en Behavioral Neuroscience Behavioral Neuroscience Original Original <p dir="ltr" style="text-align: justify;"><strong>Introduction:</strong> &beta;-Lactam antibiotics like Clavulanic Acid (CA) enhances cellular glutamate uptake through activation of Glutamate Transporter subtype 1 (GLT-1) and decreases the level of glutamate in the nervous system. Based on studies, blocking the glutamate activity inhibits morphine-induced Conditioned Place Preference (CPP) in animals. Therefore, the effects of CA on the acquisition of morphine craving were evaluated using the CPP model in the current study.<br> <strong>Methods: </strong>CA (1, 50 and 150 mg/kg, ip) was co-administered with morphine (40 mg/kg) for 4 days in the conditioning phase. On day 8, the effects of CA on morphine preference was assessed. In another experiment, the effect of CA on reinstatement of morphine preference by a single morphine injection (10 mg/kg) was evaluated after an extinction period.&nbsp;<br> <strong>Results:</strong> In the first method, the morphine-induced place preference was markedly reduced following administration of CA (50 and 150 mg/kg). In the second experiment, a single administration of CA (50 and 150 mg/kg) markedly inhibited the reinstatement of morphine preference on day 16. The results indicated that CA (50, 150 mg/kg) can block both morphine-induced CPP and the reinstatement of place preference following priming dose of morphine. Also memantine (as a positive control) (10 mg/kg) significantly inhibited both acquisition and reinstatement of morphine CPP.<br> <strong>Conclusion:</strong> Considering the important role of glutamate neurotransmission in morphine dependence, the effects of CA may be partly due to decrease in glutamate level in synaptic space and blockade of N-Methyl-D-aspartate Acid (NMDA) receptors. Although, we need further studies to determine exact cellular mechanism.</p> Clavulanic Acid, Morphine, Glutamic acid, Memantine 289 296 http://bcn.iums.ac.ir/browse.php?a_code=A-10-799-1&slc_lang=en&sid=1 Soghra Mehri mehris@mums.ac.ir 13700319475328460016379 13700319475328460016379 No Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran. Seyed Saber Sajjadi SajjadiS871@mums.ac.ir 13700319475328460016380 13700319475328460016380 No Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Seyed Meghdad Tabatabai tabatabaism@gmail.com 13700319475328460016381 13700319475328460016381 No Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Hossein Hosseinzadeh hosseinzadehh@mums.ac.ir 13700319475328460016382 13700319475328460016382 Yes Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.