Dopamine release is transiently suppressed during conditioned heroin withdrawal
Authors: Hamilton Lindsey R , Oleson Erik B. 
Published: June 2021

Discovering how the brain processes conditioned withdrawal, a central feature in drug addiction, is critical to thoroughly characterize the neurobiological basis of this pervasive disorder. The brain's mesolimbic dopamine system is most commonly studied within the context of the rewarding/reinforcing properties of abused drugs but, is also implicated in drug withdrawal. While prior studies demonstrated that dopamine function is generally depressed during withdrawal, the relatively low temporal resolution provided by previously available neurochemical techniques made in impossible to discern how dopamine release changes during the transient presentation of withdrawal associated stimuli. Here, we explored how conditioned withdrawal in heroin dependent rats affects real‐time changes in dopamine release. We provided rats 23‐hour self‐administration access to IV heroin over 28 days (0.06 mg/kg to 6 mg/kg). We then investigated how conditioned withdrawal affects dopamine release in the nucleus accumenbs (NAcc) using fast scan cyclic voltammetry (FSCV) during conditioned suppression of food maintained responding. Here, rats were trained to respond for food under a fixed‐ratio 1 schedule for 3 consecutive days. In these food seeking sessions, food availability (45mg grain pellet) was signaled by a cue‐light placed above the lever. Under these conditions, the food predictive cue typically evokes a transient increase in NAcc dopamine concentration that is believed to promote food seeking. To test whether this increase in dopamine release is suppressed during conditioned withdrawal we next associated an otherwise neutral tone to naloxone‐precipitated withdrawal. In conditioning sessions, animals were injected with either naloxone (1mg/kg SC) or vehicle and then presented with a 10s tone every 20s for 30min. Rats treated with vehicle during conditioning sessions received a naloxone injection (1mg/kg SC) 2hr following conditioning, so that both groups experienced withdrawal and the tone, but only one group experienced withdrawal in association with the tone. After three daily conditioning sessions animals were tested in the food seeking task while we concurrently performed FSCV. As predicted, the withdrawal associated tone, which was randomly presented in 33% of trials, suppressed dopamine release during food seeing. The conditioned withdrawal‐induced suppression of dopamine release was only evident in rats that received naloxone during tone presentation. Finally, we tested how heroin (6 mg/kg IV), naloxone methiodide (1 mg/kg IV) and naloxone methiodide (1 mg/kg IV) increase dopamine release in the heroin dependent rat. We found that 6mg/kg heroin increased dopamine release similarly to a 0.06mg/kg dose in the naïve rat. Naloxone methiodide failed to suppress the heroin‐induced increase in dopamine release, but naloxone HCl did, suggesting that the effects of withdrawal on dopamine release are primarily mediated by central processes.Support or Funding InformationThis work was supported by the National Science Foundation Grant IOS‐1557755, the National Institutes of Health Grant R03DA038734, the Boettcher Young Investigator Award and the National Alliance for Research on Schizophrenia and Depression Young Investigator Award (E.B.O.),This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.