Effects of berberine on acquisition and reinstatement of morphine-induced conditioned place preference in mice

Document Type : Original Research Article


1 School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Pharmacology and Toxicology, School of Pharmacy, Zabol University of Medical Sciences, Zabol, Iran

3 Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran


Objective: It has been shown that berberine, a major component of Berberis vulgaris extract, modulates the activity of several neurotransmitter systems including dopamine (Da) and N-methyl-D-aspartate (NMDA) contributing to rewarding and reinforcing effects of morphine. Drug craving and relapsing even after a long time of abstinence therapy are the most important problems of addiction. In the present study, we investigated the alleviating effects of berberine on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP) in mice.
Materials and Methods: In male NMRI mice, the acquisition of CPP was established by 40 mg/kg of morphine sulphate injection and extinguished after the extinction training and reinstated by a 10 mg/kg injection of morphine.  The effects of different doses of berberine (5, 10, and 20 mg/kg) on the acquisition and reinstatement induced by morphine were evaluated in a conditioned place preference test.
Results: The results showed that intraperitoneal administration of berberine (5, 10, and 20 mg/kg) did not induce conditioned appetitive or aversive effects. Injection of berberine (10 and 20 mg/kg) 2 h before the morphine administration reduced acquisition of morphine-induced CPP. In addition, same doses of berberine significantly prevented the reinstatement of morphine-induced CPP.
Conclusion: These results suggest that berberine can reduce the acquisition and reinstatement of morphine-induced conditioned place preference and may be useful in treatment of morphine addiction.


Main Subjects

Aguilar MA, Manzanedo C, Do Couto BR, Rodriguez-Arias M, Minarro J. 2009. Memantine blocks sensitization to the rewarding effects of morphine. Brain Res, 1288: 95-104.
Bhutada P, Mundhada Y, Bansod K, Dixit P, Umathe S, Mundhada D. 2010. Anticonvulsant activity of berberine, an isoquinoline alkaloid in mice. Epilepsy Behav, 18: 207-210.
Cami J, Farre M. 2003. Drug addiction. N Engl J Med, 349: 975-986.
Chu H, Jin G, Friedman E, Zhen X. 2008. Recent development in studies of tetrahydroprotoberberines: mechanism in antinociception and drug addiction. Cell Mol Neurobiol, 28: 491-499.
Dallimore JE, Mickiewicz AL, Napier TC. 2006. Intra-ventral pallidal glutamate antagonists block expression of morphine-induced place preference. Behav Neurosci, 120: 1103-1114.
Fatehi M, Saleh TM, Fatehi-Hassanabad Z, Farrokhfal K, Jafarzadeh M, Davodi S. 2005. A pharmacological study on Berberis vulgaris fruit extract. J Ethnopharmacol, 102: 46-52.
Harris GC, Wimmer M, Byrne R, Aston-Jones G. 2004. Glutamate-associated plasticity in the ventral tegmental area is necessary for conditioning environmental stimuli with morphine. Neuroscience, 129: 841-847.
Imanshahidi M, Hosseinzadeh H. 2008. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother Res, 22: 999-1012.
Imenshahidi M, Zafari H, Hosseinzadeh H. 2011. Effects of crocin on the acquisition and reinstatement of morphine-induced conditioned place preference in mice. Pharmacologyonline, 1: 1007-1013.
Imenshahidi M, Qaredashi R, Hashemzaei M, Hosseinzadeh H.  2014. Inhibitory Effect of Berberis vulgaris Aqueous Extract on Acquisition and Reinstatement Effects of Morphine in Conditioned Place Preferences (CPP) in Mice. Jundishapur J Nat Pharm Prod, 9:e16145.
Johnson SW, North RA. North 1992. Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci, 12: 483-488.
Kalivas PW, Duffy P, Barrow J. 1989. Regulation of the mesocorticolimbic dopamine system by glutamic acid receptor subtypes J Pharmacol Exp Ther, 251: 378-387.
Kretschmer BD. 1999. Modulation of the Mesolimbic Dopamine System by Glutamate. J Neurochem, 73: 839-848.
Lee B, Kwon S, Yeom M, Shim I, Lee H, Hahm DH. 2011. Wild ginseng attenuates repeated morphine-induced behavioral sensitization in rats. J Microbiol Biotechnol, 21: 757-765.
Leone P, Pocock D, Wise RA. 1991. Morphine-dopamine interaction: ventral tegmental morphine increases nucleus accumbens dopamine release. Pharmacol Biochem Behav, 39: 469-472.
Manzanedo C, Aguilar MaA, Rodrı́guez-Arias M, Miñarro J. 2001. Effects of dopamine antagonists with different receptor blockade profiles on morphine-induced place preference in male mice. Behav Brain Res, 121: 189-197.
Meng S, Quan W, Qi X, Su Z, Yang S. 2014. Effect of baclofen on morphine-induced conditioned place preference, extinction, and stress-induced reinstatement in chronically stressed mice. Psychopharmacology, 231: 27-36.
Mueller D, Perdikaris D, Stewart J. 2002. Persistence and drug-induced reinstatement of a morphine-induced conditioned place preference. Behav Brain Res, 136: 389-397.
Peng WH, Hsieh MT, Wu CR. 1997. Effect of long-term administration of berberine on scopolamine-induced amnesia in rats. Jpn J Pharmacol, 74: 261-266.
Pierce RC, Kalivas PW. 1997. A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Rev, 25: 192-216.
Popik P, Kolasiewicz W. 1999. Mesolimbic NMDA receptors are implicated in the expression of conditioned morphine reward. Naunyn Schmiedebergs Arch Pharmacol, 359: 288-294.
Ribeiro Do Couto B, Aguilar MA, Manzanedo C, Rodriguez-Arias M, Minarro J. 2003. Reinstatement of morphine-induced conditioned place preference in mice by priming injections. Neural Plast, 10: 279-290.
Ribeiro Do Couto B, Aguilar MA, Manzanedo C, Rodriguez-Arias M, Minarro J. 2004. Effects of NMDA receptor antagonists (MK-801 and memantine) on the acquisition of morphine-induced conditioned place preference in mice. Prog Neuropsychopharmacol Biol Psychiatry, 28: 1035-1043.
Ribeiro Do Couto B, Aguilar MA, Manzanedo C, Rodríguez-Arias M, Miñarro J. 2005. NMDA glutamate but not dopamine antagonists blocks drug-induced reinstatement of morphine place preference. Brain Res Bull, 64: 493-503.
Shin JS, Kim EI, Kai M, Lee MK. 2000. Inhibition of dopamine biosynthesis by protoberberine alkaloids in PC12 cells. Neurochem Res, 25: 363-368.
Wise RA. 2002. Brain reward circuitry: insights from unsensed incentives. Neuron, 36: 229-240.
Yoo JH, Yang EM, Cho JH, Lee JH, Jeong SM, Nah SY, Kim HC, Kim KW, Kim SH, Lee SY, Jang CG. 2006. Inhibitory effects of berberine against morphine-induced locomotor sensitization and analgesic tolerance in mice. Neuroscience, 142: 953-961.
Zhu YP, Long ZH, Zheng ML, Binsack R. 2006. Effect of glycine site/NMDA receptor antagonist MRZ2/576 on the conditioned place preference and locomotor activity induced by morphine in mice. J Zhejiang Univ Sci B, 7: 998-1005.