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

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.