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1- PhD Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.

Introduction: Β-lactam antibiotics such as clavulanic acid (CA) enhance the uptake of cellular glutamate via activation of glutamate transporter subtype 1 (GLT-1) and decrease the level of glutamate in nervous systems. Studies showed blocking the glutamate activity inhibit morphine-induced conditioned place preference (CPP) in animals. Therefore, the effects of CA on the acquisition and reinstatement of morphine craving were evaluated using the CPP model in the current study.
Methods:  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 were recorded. 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.
Results: 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) (10mg/kg) significantly inhibited both acquisition and reinstatement of morphine CPP.
Discussion:  Regarding to important role of glutamate neurotransmission in morphine dependence, it suggests that the effects of CA in the current study in some parts may be due to decrease of glutamate level in synaptic space and blockade of NMDA (N-methyl-D-aspartate)   receptors. Although, it needs more studies to determine exact cellular mechanism.

Type of Study: Original | Subject: Behavioral Neuroscience
Received: 2015/08/4 | Accepted: 2017/08/19 | Published: 2018/05/13

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