Molecular and circuit mechanisms regulating cocaine memory

Abstract

Risk of relapse is a major challenge in the treatment of substance use disorders. Several types of learning and memory mechanisms are involved in substance use and have implications for relapse. Associative memories form between the effects of drugs and the surrounding environmental stimuli, and exposure to these stimuli during abstinence causes stress and triggers drug craving, which can lead to relapse. Understanding the neural underpinnings of how these associations are formed and maintained will inform future advances in treatment practices. A large body of research has expanded our knowledge of how associative memories are acquired and consolidated, how they are updated through reactivation and reconsolidation, and how competing extinction memories are formed. This review will focus on the vast literature examining the mechanisms of cocaine Pavlovian associative memories with an emphasis on the molecular memory mechanisms and circuits involved in the consolidation, reconsolidation, and extinction of these memories. Additional research elucidating the specific signaling pathways, mechanisms of synaptic plasticity, and epigenetic regulation of gene expression in the circuits involved in associative learning will reveal more distinctions between consolidation, reconsolidation, and extinction learning that can be applied to the treatment of substance use disorders.

Keywords: Addiction; Consolidation; Extinction; Learning; Reconsolidation.

Fig. 1

Schematic illustrating the types of associative memories involved in cocaine-seeking behavior. Interoception involves associations between cocaine and its reinforcing and interoceptive effects, including increased heart rate and blood pressure, increased locomotor activity, and activation of brain regions associated with reward. Pavlovian conditioning results in associations between cocaine and discrete cues and/or the context in which cocaine is received. Goal-directed instrumental learning concerns the association between the instrumental response and cocaine, and habit learning concerns associations between contextual and discrete environmental stimuli and the instrumental response

Fig. 2

Schematic demonstrating the consolidation (blue), reconsolidation (green), and extinction (red) of cocaine Pavlovian memories. The temporally paired delivery of cocaine with discrete and contextual cues results in the consolidation of the associative memory between cocaine and these cues. Once consolidated, this memory is stable. Long or repeated exposure to these cues results in extinction learning, which involves learning about the lack of association between cocaine and these cues and reduced cue-induced cocaine seeking. Alternatively, brief exposure to these cues results in reactivation of the previously consolidated associative memory, which is de-stabilized, allowing for potential updating of the memory. Under normal conditions, memory reactivation is followed by reconsolidation, and the memory is re-stabilized, resulting in maintenance of the associative memory and cue-induced cocaine seeking. If reconsolidation is disrupted, the association between the cues and cocaine is weakened, resulting in reduced cue-induced cocaine seeking