Glutamate Release in the Nucleus Accumbens Core Is Necessary for Heroin Seeking

TLDR

Long‑term alterations in glutamate signaling within the nucleus accumbens core are known to drive drug‑seeking relapse after cocaine extinction, but it was unclear whether heroin or cue‑induced reinstatement elicits comparable glutamatergic adaptations. The study used a 2‑week heroin self‑administration and extinction protocol, then induced reinstatement with noncontingent heroin or paired cues while measuring extracellular glutamate in the NAcore via microdialysis in both self‑administering and yoked control animals. Heroin or cue‑induced reinstatement raised NAcore glutamate only in self‑administering rats, and this rise—and the associated drug seeking—was abolished by blocking synaptic transmission, prelimbic‑to‑NAcore glutamatergic inputs, or AMPA/kainate receptors, indicating that prelimbic‑derived glutamate release is essential for heroin‑seeking relapse.

Abstract

Long-term changes in glutamate transmission in the nucleus accumbens core (NAcore) contribute to the reinstatement of drug seeking after extinction of cocaine self-administration. Whether similar adaptations in glutamate transmission occur during heroin and cue-induced reinstatement of heroin seeking is unknown. After 2 weeks of heroin self-administration and 2 weeks of subsequent extinction training, heroin seeking was induced by a noncontingent injection of heroin or by presentation of light/tone cues previously paired with heroin infusions. Microdialysis was conducted in the NAcore during reinstatement of heroin seeking in animals extinguished from heroin self-administration or in subjects receiving parallel (yoked) noncontingent saline or heroin. Reinstatement by either heroin or cue increased extracellular glutamate in the NAcore in the self-administration group, but no increase was elicited during heroin-induced reinstatement in the yoked control groups. The increase in glutamate during heroin-induced drug seeking was abolished by inhibiting synaptic transmission in the NAcore with tetrodotoxin or by inhibiting glutamatergic afferents to the NAcore from the prelimbic cortex. Supporting critical involvement of glutamate release, heroin seeking induced by cue or heroin was blocked by inhibiting AMPA/kainate glutamate receptors in the NAcore. Interestingly, although a heroin-priming injection increased dopamine equally in animals trained to self-administer heroin and in yoked-saline subjects, inhibition of dopamine receptors in the NAcore also blocked heroin- and cue-induced drug seeking. Together, these findings show that recruitment of the glutamatergic projection from the prelimbic cortex to NAcore is necessary to initiate the reinstatement of heroin seeking.