Role of prefrontal cortex projections to the nucleus accumbens core in mediating the effects of ceftriaxone on cued cocaine relapse

Ceftriaxone is an antibiotic that reliably attenuates the reinstatement of cocaine-seeking after extinction while preventing the nucleus accumbens (NA) core glutamate efflux that drives reinstatement. However, when rats undergo abstinence without extinction, ceftriaxone attenuates context-primed relapse but NA core glutamate efflux still increases. Here we sought to determine if the same would occur when relapse is prompted by both context and discrete cues (context+cues) after cocaine abstinence. Male rats self-administered intravenous cocaine for 2 hr/day for 2 weeks. Cocaine delivery was accompanied by drug-associated cues (light+tone). Rats were then placed into abstinence with daily handling but no extinction training for two weeks. Ceftriaxone (200 mg/kg IP) or vehicle was administered during the last 6 days of abstinence. During a context+cue relapse test, microdialysis procedures were conducted. Rats were perfused at the end of the test for later Fos analysis. A separate cohort of rats was infused with the retrograde tracer cholera toxin B in the NA core and underwent the same self-administration and relapse procedures. Ceftriaxone increased baseline glutamate and attenuated both context+cue-primed relapse and NA core glutamate efflux during this test. Ceftriaxone reduced Fos expression in regions sending projections to the NA core (prefrontal cortex, basolateral amygdala, ventral tegmental area) and specifically reduced Fos in prelimbic cortex and not infralimbic cortex neurons projecting to the NA core. Thus, when relapse is primed by drug-associated cues and context, ceftriaxone is able to attenuate relapse by preventing NA core glutamate efflux, likely through reducing activity in prelimbic NA core-projecting neurons.

Statin administration activates system xC− in skeletal muscle: a potential mechanism explaining statin-induced muscle pain

Statins are a cholesterol-lowering drug class that significantly reduce cardiovascular disease risk. Despite their safety and effectiveness, musculoskeletal side-effects, particularly myalgia, are prominent and the most common reason for discontinuance. The cause of statin-induced myalgia is unknown, so defining the underlying mechanism(s) and potential therapeutic strategies is of clinical importance. Here we tested the hypothesis that statin administration activates skeletal muscle system xC−, a cystine/glutamate antiporter, to increase intracellular cysteine and therefore glutathione synthesis to attenuate statin-induced oxidative stress. Increased system xC− activity would increase interstitial glutamate; an amino acid associated with peripheral nociception. Consistent with our hypothesis, atorvastatin treatment significantly increased mitochondrial reactive oxygen species (ROS; 41%) and glutamate efflux (up to 122%) in C2C12 mouse skeletal muscle myotubes. Statin-induced glutamate efflux was confirmed to be the result of system xC− activation, as cotreatment with sulfasalazine (system xC− inhibitor) negated this rise in extracellular glutamate. These findings were reproduced in primary human myotubes but, consistent with being muscle-specific, were not observed in primary human dermal fibroblasts. To further demonstrate that statin-induced increases in ROS triggered glutamate efflux, C2C12 myotubes were cotreated with atorvastatin and various antioxidants. α-Tocopherol and cysteamine bitartrate reversed the increase in statin-induced glutamate efflux, bringing glutamate levels between 50 and 92% of control-treated levels. N-acetylcysteine (a system xC− substrate) increased glutamate efflux above statin treatment alone: up to 732% greater than control treatment. Taken together, we provide a mechanistic foundation for statin-induced myalgia and offer therapeutic insights to alleviate this particular statin-associated side-effect.