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

Abstract

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 (10 mg/kg) and CTX (200 mg/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.

Amoxicillin and amoxicillin/clavulanate reduce ethanol intake and increase GLT-1 expression as well as AKT phosphorylation in mesocorticolimbic regions

“…In addition, clavulanic acid appears to have anti-seizure properties, at least in invertebrates (Rawls et al, 2010), although it is unclear whether this anti-seizure effect of clavulanic acid was due to its ability to enhance glutamate uptake or not. Importantly, a recent study revealed that clavulanic acid reduced reward, as measured by a morphine-induced conditioned place preference, in rats (Schroeder et al, 2014). Therefore, more studies are needed to establish the plausible role of clavulanic acid in upregulating GLT-1 expression and restoring glutamate homeostasis.…”

“…We tested AUG, rather than AMOX, because we were interested in the possible effects of clavulanic acid found in the AUG, but not AMOX, formulation given its putative behavioral effects, including disruption of a morphine-induced conditioned place preference (Schroeder et al, 2014). Whether AMOX affects sucrose intake still needs to be examined; but, given its limited effects on GLT-1 and pAKT modulation in the mPFC of ethanol-consuming P rats, AUG appears to hold greater promise for anti-addiction treatment via restoration of glutamate homeostasis in the mesocorticolimbic reward circuit.…”

Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice

“…Doses of CTX (200 mg/kg) and CA (1, 10 mg/kg) were based on prior work (Rothstein et al 2005; Trantham-Davidson et al 2012; Sanna et al 2013; Schroeder et al 2014). Dosing schedules for CTX and CA utilized repeated injections because consistent evidence across multiple laboratories shows that CTX has to be given repeatedly, for at least 5 days, and at a dose of 200 mg/kg, to detect significant efficacy in animal models of CNS diseases (Rothstein et al 2005).…”

“…The mechanism of CTX involves enhancement of cellular glutamate uptake through activation of glutamate transporter subtype I (GLT-1), an astrocytic transporter responsible for the majority of cellular glutamate reuptake in the mammalian brain (Rothstein et al 2005; Lipski et al 2007; Miller et al 2008; Kovalevich et al 2012). In the context of drugs of abuse, previous work has demonstrated that CTX reduces: analgesic tolerance, physical dependence, and conditioned place preference (CPP) resulting from chronic morphine exposure (Rawls et al 2010a, b; Schroeder et al 2014; Shen et al 2014); relapse to heroin seeking (Shen et al 2014); relapse to cocaine seeking (Sari et al 2009; Knackstedt et al 2010); reinforcing and motivational effects of cocaine in mice; locomotor sensitization to cocaine or amphetamine (Rasmussen et al 2011; Sondheimer and Knackstedt 2011; Tallarida et al 2013); methamphetamine-induced CPP (Abulseoud et al 2012); and alcohol consumption (Rao and Sari 2012; Sari et al 2013). …”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Clavulanic acid has greater oral availability and brain penetrability compared with ceftriaxone and enhances expression of GLT-1. Studies show that clavulanic acid treatment inhibits cocaine intake (Kim et al, 2016) as well as morphine CPP (Schroeder et al, 2014). Additional experimentation is required to determine whether clavulanic acid will surpass ceftriaxone as the most effective b-lactam-based treatment of relapse vulnerability.…”