Relapse to drug use is often cited as the major obstacle in overcoming a drug addiction. Whereas relapse can occur for a myriad of reasons, it is well established that complex neuroadaptations that occur over the course of addiction are major factors. Cocaine, as a potent dopamine transporter blocker, specifically induces alterations in the dopaminergic as well as other monoaminergic neurotransmissions, which lead to cocaine abuse and dependence. Evidence also suggests that adaptations in the endogenous opioids play important roles in pathophysiology of cocaine addiction. Following this evidence, we investigated a combination medication, levo-tetrahydropalmatine (l-THP) and low dose naltrexone (LDN), targeting primarily dopaminergic and endogenous opioid systems as a cocaine-relapse-prevention treatment. In the present study Wistar rats were used to assess the effects ofl-THP and LDN on cocaine self-administration, drug-seeking behavior during cocaine reinstatement, spontaneous locomotion, and effects on the endogenous opioid system. We determined that the combination ofl-THP and LDN reduces drug-seeking behavior during reinstatement more potently thanl-THP alone. Additionally, the combination ofl-THP and LDN attenuates the sedative locomotor effect induced byl-THP. Furthermore, we revealed that treatment with the combination ofl-THP and LDN has an upregulatory effect on both plasmaβ-endorphin and hypothalamic POMC that was not observed inl-THP-treated groups. These results suggest that the combination ofl-THP and LDN has great potential as an effective and well-tolerated medication for cocaine relapse prevention.
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