COMPARISON OF BASAL AND NALOXONE-EVOKED DOPAMINE EFFLUX IN THE RAT DORSAL AND VENTRAL STRIATUM FOLLOWING PROLONGED- INTERMITTENT EXPOSURE TO MORPHINE

Abstract Background Hypodopaminergia in the ventral striatum is a putative neurobiological correlate of opioid withdrawal (1). Consistent with this view, in opioid-dependent animals, naloxone induces somatic withdrawal signs and suppresses dopamine (DA) levels in the ventral striatum for several hours (2-4). These preclinical findings stand in contrast to a recent brain imaging study showing that naloxone failed to alter DA release in the ventral striatum of chronic opioid users (5). Interestingly, DA release was enhanced by naloxone in the dorsal striatum, an effect that was positively correlated with subjective ratings of withdrawal aversion (5). Aims and Objectives To address this disparity, the present study sought to examine possible differences in dopaminergic correlates of withdrawal in the dorsal and ventral striatum of morphine-dependent rats. Method Male rats were administered morphine (15 mg/kg, IP) for five days followed by two days of drug omission each week, for five weeks. On Days 10 and 31, in vivo microdialysis was employed to monitor DA efflux in either the ventral or dorsal striatum. Results Basal DA concentrations were significantly reduced (i.e., indicating a hypodopaminergic state) in the ventral striatum on Day 10 of morphine exposure (A), whereas a more prolonged period of exposure was required to reveal hypodopaminergia in the dorsal striatum on Day 31 (B). The ventral striatum consistently exhibited naloxone-induced transient reductions in DA below the hypodopaminergic basal levels (C,D). In the dorsal striatum, DA responsivity to naloxone shifted from a significant decrease on Day 10 to a notable increase above hypodopaminergic basal levels on Day 31 (E,F), corroborating the findings in the human dorsal striatum. Discussion and Conclusion These findings indicate that prolonged-intermittent exposure to morphine results in a sustained hypodopaminergic state as reflected by basal levels in the ventral and dorsal striatum, which is accompanied by regional differences in DA responsivity to naloxone. Overall, our findings suggest that prolonging the duration of morphine exposure to 31 days is sufficient to reveal neuroadaptations that may underlie the transition from initial drug exposure to opioid dependence. Ongoing studies are examining possible regional differences in opioid-induced adaptations of DA activity in the medial prefrontal cortex. References 1.Koob, G. F. (2021) ‘Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development’, Pharmacological Reviews, 73(1), 163-201. https://doi.org/10.1124/pharmrev.120.000083. 2.Pothos, E., Rada, P., Mark, G. P., Hoebel, B. G. (1991) ‘Dopamine microdialysis in the nucleus accumbens during acute and chronic morphine, naloxone-precipitated withdrawal and clonidine treatment’, Brain Research, 566(1-2), 348-350. https://doi.org/10.1016/0006-8993(91)91724-F. 3.Ahn, S. et al. (2020) ‘Neural bases for attenuation of morphine withdrawal by Heantos-4: role of l- tetrahydropalmatine’, Scientific Reports, 10(1), 21275. https://10.1038/s41598-020-78083-x. 4.Rossetti, Z. L., Hmaidan, Y., Gessa, G. L. (1992) ‘Marked inhibition of mesolimbic dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats’, European Journal of Pharmacology, 221(2-3), 227-234. https://doi.org/10.1016/0014-2999(92)90706-a.5. 5.Shokri-Kojori, E., Wang, G.-J., Volkow, N. D. (2021) ‘Naloxone precipitated withdrawal increases dopamine release in the dorsal striatum of opioid dependent men’, Translational Psychiatry, 11(1). https://doi.org/10.1038/s41398-021-01548-8.