Striatum hyperactivity triggers relapse to morphine and methamphetamine (polydrug) dependence in mice
Nur Syafinaz Wasli1, Irna Elina Ridzwan2, Marwan Saad Azzubaidi3, Abdul Razak Kasmuri1, Qamar Uddin Ahmed4, Long Chiau Ming5, Nornisah Mohamed6, Syed Mohd Syahmi Syd Mohmad Faudzi7
1 Department of Basic Medical Sciences, Kulliyyah of Pharmacy, International Islamic University Malaysia, Kuantan, Pahang, Malaysia
2 Department of Pharmaceutical Chemistry, Kulliyyah of Pharmacy, International Islamic University Malaysia, Kuantan, Pahang, Malaysia; Substance Use Disorders Research Group, Kulliyyah of Pharmacy, International Islamic University Malaysia, Kuantan, Pahang, Malaysia
3 Department of Pharmacology, Faculty of Medicine and Health Sciences, Universiti Sultan Zainal Abidin (UniSZA), Kuala Terengganu, Terengganu, Malaysia
4 Department of Pharmaceutical Chemistry, Kulliyyah of Pharmacy, International Islamic University Malaysia, Kuantan, Pahang, Malaysia
5 PAP Rashidah Sa’adatul Bolkiah Institute of Health Sciences, Universiti Brunei Darussalam, Brunei Darussalam, Asia
6 Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Universiti Sains Malaysia (USM), Penang, Malaysia
7 Department of Pharmacy Practice, Kulliyyah of Pharmacy, International Islamic University Malaysia, Kuantan, Pahang, Malaysia
Dr. Irna Elina Ridzwan
Department of Pharmaceutical Chemistry, Kulliyyah of Pharmacy, International Islamic University Malaysia (IIUM), Kuantan Campus, Kuantan, Pahang.
Source of Support: None, Conflict of Interest: None
Introduction: κ-opioid receptor (KOPr) system has been linked to relapse to many substances, especially opioids. Positive responses were recently reported in morphine and methamphetamine (polydrug)-dependent mice treated with buprenorphine and naltrexone, a functional κ antagonist. Objectives: This study aimed to determine the specific brain region that is responsive to KOPr treatment following polydrug dependence. Materials and Methods: The polydrug-dependent mice model was developed using conditioned place preference (CPP) method. Following successful withdrawal phase, the mice were treated with 0.3 mg/kg buprenorphine and 1.0 mg/kg naltrexone. Four brain regions (hippocampus, prefrontal cortex, amygdala, and striatum) were investigated using immunohistochemistry technique. This is to quantify the changes in KOPr expression in each major brain region that was primarily involved in addiction neurocircuits of many substances. Unpaired Student’s t test was used to analyze all results, where P < 0.05 is considered significant. Results: The results showed that treatment with buprenorphine and naltrexone successfully attenuated relapse in 60% of mice (n = 14). A significant upregulation of KOPr was detected in striatum at the end of post-withdrawal phase (P < 0.01, n = 12). This treatment successfully suppressed KOPr in striatum (P < 0.001, n = 12), which supports the positive results seen in the CPP setting. No significant changes were observed in other brain regions studied. Conclusion: The hyperactivity of striatum suggests that the affected brain region following KOPr antagonist treatment is the region that primarily controls the drug rewarding activity, in which nucleus accumbens is located. This indicates that manipulation of KOPr system is one of the potential targets to treat morphine- or methamphetamine-dependence problem.