Effects of Clavulanic Acid on the Acquisition and Reinstatement Following Morphine-induced Conditioned Place Preference in Mice

β-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. 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. 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. 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