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Role of prefrontal cortex projections to the nucleus accumbens core in mediating the effects of ceftriaxone on cue‐induced cocaine seeking

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 cocaine seeking but NA core glutamate efflux still increases. Here, we sought to determine if the same would occur when cocaine seeking is prompted by both context and discrete cues (cue‐induced seeking) after cocaine abstinence. Male rats self‐administered intravenous cocaine accompanied by drug‐associated cues (light + tone) for 2 h/day for 14 days. Rats then experienced abstinence with daily handling but no extinction training for 2 weeks. Ceftriaxone (200 mg/kg IP) or vehicle was administered during the last 6 days of abstinence. During a cue‐induced cocaine seeking 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 cue‐induced cocaine seeking 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 cocaine seeking is induced by drug‐associated cues, ceftriaxone is able to attenuate relapse by preventing NA core glutamate efflux, likely through reducing activity in prelimbic NA core‐projecting neurons.