Valproate prevents the induction, but not the expression of morphine sensitization in mice

Repetitive exposure to opioids elicits sensitization to its locomotor stimulating effects. Several lines of evidence have shown that the central GABAergic system is involved in behavioral sensitization induced by morphine. Valproate, a clinically widely used anticonvulsant and mood stabilizer, can mainly inhibit gamma-aminobutyric acid (GABA) transaminase and activate glutamic acid decarboxylase, which result in decrease in the degradation and increase in the synthesis of GABA, and then the elevation of extracellular GABA in the central nervous system. However, the effects of valproate on behavioral sensitization to morphine have not been documented. Herein, we investigated the effects of valproate on the induction and the expression of behavioral sensitization to morphine. Mice treated daily for 7 days with 10 mg/kg morphine and challenged with the same dose after 7 days of washout showed increased locomotor activity. Co-administration of valproate (37.5, 75, 150 mg/kg, intraperitoneal (i.p.)), at doses that did not affect the spontaneous activity, 30 min prior to morphine dose-dependently inhibited the induction of morphine sensitization. However, neither single nor multiple administration (37.5, 75, 150 mg/kg x 7 injections) of valproate had any effect on the expression of morphine sensitization once it developed. Our results indicated that GABA plays an important role in the induction, but not in the expression of morphine sensitization in mice.