Associative processes in addiction relapse models: A review of their Pavlovian and instrumental mechanisms, history, and terminology

Animal models of relapse to drug-seeking have borrowed heavily from associative learning approaches. In studies of relapse-like behaviour, animals learn to self-administer drugs then receive a period of extinction during which they learn to inhibit the operant response. Several triggers can produce a recovery of responding which form the basis of a variety of models. These include the passage of time (spontaneous recovery), drug availability (rapid reacquisition), extinction of an alternative response (resurgence), context change (renewal), drug priming, stress, and cues (reinstatement). In most cases, the behavioural processes driving extinction and recovery in operant drug self-administration studies are similar to those in the Pavlovian and behavioural literature, such as context effects. However, reinstatement in addiction studies have several differences with Pavlovian reinstatement, which have emerged over several decades, in experimental procedures, associative mechanisms, and terminology. Interestingly, in cue-induced reinstatement, drug-paired cues that are present during acquisition are omitted during lever extinction. The unextinguished drug-paired cue may limit the model’s translational relevance to cue exposure therapy and renders its underlying associative mechanisms ambiguous. We review major behavioural theories that explain recovery phenomena, with a particular focus on cue-induced reinstatement because it is a widely used model in addiction. We argue that cue-induced reinstatement may be explained by a combination of behavioural processes, including reacquisition of conditioned reinforcement and Pavlovian to Instrumental Transfer. While there are important differences between addiction studies and the behavioural literature in terminology and procedures, it is clear that understanding associative learning processes is essential for studying relapse

The role of the basolateral amygdala in consolidation of first- and second-order conditioned fears

Learning about cues that signal innate sources of danger (i.e., first-order conditioned fear) requires an array of intracellular signalling processes within the basolateral complex of the amygdala (BLA). These processes include activation of protein kinase pathways, transcription of specific genes, and, importantly, the synthesis of proteins that stabilize the fear memory through structural changes in BLA neurons. It is unknown whether these processes also mediate learning about cues that signal learned sources of danger (i.e., second-order conditioned fear). The present thesis addressed this gap in our knowledge. It reports experiments that examined whether consolidation of the second-order fear memory involves the molecular processes in the BLA known to underlie consolidation of the first-order fear memory. The protocol used to produce second-order conditioned fear consisted of three stages. In stage 1, rats received pairings of a neutral stimulus, S1, and an aversive foot-shock in order to establish first-order conditioned fear of S1. In stage 2, they received pairings of a second neutral stimulus, S2, and the fear-eliciting S1 in order to establish second-order conditioned fear of S2. Immediately after these pairings, rats received an intra-BLA infusion of drug or vehicle. Finally, in stage 3, rats were tested for fear (freezing) to S2 (and to S1). The results of these experiments show that consolidation of first- and second-order conditioned fear overlap in some respects but differ in others. Specifically, both types of conditioned fears required neuronal activity in the BLA, activation of the CaMKII/CaMKIV signalling pathways, methylation of DNA, and gene transcription. Importantly, consolidation of first- but not second-order conditioned fear required activation of ERK/MAPK and PKA/PKC signalling pathways and de novo protein synthesis. These findings confirm that activation of various signalling pathways and nuclear processes within the BLA are required for consolidation of the first-order fear memory. They also show for the first time that the signalling cascades and nuclear processes required for consolidation of first- and second-order fears are different. These differences are discussed in terms of the distinct properties associated with the individual molecular processes