0178 protocol. 1. Role of the DA system in the human brain and in drug reward Eye-Blinking as a Dopamine Biomarker: Led by Dr Sukru Demiral. Eye-blink rate (EBR) has been proposed as a biomarker of the brain DA system, however, findings are not consistent. This study assessed the relationship between EBR, measured after oral placebo (PL) and after oral methylphenidate (MP) and striatal D1 receptor (D1R) and D2 receptor (D2R) availability (measured after PL and after MP) in healthy participants. PET measures of baseline D1R (11CNNC112) (BL-D1R) and D2R availability (11Craclopride) after PL (PL-D2R) and after MP (MP-D2R) were quantified in the striatum. MP reduced the number of blinks and increased the time participants kept their eyes open. Correlations with dopamine receptors were only significant for EBR measures obtained after MP; being positive for BL-D1R in putamen and MP-D2R in caudate (PL-D2R was not significant). MP-induced changes in EBR (PL minus MP) were negatively correlated with BL-D1R in caudate and putamen. Our findings suggest that EBR measures obtained while stressing the dopamine system might provide a more sensitive behavioral biomarker of striatal D1R and D2R than when obtained at baseline. Dynamic changes in DA and its association with drug reward: Led by Dr Dardo Tomasi. DA facilitates cognition and is implicated in reward processing. Methylphenidate (MP), a dopamine transporter blocker widely used orally to treat ADHD, but when injected it has strong rewarding effects. Since MPs brain uptake is much faster when injected than when taken orally, we hypothesized that not only the amplitude but also the speed of DA increases in the striatum underlie drug reward. Simulations of 11Craclopride PET data suggest that the time-varying difference in standardized uptake value ratio in striatum to cerebellum, DSUVr(t), between placebo and MP conditions is a proxy for the time-varying DA increases induced by MP. Using a placebo-controlled double-blind within-subjects design, we show in 20 healthy controls that DA release induced by IV MP (0.25 mg/kg) in the striatum was significantly faster than that induced by oral MP (60 mg) and that its time-to-peak was strongly associated with the intensity of self-reports of high. This novel approach for measuring dynamic changes in DA triggered by MP, shows for the first time in humans, that faster DA increases are associated with stronger subjective experience of drug reward 2. DA's role in the neurobiology of addiction in the human brain DA's role in opioid use disorder (OUD) and its implication to treatment: Led by Peter Manza. This is an ongoing project that aims to measure D1R and D2R along with DA release in the striatum in individual with OUD with or without medications for OUD (MOUD) and its associations with brain function. We hypothesize that in individuals with OUD there is: (1) reduced striatal D2R signaling that leads to reduced activity of prefrontal executive control network and increased intrusion from DMN, (2) increased striatal D1R signaling associated with increased activity of saliency network (ACC and insula) (3) reduced striatal DA release when challenged with methylphenidate, and (4) deficits will be ameliorated by MOUD. We have completed studies in 30 OUD (20 methadone, 10 buprenorphine, 0 naltrexone) and 36 matched HC. Due to the difficulty in recruiting naltrexone participants we modified the protocol to recruit individuals who are on recovery but not on MOUD, 3. Neuropathological consequences of chronic drug use Sleeps involvement in AUD neuropathology. This aim included: 3.a Characterization of sleep in healthy controls (HC) and 3.b Interactions between sleep and brain function and structure in AUD 3.a Brain interactions with Autonomic signals during Sleep in HC. Led by Ehsan Shokri-Kojori. The interactions between autonomic and central nervous systems, particularly under sleep deprivation (SD), which is considered a physiological stressor are not well understood. We measured brain fMRI, pulse, and amyloid beta burden in HC studies during rested wakefulness (RW) and SD. SD relative to RW resulted in a significant increase in low frequency (LF, < 0.1 Hz) power in an autonomic network (AN) (pFWE < 0.05) comprised of dorsal attention, visual, and sensorimotor regions, which exhibit consistent temporal coupling with LF pulse amplitude changes that are reflective of peripheral sympathetic tone. Higher LF power of AN during SD (but not RW) was associated with less brain amyloid beta burden (pFWE < 0.05). The enhanced AN activity during SD may reflect autonomic-central interactions necessary for clearance of waste products such as beta myeloid from the brain. 3.b Interactions between sleep and brain function and structure in AUD. Led by Rui Zhang Sleep disturbances in AUD contribute to brain neuropathology and to relapse. Though detoxification appears to have limited effects on sleep problems, inter-individual differences and related brain mechanisms have not yet been examined. We assessed the association between N3 sleep and brain function and structure changes in 30 AUD patients undergoing a 3-week inpatient detoxification. Patients did not show N3 sleep recovery after 3-weeks of detoxification, but there was large inter-subject variability. Increases in N3 were associated with increases in DMN RSFC but not with GMV. AUD females showed greater N3 increases than AUD males. These findings reveal a significant relationship between N3 and DMN functional changes in AUD over time/abstinence that might help predict outcomes and guide therapeutic interventions. 4. Development of experimental methods, radiotracers and data analytics - Motion networks predict head motion during rest and task fMRI. Led by Dardo Tomasi The capacity to stay still during scanning, which is necessary to avoid motion confounds while imaging, varies markedly between people. Here we investigated the neurobiological underpinnings of head motion using connectome-based predictive modeling and publicly available brain fMRI data from 424 individuals. Two motion networks, comprised of cerebellum and default-mode regions relevant to proprioception (prefrontal and temporal cortices) and interoception (insula), forecasted individual differences in absolute and relative head motion during six different tasks- and two rest-fMRI sessions. These findings, which generalized to a novel group of 1422 individuals, suggest that head motion reflects necessary functional connectivity for exerting inhibitory motor control during scanning. These motion networks could serve as head motion neuromarkers valuable for understanding developmental and disease conditions associated with impaired inhibitory motor control, including restlessness, hyperactivity and behavioral impulsivity.