Neurobiology of Drug Reward and Addiction

National Institute On Alcohol Abuse And Alcoholism

Investigators

Linked publications, trials & patents

Abstract

During FY25 we pre-screened 226 subjects (n= 29 with OUD, n= 50 with AUD). From the phone screening process and 10 OUD and 6 AUD fit criteria and were screened. We enrolled 6 OUD and 5 AUD participants and 18 HC. We performed 53 PET scans and 28 MRI scans, In 2025 for protocol 17-AA-0114, we completed studies in 6 OUD participants and for protocol 001561-AA, in 4 AUD and 10 HC participants. 1. Role of the DA system in the human brain and in drug reward Methylphenidate Reshapes Cortical Hierarchy: Linking Functional Gradients to Striatal Dopaminergic Function. Dopamine (DA) plays a critical role in motivation, cognitive control, and large-scale brain organization. Methylphenidate (MP), a psychostimulant that blocks DA and norepinephrine transporters, increases extracellular DA levels and enhances cognitive performance. It remains unclear whether MP reshapes the brain’s functional hierarchy. Recent evidence suggests that DA influences the principal gradient of cortical organization, a dominant axis of functional connectivity that spans from unimodal sensorimotor regions to transmodal association areas. Thirty-eight healthy adults underwent PET imaging with [¹¹C]NNC-112 and [¹¹C]raclopride to measure D1 (D1R) and D2 receptor (D2R) availability, alongside precision functional mapping at 3T to capture resting-state functional gradients. Using diffusion embedding, we assessed changes in cortical hierarchy under placebo and MP conditions. MP administration significantly compressed the principal gradient, reducing differentiation between unimodal and transmodal regions. Partial least squares regression revealed that MP-induced shifts in cortical gradients predicted individual differences in D1R availability in putamen and nucleus accumbens and D2R in the caudate. These findings suggest that MP shifts large-scale cortical organization toward a more integrated state, with functional gradients providing a novel link between cortical hierarchy and striatal DA function. 2. DA’s role in the neurobiology of addiction in the human brain Disruption of Dopaminergic signaling in individuals with opioid use disorder (OUD) and effects of medication treatment: We assessed the striatal DA system in people with opioid use disorder (OUD) who were in treatment and/or long-term recovery. Previous studies in people with OUD who were actively using opioids found that, compared to matched controls, the OUD group had lower striatal D2R availability and blunted DA increases in response to a stimulant challenge. We sought to test whether an OUD population in recovery would also show these deficits, and additionally whether they showed differences in D1R. We enrolled 40 healthy controls (HC) (age 42.6 ± 11.6 years; 25 Male, 15 Female) and 85 participants with a history of moderate-to-severe OUD (age 42.8 ± 11.9 years; 52 Male, 33 female), of whom 33 were receiving methadone, 29 were receiving buprenorphine, and 23 were in recovery without medications for a minimum of 3 months. We assessed D1R and D2R, and the D1R/D2R ratio, using PET imaging. We found that striatal D2R availability in OUD participants when compared with HC when assessed at the voxel wise level did not reach significance; however when we computed measures based on predefined regions of interest we observed significantly lower D2R availability between OUD and HC though not between different medications. OUD patients also showed significant increases in D1R availability (and hence, an elevated D1R/D2Rratio) throughout the striatum and in cortex, which was not significantly associated with treatment duration or ‘wanting’ ratings for drug cues. There were no significant differences in any striatal dopamine measures between the OUD patients taking medications and those in long term recovery without medications. 3. Neuropathological consequences of drugs. Assessing in vivo Binding of Kratom to Brain Mu Opioid Receptors (MOR). Respiratory depression from inhibition of respiratory centers in the brain is the main cause of opioid overdose deaths. Kratom, a natural product from Southeast Asia, has been used to manage pain and opioid withdrawal. However the increase consumption of kratom has raised concerns about its risk for addiction and overdose. Kratom’s major alkaloid, mitragynine (MTG), and its metabolite, 7-hydroxymitragynine (7-OH MTG) bind to MOR with limited affinity acting as partial agonists. We used PET to investigate binding of kratom and MTG to MOR and to assess its pharmacokinetics in the rat brain. We radiolabeled MTG with C-11, demonstrating high and fast brain uptake (Tmax, 1.5 min; SUV, 1.5-2 g/mL) and rapid brain clearance. To quantify MOR occupancy, different doses and drug regimens were administered prior to injection of the MOR radiotracer ([11C]carfentanil, [11C]CFN): IV MTG (5 mg/Kg), PO MTG (100 mg/Kg), PO kratom (organic extract 100 mg/Kg), and IV 7-OH MTG (2 mg/Kg). Notably, only the very high dose of IV 7-OH MTG (2mg/kg) decreased the specific binding of [11C]CFN, providing evidence of negligible MOR engagement by kratom and MTG in vivo. Given that the doses of IV 7-OH MTG needed to observe MOR occupancy are higher than those typically achieved by kratom users, the potential addictive effects of Kratom likely reflect its effects at other pharmacological targets. Effects of Acute Opioid Exposure on Brain Phosphodiesterase 4B (PDE4B). LBI Lead: Sunny Kim in collaboration with Dr Victor Pike at NIMH and Dr George Koob at NIDA. The cyclic adenosine monophosphate (cAMP) cascade is crucial in regulating opioid effects. This study assessed the effects of acute opioid administration (fentanyl, SC 0.05 mg/kg) on brain PDE4B using PET and the PDE4B-preferring radioligand, [18F]PF-06445974, in rats. Acute fentanyl administration resulted in decreased brain uptake of [18F]PF-06445974 at 2–3 hours, with recovery observed at 4–6 hours. This finding demonstrates opioid-induced cAMP reduction in vivo, consistent with fentanyl's effect on cAMP via mu-opioid receptors observed in cell-based assays. To further explore the dynamic fluctuation of intracellular cAMP levels, we have synthesized a C-11 labeled PDE4B radiotracer ([11C]ZTP-1), which enables multiple PET studies per day on the same subject. This radiotracer will allows us to investigate the temporal effects of fentanyl and the effects of chronic fentanyl exposure and withdrawal on cAMP. 4. Development of experimental methods, radiotracers and data analytics Artificial Intelligence Models to Generate PET Brain D1R images from D2R images and provide information about their interactions. To assess regional brain differences in the pattern of interactions between D1R and D2R in OUD and HC we used a deep learning-based synthetic imaging framework, attentional 3D-UNet (A3UNet) model, capable of generating high-fidelity D1R PET images (measured by [11C]NNC) from D2R PET images (measured by [11C]Raclopride) and vice versa. The model is trained on paired D1R-D2R PET samples comprising individuals with OUD (n=67) and HC (n=39). A ROI-based sensitivity analysis was also implemented for interpretating the regional contribution driving successful synthesis. The model demonstrated robust performance across both structural similarity (SSIM>0.94 and region-wise evaluations (averaged percentage bias in striatum < 3%), achieving high structural and statistical agreement with ground truth. Comparative ablation experiments confirmed the robustness of the A3UNet. The variety of synthesis performance across networks and striatum showed that the OUD group showed better prediction performance than the NC group when predicting D1R from D2R. In contrast, the OUD group performed worse than the NC group when predicting D2R from D1R, suggesting homogeneous spatial distribution and loss of information diversity in D1R induced by OUD. Pupil Size as Biomarker of the Ascending Arousal Network (AAN): Pupil size has been proposed as biomarker of AAN in association with the autonomic nervous system and in preclinical models has been associated with activity in the Locus Coeruleus, a key AAN nucleus. In this study we tested the hypothesis, using resting state fMRI scans from healthy volunteers (HCP 7T), that arousal changes indexed by pupil size would be associated with changes in activity of the AAN and fronto-parietal cortex (FPC) which play a crucial role in attention networks. Our analyses showed that changes in pupil size were linked with changes in activity in AAN and FPC in inverse association with ventricular changes in CSF. Specifically, CSF flow in the ventricles increased as the activity in AAN and FPC decreased concomitant with pupil size reductions. The coupling between pupil changes and BOLD activity emerged earlier for LC than for other AAN nuclei, and Granger causality analysis showed strong LC-pupil coupling. The associations of BOLD signal with changes in pupil size were stronger during vigilant than drowsy states. Our results show that pupil measure can be used to predict activation responses in AAN nuclei and FPC and inflow of CSF intro the ventricles in a vigilance dependent manner.