Evidence from rodent studies suggests that drug-induced reinstatement is mediated by the circuit that links the prelimbic prefrontal cortex to the ventral striatum94 (for correspondence with humans, see figure 2; tables 1, 2, circuits 12 and possibly 13). In rats, neurotransmitter systems that are involved in drug-induced reinstatement involve a glutamatergic projection from the prelimbic prefrontal cortex to the nucleus accumbens that is modulated by dopamine activity through D1 and D2 receptors in the frontal cortex. Cue-induced reinstatement also involves a glutamatergic projection from the prelimbic prefrontal cortex, basolateral amygdala, and ventral subiculum to the nucleus accumbens, and dopamine modulation in the basolateral amygdala and dorsal striatum (tables 1, 2, circuits 14 and 15).51,52,95 By contrast, the stress-induced reinstatement of drug-related responding in animal models appears to depend on the activation of both CRF and norepinephrine in elements of the extended amygdala (ie, central nucleus of the amygdala and bed nucleus of the stria terminalis; tables 1, 2, circuits 16 and 17)22,33,53,96–98 and the ventral tegmental area (tables 1, 2, circuit 9). Protracted abstinence, largely described in alcohol dependence models,
