Treatment with dopamine β-hydroxylase (DBH) inhibitors prevents morphine use and relapse-like behavior in rats

• Published in: Pharmacological reports 2021-12, Vol.73 (6), p.1694-1711
• Main Authors: Frankowska, Małgorzata, Surówka, Paulina, Suder, Agata, Pieniążek, Renata, Pukło, Renata, Jastrzębska, Joanna, Daniel, Władysława A., Filip, Małgorzata, Zadrożny-Bujalska, Magdalena, Kleczkowska, Patrycja
• Format: Article
• Language: English
• Subjects: Animals; Disulfiram - pharmacology; Dopamine - metabolism; Dopamine beta-Hydroxylase - antagonists & inhibitors; Drug Safety and Pharmacovigilance; Drug-Seeking Behavior - drug effects; Enzyme Inhibitors - pharmacology; Extinction, Psychological - drug effects; Imidazoles - pharmacology; Male; Medicine; Morphine - administration & dosage; Nucleus Accumbens - metabolism; Opioid-Related Disorders - drug therapy; Pharmacotherapy; Pharmacy; Rats; Rats, Wistar; Recurrence; Self Administration; Thiones - pharmacology
• ISSN: 1734-1140; 2299-5684
• DOI: 10.1007/s43440-021-00307-2

Background Opioid 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 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. 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. Results We 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. Conclusion These results seem to point to the significance  of DBH inhibition as a potential pharmacotherapy against morphine use disorders. Graphic abstract