Ceftriaxone attenuates locomotor activity induced by acute and repeated cocaine exposure in mice

Abstract

Ceftriaxone (CTX) decreases locomotor activation produced by initial cocaine exposure and attenuates development of behavioral sensitization produced by repeated cocaine exposure. An important question that has not yet been answered is whether or not CTX reduces behavioral sensitization to cocaine in cases in which the antibiotic is administered only during the period of cocaine absence that follows repeated cocaine exposure and precedes reintroduction to cocaine. We investigated this question using C57BL/6 mice. Mice pretreated with cocaine (15 mg/kg × 14 days) and then challenged with cocaine (15 mg/kg) after 30 days of cocaine absence displayed sensitization of locomotor activity. For combination experiments, CTX injected during the 30 days of cocaine absence attenuated behavioral sensitization produced by cocaine challenge. In the case in which CTX was injected together with cocaine for 14 days, development of behavioral sensitization to cocaine challenge was also reduced. CTX attenuated the increase in locomotor activity produced by acute cocaine exposure; however, its efficacy was dependent on the dose of cocaine as inhibition was detected against 30 mg/kg, but not 15 mg/kg, of cocaine. These results from mice indicate that CTX attenuates locomotor activity produced by acute and repeated cocaine exposure and counters cocaine's locomotor activating properties in a paradigm in which the antibiotic is injected during the period of forced cocaine absence that follows repeated cocaine exposure.

Ceftriaxone attenuates acquisition and facilitates extinction of cocaine-induced suppression of saccharin intake in C57BL/6J mice

“…The degree to which such an effect would influence the observed attenuation of suppression (i.e., increased intake) in the current data is minimal as neophobia to a novel gustatory cue dissipates between the first and second taste access periods (Domjan, 1976, Monk et al , 2014). Finally, the results presented are not likely due to increased locomotor activity in response to ceftriaxone as the antibiotic does not alter locomotor activity (open field test, Knackstedt et al , 2010) and attenuates locomotor sensitization in response to cocaine (Sondheimer and Knackstedt, 2011, Tallarida et al , 2013). …”

“…There are, however, a few studies that demonstrate attenuating effects of ceftriaxone in more acute designs. For example, ceftriaxone attenuates acute locomotor effects of cocaine [Tallarida, et al, 2013] and ceftriaxone begins to attenuate cocaine self-administration in mice by the 3 rd day [Ward et al, 2011, but see Sondheimer et al, 2011]. The design in the current manuscript would probably more closely align with these studies but the possibility exists that the protective effect of ceftriaxone in drug-induced suppression may be due to, or at least includes, an additional mechanism.…”

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

“…Prior work has shown that CTX disrupts pharmacological effects of different classes of drugs of abuse. Some of the effects of CTX are prevention of analgesic tolerance and physical dependence that develops during chronic morphine exposure (Rawls et al, 2007, 2010a, b), inhibition of opioid-induced hyperalgesia (Chen et al, 2012), inhibition of relapse to cocaine seeking (Knackstedt et al, 2010; Sari et al, 2009), inhibition of the direct reinforcing effects of cocaine in mice maintained under a progressive-ratio responding schedule (Ward et al, 2011), inhibition of locomotor sensitization produced by cocaine and amphetamine (Tallarida et al, 2013; Sondheimer and Knackstedt, 2011; Rasmussen et al, 2011), prevention of methamphetamine-induced CPP (Abulseoud et al, 2013), and reduction of alcohol consumption (Sari et al, 2013; Rao and Sari, 2012). Despite structural similarities between CA and CTX, and the more favorable pharmacokinetic and physiochemical properties of CA as related to CNS activity (Nakagawa et al, 1994; Bolton et al, 1986), the potential effectiveness of CA as a therapeutic for CNS diseases is limited to studies that have examined neuroprotection, anxiety, and erectile dysfunction (Kim et al, 2009; Kost et al, 2011, 2012; Sanna et al, 2013).…”

“…Basal activity was recorded for 60 min prior to morphine injection, followed by recording of activity for 60 min. The Digiscan DMicro system (Accuscan, Inc., Columbus, OH) was used to measure locomotor activity as described (Tallarida et al, 2013; Lisek et al, 2012; Rasmussen et al, 2011). Chambers consisted of transparent plastic boxes (45 cm × 20 cm × 20 cm) set inside metal frames equipped with 16 infrared light emitters and detectors.…”

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

“…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). …”