Behavioural Brain Research 267 (2014) 74–82 Contents lists available at ScienceDirect Behavioural Brain Research jou rn al hom epage: www.elsevier.com/locate/bbr Research report Increased calcium/calmodulin-dependent protein kinase II activity by morphine-sensitization in rat hippocampus Mehdi Kadivar a , Maryam Farahmandfar b,c,d,∗ , Faezeh Esmaeli Ranjbar a , Mohammad-Reza Zarrindast b,c,e a Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran b Department of Neuroscience, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran c Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran d Electrophysiology Research Center, Tehran University of Medical Sciences, Tehran, Iran e Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Iran h i g h l i g h t s • Acute morphine did not alter mRNA expression and activity of CaMKII in hippocampus. • Morphine sensitization increased mRNA expression of CaMKII in the hippocampus. • Morphine sensitization increased CaMKII activity in the rat hippocampus. • Naloxone decreased mRNA expression of CaMKII in morphine-sensitized rats. • Naloxone decreased CaMKII activity in morphine-sensitized rats. a r t i c l e i n f o Article history: Received 8 December 2013 Received in revised form 14 March 2014 Accepted 18 March 2014 Available online 25 March 2014 Keywords: Behavioral sensitization Morphine CaMKII Hippocampus Rat a b s t r a c t Repeated exposure to drugs of abuse, such as morphine, elicits a progressive enhancement of drug- induced behavioral responses, a phenomenon termed behavioral sensitization. These changes in behavior may reflect long-lasting changes in some of the important molecules involved in memory processing such as calcium/calmodulin-dependent protein kinase II (CaMKII). In the present study, we investigated the effect of morphine sensitization on mRNA expression of  and  isoforms and activity of CaMKII in the hippocampus of male rats. Animals were treated for 3 days with saline or morphine (20 mg/kg) and following a washout period of 5 days, a challenge dose of morphine (5 mg/kg) were administered. The results indicate that morphine administration in pre-treated animals produces behavioral sensitization, as determined by significant increase in locomotion and oral stereotypy behavior. In addition, repeated morphine treatment increased mRNA expression of both  and  isoforms of CaMKII in the hippocam- pus. The present study also showed that induction of morphine sensitization significantly increased both Ca2+/calmodulin-independent and Ca2+/calmodulin-dependent activities of CaMK II in the rat hippocam- pus. However, acute administration of morphine (5 mg/kg) did not alter either  and  CaMKII mRNA expression or CaMKII activity in the hippocampus. The stimulation effects of morphine sensitization on mRNA expression and activity of CaMKII were completely abolished by administration of naloxone, 30 min prior to s.c. injections of morphine (20 mg/kg/day × 3 days). Our data demonstrated that induction of morphine sensitization could effectively modulate the activity and the mRNA expression of CaMKII in the hippocampus and this effect of morphine was exerted by the activation of opioid receptors. © 2014 Elsevier B.V. All rights reserved. ∗ Corresponding author at: Department of Neuroscience, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, P.O. Box 13145-784, Iran. Tel.: +98 21 88991117; fax: +98 21 88991117. E-mail address: mfarahmandfar@razi.tums.ac.ir (M. Farahmandfar). 1. Introduction Calcium/calmodulin-dependent protein kinase II (CaMKII), a multiple functional enzyme, is one of the most abundant kinases in the brain, comprising 2% of total hippocampal proteins [16]. CaMKII is a major calcium-regulated signal transducer that http://dx.doi.org/10.1016/j.bbr.2014.03.035 0166-4328/© 2014 Elsevier B.V. All rights reserved.