RESUMEN
Polysubstance use (PSU), involves the consumption of more than one drug within a period of time and is prevalent among cocaine users. Ceftriaxone, a beta-lactam antibiotic, reliably attenuates reinstatement of cocaine seeking in pre-clinical models by restoring glutamate homeostasis following cocaine self-administration but fails to do so when rats consume both cocaine and alcohol (cocaine + alcohol PSU). We previously found that cocaine + alcohol PSU rats reinstate cocaine seeking similarly to cocaine-only rats, but demonstrate differences in reinstatement-induced c-Fos expression throughout the reward system, including a lack of change upon ceftriaxone treatment. Here, we used this model to determine if previous findings were caused by tolerance or sensitization to the pharmacological effects of cocaine. Male rats underwent intravenous cocaine self-administration immediately followed by 6 h of home cage access to water or unsweetened alcohol for 12 days. Rats subsequently underwent 10 daily instrumental extinction sessions, during which time they were treated with either vehicle or ceftriaxone. Rats then received a non-contingent cocaine injection and were perfused for later immunohistochemical analysis of c-Fos expression in the reward neurocircuitry. c-Fos expression in the prelimbic cortex correlated with total alcohol intake in PSU rats. There were no effects of either ceftriaxone or PSU on c-Fos expression in the infralimbic cortex, nucleus accumbens core and shell, basolateral amygdala, or ventral tegmental area. These results support the idea that PSU and ceftriaxone alter the neurobiology underlying drug-seeking behavior in the absence of pharmacological tolerance or sensitization to cocaine.
RESUMEN
A large body of research supports the notion that regions of the rodent frontal cortex regulate reinstatement of cocaine seeking after cessation of intravenous cocaine self-administration. However, earlier studies identifying the roles of medial (mPFC) and orbital prefrontal cortices (OFC) in reinstatement relied on pharmacological inactivation methods, which indiscriminately inhibited cells within a target region. Here, we first review the anatomical borders and pathways of the rat mPFC and OFC. Next, we compare and contrast findings from more recent cocaine seeking and reinstatement studies that used chemogenetics, optogenetics, or advanced tracing to manipulate specific local cell types or input/output projections of the mPFC and OFC subregions. We found that these studies largely corroborated the roles for mPFC subregions as ascribed by pharmacological inactivation studies. Namely, the prelimbic cortex generally drives cocaine seeking behaviors while the infralimbic cortex is recruited to inhibit cocaine seeking by extinction training but may contribute to seeking after prolonged abstinence. While the OFC remains understudied, we suggest it should not be overlooked, and, as with prelimbic and infralimbic cortices, we identify specific pathways of interest for future studies.