Role of projections from ventral subiculum to nucleus accumbens shell in context-induced reinstatement of heroin seeking in rats

Abstract

Rationale and objective In humans, exposure to contexts previously associated with heroin use can provoke relapse. In rats, exposure to heroin-paired contexts after extinction of drug-reinforced responding in different contexts reinstates heroin seeking. We previously demonstrated that the projections from ventral medial prefrontal cortex (vmPFC) to nucleus accumbens (NAc) shell play a role in this reinstatement. The ventral subiculum (vSub) sends glutamate projections to NAc shell and vmPFC. Here, we determined whether these projections contribute to context-induced reinstatement. Methods We trained rats to self-administer heroin (0.05–0.1 mg/kg/infusion) for 3 h per day for 12 days; drug infusions were paired with a discrete tone-light cue. Lever pressing in the presence of the discrete cue was subsequently extinguished in a different context. We then tested the rats for reinstatement in the heroin- and extinction-associated contexts under extinction conditions. We combined Fos with the retrograde tracer Fluoro-Gold (FG) to determine projection-specific activation during the context-induced reinstatement tests. We also used anatomical disconnection procedures to determine whether the vSub→NAc shell and vSub→vmPFC projections are functionally involved in this reinstatement. Results Exposure to the heroin but not the extinction context reinstated lever pressing. Context-induced reinstatement of heroin seeking was associated with increased Fos expression in vSub neurons, including those projecting to NAc shell and vmPFC. However, anatomical disconnection of the vSub→NAc shell projection, but not the vSub→vmPFC projection, decreased this reinstatement. Conclusions Our data indicate that the vSub→NAc shell glutamatergic projection, but not the vSub→vmPFC projection, contributes to context-induced reinstatement of heroin seeking.

How contexts promote and prevent relapse to drug seeking

“…As noted above, vSUB inputs to AcbSh are important for context‐induced reinstatement. The vSUB neurons projecting to the AcbSh are recruited during context‐induced reinstatement of heroin seeking (Bossert et al ) and alcohol seeking (Marchant et al ). Pharmacological disconnection of the vSUB→AcbSh pathway prevents this reinstatement of heroin seeking (Bossert et al ) and chemogenetic disconnection of this pathway prevents this reinstatement after punishment‐imposed abstinence from alcohol seeking (Marchant et al ).…”

“…The vSUB neurons projecting to the AcbSh are recruited during context‐induced reinstatement of heroin seeking (Bossert et al ) and alcohol seeking (Marchant et al ). Pharmacological disconnection of the vSUB→AcbSh pathway prevents this reinstatement of heroin seeking (Bossert et al ) and chemogenetic disconnection of this pathway prevents this reinstatement after punishment‐imposed abstinence from alcohol seeking (Marchant et al ). One attractive possibility is that glutamate derived from these vSUB inputs acts in combination with dopamine inputs from VTA to enable context‐induced reinstatement (Crombag et al ; Marchant et al ).…”

Role of mu, but not delta or kappa, opioid receptors in context‐induced reinstatement of oxycodone seeking

“…Our previous research has focused on the neuropharmacology of context-induced heroin seeking (Bossert et al, 2007(Bossert et al, , 2009(Bossert et al, , 2011(Bossert et al, , 2012(Bossert et al, , 2016. However, in light of the current prescription opioid epidemic, we recently changed our focus to studying relapse to oxycodone, a prototypical prescription opioid drug that is widely used for pain management (Van Zee, 2009;Yaksh & Wallace, 2011).…”

The nucleus accumbens shell in reinstatement and extinction of drug seeking

“…vSUB inputs to AcbSh are important for context‐induced reinstatement. vSUB neurons projecting to the AcbSh express the c‐Fos protein during context‐induced reinstatement of heroin (Bossert et al ., ) and alcohol seeking (Marchant et al ., ). Pharmacological disconnection of vSUB → AcbSh pathway prevents context‐induced reinstatement of heroin seeking (Bossert et al ., ) and chemogenetic disconnection of this pathway prevents this reinstatement after punishment‐imposed abstinence from alcohol seeking (Marchant et al ., ).…”

“…vSUB inputs to AcbSh are important for context-induced reinstatement. vSUB neurons projecting to the AcbSh express the c-Fos protein during context-induced reinstatement of heroin (Bossert et al, 2016) and alcohol seeking . Pharmacological disconnection of vSUB ?…”