Japarin, Rima Atria
(2024)
Cross-reinstatement Models Of
Mitragynine-morphine Drugseeking
Addictive Behaviour And
Dopaminergic Involvement In
Sprague-dawley Rats.
Masters thesis, Universiti Sains Malaysia.
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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