The Winding Road to Relapse: Forging a New Understanding of Cue-Induced Reinstatement Models and Their Associated Neural Mechanisms

Abstract

In drug addiction, cues previously associated with drug use can produce craving and frequently trigger the resumption of drug taking in individuals vulnerable to relapse. Environmental stimuli associated with drugs or natural reinforcers can become reliably conditioned to increase behavior that was previously reinforced. In preclinical models of addiction, these cues enhance both drug self-administration and reinstatement of drug seeking. In this review, we will dissociate the roles of conditioned stimuli as reinforcers from their modulatory or discriminative functions in producing drug-seeking behavior. As well, we will examine possible differences in neurobiological encoding underlying these functional differences. Specifically, we will discuss how models of drug addiction and relapse should more systematically evaluate these different types of stimuli to better understand the neurobiology underlying craving and relapse. In this way, behavioral and pharmacotherapeutic interventions may be better tailored to promote drug use cessation outcomes and long-term abstinence.

Keywords: addiction; conditioned stimulus; discriminative stimulus; neurobiology; reinstatement; relapse.

Figure 1

Dopamine-glutamate circuitry underlying CS-induced reinstatement of drug seeking. VTA dopamine (DA) input into the NAcore mediates CS-induced reinstatement. DA input into the PFC may also modulate rapid, transient glutamatergic plasticity in the NAcore in response to drug-associated CSs and mediates drug seeking behavior. DA input into the BLA may alter excitatory inputs into the NAcore and reciprocal BLA-PFC signaling. As well, DA input into the vHPC has been implicated in CS-induced reinstatement of drug seeking, and glutamatergic projections from the vHPC to the VTA may be an indirect pathway through which the HPC modulates dopaminergic input into other brain regions.

Figure 2

Dopamine-glutamate circuitry underlying S^D-induced reinstatement of drug seeking. VTA dopamine (DA) input into the NAcore and NAshell mediates S^D-induced reinstatement. DA input into the BLA and PFC have also been implicated in S^D-induced reinstatement of drug seeking. Projections from the PFC to the NAshell have been implicated in S^D-induced reinstatement; however, it is not known if PFC projections to the NAcore play a specific role in S^D-induced reinstatement. Likewise, it is unclear if projections from the BLA directly to the NA play a role in S^D-induced reinstatement akin to CS-induced reinstatement. The dHPC receives converging input from the BLA and VTA and has been implicated in S^D-induced reinstatement. Similar to CS-induced reinstatement, the vHPC communicates bidirectionally with the VTA and may modulate dopaminergic input into the NA, PFC, and BLA. As well, glutamatergic projections from the PVT to the NAshell have also been shown to be involved in S^D-induced drug seeking. Dotted lines indicate unknown effects of specific projecting pathways.