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

Abstract

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.

MC-100093, a Novel β-Lactam Glutamate Transporter-1 Enhancer Devoid of Antimicrobial Properties, Attenuates Cocaine Relapse in Rats

“…Following cocaine self-administration, sub-chronic (5-7 days) ceftriaxone rescues GLT-1 expression in the NA core and attenuates the reinstatement of cocaine seeking that is primed by cues and cocaine (Sari et al, 2009;Knackstedt et al, 2010;Fischer et al, 2013;LaCrosse et al, 2017;Bechard et al, 2018Bechard et al, , 2020. These effects persist weeks after the cessation of ceftriaxone administration, indicating that short-term administration of ceftriaxone restores glutamate homeostasis in the long term (Sondheimer and Knackstedt, 2011).…”

CB1R activation in nucleus accumbens core promotes stress-induced reinstatement of cocaine seeking by elevating extracellular glutamate in a drug-paired context

“…Consistent with a large body of research on therapeutic strategies for cocaine addiction 5 , different pharmacological treatments that target the glutamatergic system were able to prevent stress-induced reinstatement 6 – 9 . Specifically, a glutamatergic projection from the medial prefrontal cortex (mPFC) to the core subregion of the nucleus accumbens (NA) was reported to be critical for stress-induced reinstatement of cocaine seeking 10 , as is the case for cue- and drug-triggered reinstatement 11 , 12 . Stress causes changes in glutamate neurotransmission 13 , and it has been hypothesized that the recruitment of stress-responsive mechanisms contribute greatly to the persistence of drug addiction 14 .…”

Extinction vs. Abstinence: A Review of the Molecular and Circuit Consequences of Different Post-Cocaine Experiences

“…Here, we summarize a large body of work aimed at understanding such changes in a brain region that underlies cocaine relapse after extinction and abstinence: the NA core. The examination of glutamate receptors, transporters, and proteins regulating their trafficking was chosen because of the established role of glutamate release in the NA core in driving cue-primed reinstatement after extinction [ 45 ] and both cue- and context-primed relapse following abstinence [ 46 , 47 ]. Within the NA core, antagonism of post-synaptic glutamate receptors attenuates cue-primed reinstatement of cocaine seeking (e.g., [ 24 , 26 , 48 ]).…”

“…Two drugs that target glutamate homeostasis, the antibiotic ceftriaxone and N-acetylcysteine, have been tested in both extinction and abstinence models. Ceftriaxone attenuates cue-primed reinstatement after extinction and abstinence and context-primed relapse after abstinence [ 46 , 47 , 70 ]. Ceftriaxone prevents the glutamate efflux that drives relapse when it is administered for 5–7 days during extinction training preceding a cue + cocaine or cocaine-primed reinstatement test and when administered during the 6 days of abstinence preceding a cue + context primed relapse test [ 5 , 47 , 80 ].…”

“…Ceftriaxone attenuates cue-primed reinstatement after extinction and abstinence and context-primed relapse after abstinence [ 46 , 47 , 70 ]. Ceftriaxone prevents the glutamate efflux that drives relapse when it is administered for 5–7 days during extinction training preceding a cue + cocaine or cocaine-primed reinstatement test and when administered during the 6 days of abstinence preceding a cue + context primed relapse test [ 5 , 47 , 80 ]. However, the ability of ceftriaxone to attenuate such glutamate efflux is not as robust during a context primed relapse test after abstinence, indicating that ceftriaxone interacts with the circuitry mediating context-primed relapse to a lesser degree than with circuitry mediating cocaine- and cue-primed relapse [ 46 ].…”