Abstract
BackgroundOpioid use disorders are serious contributors to the harms associated with the drug use. Unfortunately, therapeutic interventions for opioid addicts after detoxification have been limited and not sufficiently effective. Recently, several studies have led to promising results with disulfiram (DSF), a dopamine β-hydroxylase (DBH) inhibitor, showing that it is a potent agent against not only alcohol but also addiction to various drugs.Materials and methodsThis study was designed to examine whether DSF and nepicastat (NEP; another DBH inhibitor) modify morphine intake and reinstatement of seeking-behavior using the rat model of intravenous morphine self-administration. Additionally, we intended to estimate the effects of both inhibitors on the locomotor activity as well as on extracellular dopamine and its metabolite levels in the nucleus accumbens using microdialysis in naive rats.ResultsWe demonstrated that both DBH inhibitors reduced responding to morphine self-administration. Moreover, DSF and NEP administered acutely before reinstatement test sessions consistently attenuated the reinforcing effects of morphine and a morphine-associated conditioned cue. The observed effects for lower doses (6.25–25 mg/kg; ip) of both DBH inhibitors seem to be independent of locomotor activity reduction and dopamine level in the nucleus accumbens. Neither DSF nor NEP administered daily during morphine abstinence with extinction training sessions had any effect on active lever-responding and changed the reinstatement induced by morphine priming doses. Reinstatement of drug-seeking behavior induced by a conditioned cue previously associated with morphine delivery was attenuated following repeated administration of DSF or NEP during the abstinence period.ConclusionThese results seem to point to the significance of DBH inhibition as a potential pharmacotherapy against morphine use disorders.Graphic abstract
Highlights
According to the Department of Mental Health and Substance Abuse (World Health Organization) as well as the European Monitoring Center for Drugs and Drug Addiction, the opioid use disorders (OUD), including compulsive using of pain relievers, heroin, and synthetic opioids, are serious contributors to the harms associated with the drug use in the world [1]
A two-way ANOVA for repeated measures indicated a significant effect for the session [F36,648 = 24.70, p = 0.00002], lever [F2,18 = 243.49, p = 0.00002] and session × lever interaction [F36,648 = 16.41, p = 0.00002], while the Newman–Keuls’ post hoc analyses revealed that rats responded more on the active lever than the inactive lever from the 3rd till 29th (7th extinction) experimental day
The total quantity of morphine taken by rats during 22-day morphine self-administration was 102.74 ± 4.77 mg/rat, with a daily number of infusions during the last 3 sessions of maintenance of morphine self-administration in two trained groups ranging between 11.7 ± 0.40 and 12.60 ± 0.54
Summary
Recent studies demonstrated that other DBH inhibitors, like disulfiram (DSF) or nepicastat (NEP), effectively attenuated reinstatement of cocaine-seeking behavior in rats [12,13,14,15]. Several studies have led to promising results with disulfiram (DSF), a dopamine β-hydroxylase (DBH) inhibitor, showing that it is a potent agent against alcohol and addiction to various drugs. Materials and methods This study was designed to examine whether DSF and nepicastat (NEP; another DBH inhibitor) modify morphine intake and reinstatement of seeking-behavior using the rat model of intravenous morphine self-administration. Reinstatement of drug-seeking behavior induced by a conditioned cue previously associated with morphine delivery was attenuated following repeated administration of DSF or NEP during the abstinence period. Conclusion These results seem to point to the significance of DBH inhibition as a potential pharmacotherapy against morphine use disorders
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