Publication: Cross-reinstatement Models Of Mitragynine-morphine Drugseeking Addictive Behaviour And Dopaminergic Involvement In Sprague-dawley Rats
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Date
2024-09
Authors
Japarin, Rima Atria
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Abstract
Kratom (Mitragyna speciosa Korth.) is a medicinal herb which gained fame for its potential as an opioid substitute. Nevertheless, little is known about the abuse potential of its major alkaloid, mitragynine, especially in relapse to drug abuse. Therefore, the extinction-reinstatement models including the conditioned place preference (CPP) and intravenous self-administration (IVSA) paradigms, were employed to model the relapse mechanism in Sprague-Dawley rats. In the first part of the study, mitragynine administered non-contingently in morphine-addicted rats following extinction was investigated. Following CPP acquisition induced by either mitragynine (30 mg/kg, i.p.) or morphine (10 mg/kg, i.p.), rats were subjected to repeated CPP extinction sessions. A priming injection of morphine (1, 3 and 10 mg/kg, i.p.) dose-dependently reinstated mitragynine-induced CPP. Similarly, a priming injection of mitragynine (3, 10 and 30 mg/kg, i.p.) dose-dependently reinstated morphine-induced CPP. In the IVSA study, rats were initially trained to intravenously self-administer morphine (0.5 mg/kg/infusion) under a fixed ratio-3 schedule of reinforcement. Removal of both morphine infusions and drug-associated cues led to the extinction of drug-seeking behaviour. Reinstatement tests were made following a randomised order of mitragynine (3, 10 and 30 mg/kg), morphine (5 mg/kg) and vehicle injections. Mitragynine priming at 10 mg/kg resulted in the reinstatement of morphine-seeking behaviour but higher mitragynine dose (30 mg/kg) suppressed the seeking response. In order to understand the mechanism underlying the rewarding properties of mitragynine in relapse, the involvement of dopaminergic system in the acquisition, expression and reinstatement phase was studied. Therefore, the second part of the study was conducted using a selective dopamine (DA) D1 receptor antagonist, SCH-23390. For acquisition, rats were pre-treated with SCH- 23390 (0, 0.1 and 0.3 mg/kg, i.p.) prior to mitragynine (10 mg/kg) conditioning sessions. Next, the effects of DA D1 receptor antagonist were tested on the expression of mitragynine-induced CPP. Subsequently, the effects of a mitragyninepriming dose (5 mg/kg) on the reinstatement of extinguished CPP were tested. The results showed that SCH-23390 dose-dependently suppressed the acquisition of mitragynine-induced CPP but no effect on the expression of mitragynine-induced CPP. Additionally, blockade of the D1-like receptor during conditioning did not prevent mitragynine priming effects in CPP reinstatement test, implying no role of the DA D1 receptor in reinstatement sensitivity. Altogether, these findings suggest that exposure to mitragynine may increase the likelihood of relapsing to opioids, suggesting that mitragynine’s potential as an opioid management treatment merits further scientific assessment of its ability to trigger relapse to opioid abuse.
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Keywords
Cross-reinstatement Models , Mitragynine-morphine Drugseeking Addictive Behaviour , Dopaminergic Involvement In Sprague-dawley Rats , Dopaminergic Involvement , Japarin , Rima Atria , Pusat Penyelidikan Dadah dan Ubat-Ubatan