Neurobiology of Drug Reward and Addiction

National Institute On Alcohol Abuse And Alcoholism

Investigators

Linked publications, trials & patents

Abstract

We recruited and screened 56 participants into NIAAA Screening protocol #14-AA-0181. We enrolled 22 participants into protocol 17-AA-0114. During FY23 we pre-screened 314 subjects (n= 313 with OUD), 208 of whom underwent a phone screening process and 81 fit criteria. We performed 65 PET and 19 MRI in FY23 with 14 completing the protocol. 1. Role of the DA system in the human brain and in drug reward Neural circuit selective for fast but not slow DA increases in drug reward: Lead: Peter Manza. The faster a drug enters the brain, the greater its addictiveness, yet the brain circuits underlying the rate dependency to drug reward remain unresolved. We used simultaneous PET-fMRI to link dynamics of DA signaling, brain activity/connectivity, and self-reported high in 20 adults receiving methylphenidate (MP) orally (results in slow delivery) and intravenously (IV, results in fast delivery). We estimated speed of striatal DA increases to oral and IV MP and then tested where brain activity was associated with slow and fast DA dynamics. A frontostriatal circuit comprising the dorsal anterior cingulate (dACC) and its connections with dorsal caudate was activated by fast (but not slow) DA increases and paralleled high ratings. These data provide first evidence in humans for a link between dACC activation and fast but not slow DA increases. This demonstrates dACC's key role in drug reward, and identify it as a neuromodulation target to treat SUD. Brain connectivity changes to fast versus slow DA increases: Lead: Peter Manza. To assess how the rate of DA increases impacts brain network connectivity we compared fast versus slow DA increases by giving MP IV (0.25mg/kg) versus orally (60 mg). We assessed global brain connectivity (GBC) and its association with D1 receptors (D1R), which are critical for drug reward in 20 healthy participants during simultaneous 11Craclopride PET-fMRI scans. Dynamic changes in GBC were temporally associated with DA increases and showed strikingly different pattern with slow versus fast DA increases with patterns correlating negatively with one another (rho = -.54, pspin = .009). GBC showed significant fast > slow associations in dorsomedial and dorsolateral prefrontal cortex, bilateral insulae, posterior thalamus and brainstem, caudate and precuneus; and significant slow > fast associations in ventral striatum, medial orbitofrontal cortex, and frontopolar cortex (pFDR < .05). The degree to which dorsal prefrontal GBC tracked fast DA increases correlated with high ratings to IV MP (p = .004). Whole-brain GBC patterns to fast versus slow DA increases had spatial correspondence with D1R (normative maps 11CNNC-112; rho = .22, pspin < .05). The divergent patterns of brain connectivity with fast versus slow DA increases could explain why MP can have both rewarding and therapeutic effects depending on its route of administration. DA increases with MP reduce central-autonomic coupling in association with D2R Lead: Ehsan Shokri-Kojori. MP reduces low-frequency (LF < 0.1 Hz) activity and connectivity in sensorimotor and visual regions, which are regions that show temporal coupling with LF pulse changes (regulated by sympathetic innervation) and that we labeled as an autonomic network (AN). We tested whether MP reduced the LF synchronization in AN and assessed the role of D1 and D2 receptors (measured with 11CNNC112-PET and 11Craclopride-PET, respectively). MP (60 mg oral) decreased the fractional amplitude of LF fluctuations in the visual and sensorimotor regions of AN (pFWE < 0.05). MP diminished LF phase between pulse and brain in AN, medial and orbito-frontal regions, insula, thalamus, and pons (pFWE < 0.05). Greater reductions in cortical LF power were associated with more reductions in LF phase coupling between brain and pulse (r(24) = 0.62, p < 0.001). Reductions in phase coupling between pulse and brain were inversely associated with D2R (but not D1R) (r(23) = -0.58, p = 0.002). Reductions in central-autonomic coupling implicate a modulatory role of DA via D2R . 2. DAs role in the neurobiology of addiction in the human brain Disrupted brain state dynamics in opioid and alcohol use disorder: Lead: Rui Zhang. Substance use disorders (SUD) are chronic disorders with long-lasting changes in brain intrinsic networks. Few studies have assessed brain network dynamics in SUD. We investigated brain state dynamics in opioid use (OUD) and alcohol use disorder (AUD). Resting-state fMRI data of 27 OUD, 107 AUD and 137 healthy participants were analyzed to identify recurrent brain states and their dynamics. OUD and AUD non-smokers displayed similar changes in brain state dynamics including decreased fractional occupancy or dwell time in default mode network (DMN)-dominated brain states and increased appearance rate in visual network (VIS)-dominated brain states. Co-use of nicotine affected brain states in an opposite manner: lowering VIS-dominated and enhancing DMN-dominated brain states in OUD and AUD participants. These findings highlight the relevance of co-morbid drug use in studies of neurocircuitry but also in their treatment. 3. Neuropathological consequences of chronic drug use. Effects of Acute and Chronic Alcohol Exposure on Phosphodiesterase 4B (PDE4B). LBI Lead: Sunny Kim. In collaboration with Dr Robert Innis at NIMH and Dr George Koob at NIDA we are assessing the sensitivity of 18F-PF974, a phosphodiesterase 4B (PDE4B) PET radiotracer developed by Dr Innis, to neuroinflammation after acute and chronic alcohol. If successful we plan to conduct studies in individuals with AUD. 4. Development of experimental methods, radiotracers and data analytics Mu opioid receptor occupancy of mitragynine. Lead: Sunny Kim. Kratom, is used as self-medication for pain and opioid withdrawal. Mitragynine (MTG), and its metabolite, 7-hydroxymitragynine (7-OH-MTG), are partial agonists at mu opioid receptors (MORs) in vitro, and are believed to be responsible for Kratom's pharmacological effects. To assess MOR engagement by MTG (given IV or orally) and 7-OH-MTG (IV) in vivo we performed PET studies with 11Ccarfentanil (11CCFN), in rats. IV MTG (0.1 mg/kg, n=3; 5 mg/kg, n=3) or placebo (2.5% DMSO, n=5) were injected 5 min prior to 11CCFN; for oral administration, MTG (100 mg/kg) 30 (n=3) or 90 (n=3) minutes before 11CCFN; and 7-OH-MTG 2 mg/kg (n=5) was injected 5 minutes prior to 11CCFN. 11CCFN nondisplaceable binding potential (BPND) in thalamus was not affected by MTG but was reduced by 16% with IV 7-OH-MTG, though this was not significant (p=0.16). In contrast to in vitro data of MTG and 7-OH-MTG, MOR occupancy at pharmacologically relevant doses in vivo was negligible. These findings indicate low addictive potential or overdose risk with MTG. Work is ongoing to label mitragynine to assess its pharmacokinetics in vivo. Distinct Effects of Methylphenidate on fMRI measures of Brain Function (ALFF and gFCD) Lead: Dardo Tomasi. The amplitude of low-frequency fluctuations (ALFF) and global functional connectivity density (gFCD) are fMRI metrics widely used to assess resting brain function. However, their differential sensitivity to vasoactive changes has not been investigated. We examined the differential sensitivity of ALFF and gFCD to IV or oral MP. MP significantly increased gFCD and reduced ALFF for IV-MP (Cohens d>1.6) but less so for oral-MP (Cohens d<0.6). We showed an inverse association between gFCD and ALFF that was markedly enhanced during IV-MP, which could reflect ALFFs increased sensitivity to MP's vasoconstricting effects.