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

Psychopharmacology (Berl). 2016 May;233(10):1991-2004. doi: 10.1007/s00213-015-4060-5. Epub 2015 Sep 7.


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. 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.

Keywords: Baclofen; Conditioned cues; Dopamine; Drug environment; Extinction; Fluoro-Gold; Fos; GABA; Glutamate; Heroin self-administration; Hippocampus; Muscimol; Opiates; Relapse; SCH 23390.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cues
  • Extinction, Psychological / drug effects
  • Glutamic Acid / metabolism
  • Heroin / administration & dosage*
  • Heroin Dependence / etiology
  • Heroin Dependence / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Male
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Reinforcement, Psychology
  • Self Administration


  • Glutamic Acid
  • Heroin