Differential Effects of Blockade of Dopamine D₁-Family Receptors in Nucleus Accumbens Core or Shell on Reinstatement of Heroin Seeking Induced by Contextual and Discrete Cues

Abstract

In humans, exposure to environmental contexts previously associated with heroin intake can provoke drug relapse, but the neuronal mechanisms mediating this relapse are unknown. Using a drug relapse model, we found previously that reexposing rats to heroinassociated contexts, after extinction of drug-reinforced responding in different contexts, reinstates heroin seeking. This effect is attenuated by inhibition of glutamate transmission in the ventral tegmental area and medial accumbens shell, components of the mesolimbic dopamine system. Here, we explored the role of dopamine of the accumbens in context-induced reinstatement by using the D 1 -family receptor antagonist SCH 23390 [R(ϩ)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride]. Rats were trained to self-administer heroin for 12 d; drug infusions were paired with a discrete tone-light cue. Subsequently, the heroin-reinforced lever pressing was extinguished in the presence of the discrete cue in a context that differed from the drug selfadministration context in terms of visual, auditory, tactile, and circadian cues. When tested in the original drug self-administration context, systemic and medial or lateral accumbens shell SCH 23390 injections attenuated context-induced reinstatement of heroin seeking, whereas accumbens core SCH 23390 injections were ineffective. In contrast, core but not lateral or medial shell SCH 23390 injections attenuated discrete-cue-induced reinstatement in a nondrug context after extinction of lever presses without this cue. Results indicate that activation of medial and lateral accumbens shell D 1 -family dopamine receptors mediate context-induced reinstatement of heroin seeking and provide the first demonstration for a role of lateral shell dopamine in conditioned drug effects. Results also demonstrate novel dissociable roles of accumbens core and shell in context-versus discrete-cue-induced reinstatement of heroin seeking.

Context-induced relapse to drug seeking: a review

“…We found that medial and lateral accumbens shell (but not core) SCH 23390 injections attenuate contextinduced reinstatement of heroin seeking (Bossert et al 2007). These findings are consistent with those of Hamlin et al (2007): context-induced reinstatement of alcohol seeking is associated with increased Fos (a neuronal activity marker) expression in accumbens shell, an effect reversed by systemic SCH 23390 injections.…”

Lateral Hypothalamus Is Required for Context-Induced Reinstatement of Extinguished Reward Seeking

“…AcbSh infusion of D 1 dopamine receptor antagonists attenuates renewal of heroin seeking (Bossert et al, 2007), whereas B/M infusions attenuate renewal of cocaine seeking (Fuchs et al, 2008). AcbSh neurons respond to stimuli associated with drug-availability (Ghitza et al, 2003), and increased c-Fos in the AcbShV is associated with renewal (Hamlin et al, 2007).…”

“…Petrovich et al (2005) showed upregulated immediate early genes in LH-projecting neurons in orbitomedial PFC, BLA, and basomedial amygdala after presentation of a stimulus paired with food. A large number of forebrain afferents to LH have been implicated in renewal of drug seeking, including BLA, dmPFC (Fuchs et al, 2005), and AcbSh (Bossert et al, 2007;Fuchs et al, 2008). Different afferents may converge on LH as a final common pathway for reinstating extinguished reward seeking.…”

“…It shows that extinction training does not erase the original learning that mediates drug seeking but instead imposes a mask on that learning to actively inhibit drug seeking in the extinction context. Studies using microinjections of dopamine and glutamate receptor antagonists, as well as reversible inactivation via baclofen/ muscimol or tetrodotoxin infusion, have implicated hippocampus, basolateral amygdala (BLA), nucleus accumbens shell (AcbSh), nucleus accumbens core (AcbC), ventral tegmental area (VTA), and dorsomedial prefrontal cortex (dmPFC) in contextinduced reinstatement of drug seeking (Bossert et al, 2004(Bossert et al, , 2006(Bossert et al, , 2007Fuchs et al, 2005Fuchs et al, , 2007Fuchs et al, , 2008. Recently, we have used c-Fos expression to identify the neural correlates of context-induced reinstatement.…”

Cannabinoid Receptor Activation Shifts Temporally Engendered Patterns of Dopamine Release

“…Once electrically evoked dopamine release was detected in the nucleus accumbens core, a layer of dental cement was applied to secure the electrodes in place and allowed to dry. We focused on the core region of the NAc because of previous evidence suggesting that the core is critically involved in modulating cue-driven behavioral responses, whereas the shell is more involved in modulating context-driven behavioral responses (Bossert et al, 2007;Chaudhri et al, 2009;Ito and Hayen, 2011).…”