Brain circuitry and the reinstatement of cocaine-seeking behavior

Rationale. Recent studies have attempted to identify the neuroanatomical substrates underlying primed reinstatement of drug-seeking behavior. Identification of neuronal substrates will provide a logical rationale for designing pharmacological interventions in treating drug relapse. Objective. The objective was to identify brain circuitry that is shared between cue-, drug- and stress-primed reinstatement, as well as identifying aspects of brain circuitry that are distinct for each stimulus modality. The resulting circuit offers theoretical interpretations for consideration in future studies. Results. Aspects of the circuitry mediating reinstatement can be identified with reasonable confidence. The role of the basolateral amygdala in cue-primed reinstatement, the role of the ventral tegmental area in drug-primed reinstatement and the role of adrenergic innervation of the extended amygdala in stress-primed reinstatement are well characterized. Also, all three modes for priming reinstatement may converge on the anterior cingulate cortex and have a final common output through the core of the nucleus accumbens. Lacunae in our understanding of the circuit were identified, especially with regard to how stress priming is conveyed from the extended amygdala to the shared anterior cingulate accumbens core circuit. Conclusions. The proposed convergence of priming stimuli into the glutamatergic projection from anterior cingulate to the accumbens core combined with the changes in glutamate transmission and signaling that accompany repeated psychostimulant administration points to the potential value of pharmacological agents that manipulate glutamate release or postsynaptic glutamate receptor signaling and trafficking in treating primed relapse in addicts.