Clavulanic acid reduces rewarding, hyperthermic and locomotor-sensitizing effects of morphine in rats: a new indication for an old drug?

Abstract

Despite the efficacy of ceftriaxone (CTX) in animal models of CNS diseases, including drug addiction, its utility as a CNS-active therapeutic may be limited by poor brain penetrability and cumbersome parenteral administration. An alternative is the β-lactamase inhibitor clavulanic acid (CA), a constituent of Augmentin that prevents antibiotic degradation. CA possesses the β-lactam core necessary for CNS activity but, relative to CTX, possesses: (1) oral activity; (2) 2.5-fold greater brain penetrability; and (3) negligible antibiotic activity. To compare the effectiveness of CA (10mg/kg) and CTX (200mg/kg) against centrally-mediated endpoints, we investigated their effects against morphine's rewarding, hyperthermic, and locomotor-sensitizing actions. Endpoints were based on prior evidence that CTX attenuates morphine-induced physical dependence, tolerance, and hyperthermia. As expected, rats treated with morphine (4 mg/kg) displayed hyperthermia and conditioned place preference (CPP). Co-treatment with CTX or CA inhibited development of morphine-induced CPP by approximately 70%. Morphine's hyperthermic effect was also suppressed, with CTX and CA producing 57% and 47% inhibition, respectively. Locomotor sensitization induced by repeated morphine exposures was inhibited by CA but not CTX. The present findings are the first to suggest that CA disrupts the in vivo actions of morphine and point toward further studying CA as a potential therapy for drug addiction. Further, its ability to disrupt morphine's rewarding effects at 20-fold lower doses than CTX identifies CA as an existing, orally-active alternative to direct CTX therapy for CNS diseases.