Intermittent access to oxycodone decreases dopamine uptake in the nucleus accumbens core during abstinence

Abstract

A major obstacle in treating opioid use disorder is the persistence of drug seeking or craving during periods of abstinence, which is believed to contribute to relapse. Dopamine transmission in the mesolimbic pathway is posited to contribute to opioid reinforcement, but the processes by which dopamine influences drug seeking have not been completely elucidated. To examine whether opioid seeking during abstinence is associated with alterations in dopamine transmission, female and male rats self‐administered oxycodone under an intermittent access schedule of reinforcement. Following self‐administration, rats underwent a forced abstinence period, and cue‐induced seeking tests were conducted to assess oxycodone seeking. One day following the final seeking test, rats were sacrificed to perform ex vivo fast scan cyclic voltammetry and western blotting in the nucleus accumbens. Rats displayed reduced dopamine uptake rate on abstinence day 2 and abstinence day 15, compared to oxycodone‐naïve rats. Further, on abstinence day 15, rats had reduced phosphorylation of the dopamine transporter. Additionally, local application of oxycodone to the nucleus accumbens reduced dopamine uptake in oxycodone‐naïve rats and in rats during oxycodone abstinence, on abstinence day 2 and abstinence day 15. These observations suggest that abstinence from oxycodone results in dysfunctional dopamine transmission, which may contribute to sustained oxycodone seeking during abstinence.

Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments

“…More recently, Samson et al (2022) were interested in determining whether alterations in dopamine transmission in the mesolimbic pathway were related to abstinence from oxycodone.…”

Overview of the structure and function of the dopamine transporter and its protein interactions

“…Further, phosphorylation of DAT at Thr53 also contributes to enhanced DAT sensitivity to cocaine and its analogs (Foster et al, 2012;Vaughan and Foster, 2013;Challasivakanaka et al, 2017). In these studies, pDAT levels correlated with cocaine and opioid induced increases in DAT kinetics (Alonso et al, 2021;Samson et al, 2022). However, PKC-mediated phosphorylation was found to reduce the Vmax of DAT and enhanced clathrin-mediated DAT internalization.…”

Hypocretin / Orexin Receptor 1 Knockdown in GABA or Dopamine Neurons in the Ventral Tegmental Area Differentially Impact Mesolimbic Dopamine and Motivation for Cocaine

“…In addition to potential changes in total membrane DAT expression, there is accumulating evidence suggesting that phosphorylation of the DAT at threonine 53 influences DA transmission [ 56 , 60 , 94 , 95 ], with lower pDAT tied to reduced DA uptake and DA responses to cocaine. In fact, we previously showed that acute Hcrtr1 blockade preferentially reduces pDAT expression in the NAc, which was associated with both reduced DA uptake rate and attenuated DAT sensitivity to cocaine [ 59 ].…”