Morphine Reward Promotes Cue-Sensitive Learning: Implication of Dorsal Striatal CREB Activity

Abstract

Different parallel neural circuits interact and may even compete to process and store information: whereas stimulus–response (S–R) learning critically depends on the dorsal striatum (DS), spatial memory relies on the hippocampus (HPC). Strikingly, despite its potential importance for our understanding of addictive behaviors, the impact of drug rewards on memory systems dynamics has not been extensively studied. Here, we assessed long-term effects of drug- vs food reinforcement on the subsequent use of S–R vs spatial learning strategies and their neural substrates. Mice were trained in a Y-maze cue-guided task, during which either food or morphine injections into the ventral tegmental area (VTA) were used as rewards. Although drug- and food-reinforced mice learned the Y-maze task equally well, drug-reinforced mice exhibited a preferential use of an S–R learning strategy when tested in a water-maze competition task designed to dissociate cue-based and spatial learning. This cognitive bias was associated with a persistent increase in the phosphorylated form of cAMP response element-binding protein phosphorylation (pCREB) within the DS, and a decrease of pCREB expression in the HPC. Pharmacological inhibition of striatal PKA pathway in drug-rewarded mice limited the morphine-induced increase in levels of pCREB in DS and restored a balanced use of spatial vs cue-based learning. Our findings suggest that drug (opiate) reward biases the engagement of separate memory systems toward a predominant use of the cue-dependent system via an increase in learning-related striatal pCREB activity. Persistent functional imbalance between striatal and hippocampal activity could contribute to the persistence of addictive behaviors, or counteract the efficiency of pharmacological or psychotherapeutic treatments.

Genesis of the Heroin-Induced Addictive Process: Articulation Between Psychodynamic and Neurobiological Theories

“…Moreover, chronic use of addictive drugs elicits a persistent striatal hyperactivity, associated with an impairment in hippocampus-dependent forms of memory, which may lead to cognitive rigidity and a higher risk of relapse. Therefore, this mechanism could promote conditioning to the detriment of more flexible forms of memory (68)(69)(70). Finally, emotional and stressful events are potent modulators of striatum-hippocampus interactions: they promote habitual over cognitive forms of learning, through mineralocorticoids and adrenaline interaction (71).…”

Correlations Between Mutant Huntingtin Aggregates and Behavioral Changes in R6/1 Mice

“…The room was illuminated excessively (270 lux) and a wind blowing from a fan was used to provide a further aversive environment to the rodent. The task was an adaptation of previously published procedures using competition between hippocampusdependent spatial learning and striatum-dependent cued learning in the water maze (12)(13)(14) or in the Barnes maze (15). For acquisition, one arbitrary chosen hole gave access to a shelter, whose location could be determined using the layout of extra-maze cues in the room (spatial strategy).…”

Chronic alcohol consumption shifts learning strategies and synaptic plasticity from hippocampus to striatum-dependent pathways

“…For instance, spatial learning with reference to an array of distal cues can be subject to competition with striatal-dependent response learning, and dorsolateral striatal lesions facilitate spatial learning (17). It was proposed that a persistent cognitive imbalance could maintain addictive behaviors and increase the risk of relapse by disrupting spatial/declarative memory while facilitating cue-dependent learning (18)(19)(20)(21)(22). These qualitative changes in memory formation are also induced by stress, which promotes a shift from spatial/declarative memory to cued/procedural memory systems in both rodents and humans (15, [23][24][25][26].…”