Hierarchical cue control of drug seeking in the face of cost

Addiction is characterized by intermittent drug seeking despite rising costs. This behavior is heavily influenced by environmental stimuli that signal drug availability and reinforce seeking. We aimed to establish the relationship between three key aspects of human drug use in rats: the intermittent, binge nature of drug intake, the motivational conflict of drug seeking in the face of escalating negative costs, and the ability of different drug cues to interact to modulate relapse. Rats were trained to self administer cocaine on an intermittent access schedule, where brief drug availability states were signaled by a shift in the ambient lighting of the environment and cocaine delivery was signaled by a separate proximal cue. Rats then went through a conflict procedure, where foot shock intensity associated with cocaine seeking was escalated until intake was suppressed. We completed relapse tests where the drug delivery cue was non contingently presented alone, or in the context of dynamic drug availability state transitions. Intermittent access spurred psychomotor sensitization and binge-like cocaine intake. The intensity of binge-like drug taking during training was predictive of later drug seeking despite escalating costs. In relapse tests, the ability of a proximal drug cue to trigger relapse was gated by the presence of a global cue signaling drug-availability state transitions. Our results suggest that the pattern of drug intake plays a role in many features of addiction, including modifying an individual’s willingness to endure high costs associated with drug seeking. Further, our results indicate that drug-related sensory information can be hierarchically organized to exert a dynamic modulating influence on drug-seeking motivation. ### Competing Interest Statement The authors have declared no competing interest.