Neurobiology of Drug Reward and Addiction

National Institute On Alcohol Abuse And Alcoholism

Investigators

Linked publications & trials

Abstract

We recruited and screened 65 participants into NIAAA Screening protocol #14-AA-0181. We enrolled 31 participants into the following 3 protocols: 14-AA-0144 (n=5), 17-AA-0114 (n=17) and 17-AA-0178 (n=9). The circadian protocol #14-AA-0187 is on hold as we are prioritizing OUD studies (17-AA-0114). During FY21 we pre-screened 163 subjects (n=121 with OUD), 120 of whom (n=82 with OUD) continued to complete the phone screening process. We completed a total of 35 PET scans, 24 MRI scans and 19 combined PET/MR scans which resulted in a total of 15 subjects completing the procedures on three protocols in FY20. We also obtained a total of 20 clinical brain MR scans while the subjects were in our charge during study participation. 1. Role of the DA system in the human brain and in drug reward Role of the DA system in Circadian Activity ): Led by Rui Zhang. Certain components of rest-activity rhythms such as greater eveningness (delayed phase), physical inactivity (blunted amplitude) and shift work (irregularity) are associated with increased drug use . To assess if DA signaling contributes to rest-activity rhythms (measured with one-week actigraphy) we examined their associations with striatal D1 (D1R) and D2/D3 (D2R) availability (measured with PET and 11CNNC112 and 11Craclopride) in 32 healthy adults (12 F, age: 42.4012.22). Additionally, we assessed self-reports for the drug-rewarding effects to the administration of 60 mg oral MP. We found that delayed rhythm was associated with higher D1R in caudate, whereas physical inactivity was associated with higher D2R in nucleus accumbens (NAc). Delayed rest-activity rhythm, higher caudate D1R and NAc D2R were associated with greater sensitivity to MPs rewarding effects. These findings reveal specific components of rest-activity rhythms associated with striatal D1R and D2/3R and with the sensitivity to MPs rewarding effects. Interventions that target rest-activity rhythms may help prevent and treat SUD Dependency of drug reward on the rate of DA increases: Led by Dr Manza. DA increase in striatum (including NAc) are associated with drug reward (high) and that the speed at which drugs enter the brain influences their rewarding effects , which explains why intravenous (iv) injection and smoking are the most addictive routes of drug administration. However, the rate of DA changes and brain activation patterns associated with the speed of drug entry into the brain have not been investigated in humans. To address this we are conducting dynamic studies with the PET/MRI (using 11Craclopride) that compare the speed of DA increase along with the brain activation patterns after iv MP (0.025 mg/kg) versus oral MP (60 mg po). Based on preclinical findings , we hypothesize that DA increases would be faster and higher for iv- than oral- MP, and that iv but not oral MP would activate reward regions reflecting stimulation of D1R (overpowering D2R) whereas oral would decrease brain activity due to stimulation of D2R, which are inhibitory. The following are preliminary results obtained in 15 healthy participants (36.79.5 years old; 7 F). We fitted gamma variate functions to the BOLD timeseries in a whole-brain, voxelwise general linear modeling analysis. In line with our hypothesis, iv MP elicited a pattern of relatively fast and short lasting (5 min duration) increased activation in striatum, with a bilateral cluster centered on the caudate and additional activation of insula, anterior cingulate and paracingulate gyrus whereas oral MP elicited a pattern of slow, plateauing reduction in activation in ventral striatum, right temporal pole, ventral prefrontal cortex and amygdala/hippocampus (pFWE < 0.05). 2. DAs role in the neurobiology of addiction in the human brain DAs role in opioid use disorder (OUD) and its implication to treatment: Led by Peter Manza. We are investigating the interactions of D1R and D2R in striatum on brain activity in individual with OUD with or without medications for OUD (MOUD). We hypothesize that in addiction there is: (1) reduced D2R signaling that leads to reduced activity of prefrontal control network and increased intrusion from DMN and increased D1R signaling associated with increased activity of saliency network (2) and deficits will be ameliorated by MOUD. Preliminary analyses from 13 OUD individuals (11 methadone, 2 buprenorphine) and 36 matched HC showed that OUD participants had lower striatal D2R compared to HC but did not differ in D1-to-D2R striatal ratio nor on DA release. These preliminary results suggest that MOUD might help normalize D1R and DA release but be less effective in normalizing reduced striatal D2R signaling). 3. Neuropathological consequences of chronic drug use Ketogenic diet: Led by Corinde Wiers who is now an assistant professor at U Penn where she will investigate the effects of a ketone ester on alcohol reward. In collaboration with Dr Fink Jensen we are pursuing a small outpatient clinical trial in Denmark to assess if a KD reduces alcohol drinking and to assess compliance. We will pursue clinical trials with KD if results from the Danish study document good compliance when given in an outpatient basis. Otherwise we will pursue this line of work through our preclinical and clinical collaborations. 4. Development of experimental methods, radiotracers and data analytics - Radiotracer Development: Studies to inform on reversal of fentanyl induced overdoses. Led by Sunny Kim. The urgency of the opioid overdose deaths exacerbated by fentanyl and fentanyl analogues and the difficulty or reversing fentanyl overdoses with naloxone has led us to prioritize this in our radiochemistry work. It has been proposed that the difficulty in reversing fentanyl overdoses reflects: (1) naloxones inability to displace fentanyl from the mu opioid receptor (MOR) and (2) fentanyls longer duration of action than naloxone resulting in narcotization following an initial reversal. To address this we used PET and carbon-11 labeled carfentanil (11CCFN) in the rat model, and showed that iv naloxone (0.4 mg/Kg, 2 mg Human Equivalent Doses) displaced 11CCFN binding in the brain rapidly and efficiently indicating that adequate doses of iv naloxone should reverse opioid-induced respiratory depression from carfentanyl. Quantification of MOR blockade by naloxone at different pretreatment times revealed that MOR occupancy by naloxone was high (>70%) 5 minutes after administration of both doses but MOR occupancy decreased rapidly and was only 20% within 2 hours of its administration and higher for 2 mg han 0.4 mg/Kg HED doses. These results indicate that MOR blockade by iv naloxone is very short-lasting, which would explain fatalities even after initial successful naloxone reversal from re-narcotization. It also indicates that higher naloxone doses would prolong the duration of MOR blockade.