Disrupting Effect of Drug-Induced Reward on Spatial But Not Cue-Guided Learning: Implication of the Striatal Protein Kinase A/cAMP Response Element-Binding Protein Pathway

Abstract

The multiple memory systems hypothesis posits that different neural circuits function in parallel and may compete for information processing and storage. For example, instrumental conditioning would depend on the striatum, whereas spatial memory may be mediated by a circuit centered on the hippocampus. However, the nature of the task itself is not sufficient to select durably one system over the other. In this study, we investigated the effects of natural and pharmacological rewards on the selection of a particular memory system during learning. We compared the effects of food-or drug-induced activation of the reward system on cue-guided versus spatial learning using a Y-maze discrimination task. Drug-induced reward severely impaired the acquisition of a spatial discrimination task but spared the cued version of the task. Immunohistochemical analysis of the phosphorylated form of the cAMP response element binding (CREB) protein and c-Fos expression induced by behavioral testing revealed that the spatial deficit was associated with a decrease of both markers within the hippocampus and the prefrontal cortex. In contrast, drug reward potentiated the cued learning-induced CREB phosphorylation within the dorsal striatum. Administration of the protein kinase A inhibitor 8-Bromo-adenosine-3',5'-cyclic monophosphorothioate Rp isomer (Rp-cAMPS) into the dorsal striatum before training completely reversed the drug-induced spatial deficit and restored CREB phosphorylation levels within the hippocampus and the prefrontal cortex. Therefore, drug-induced striatal hyperactivity may underlie the declarative memory deficit reported here. This mechanism could represent an important early step toward the development of addictive behaviors by promoting conditioning to the detriment of more flexible forms of memory.

Inhibition of the cAMP/PKA/CREB Pathway Contributes to the Analgesic Effects of Electroacupuncture in the Anterior Cingulate Cortex in a Rat Pain Memory Model

“…Reports from earlier studies have demonstrated that cAMP mediates almost all of its actions through PKA [13, 40]. When cAMP increases in cells, the cAMP-binding regulatory subunit of PKA is freed from the catalytic subunit of PKA and is allowed to phosphorylate its substrates [43]. A similar experiment performed in 1980 injected a catalytic subunit of PKA directly into the sensory neurons and found that PKA also sufficiently enhances transmitter release for synaptic plasticity in long-term memory [13, 44].…”

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

“…On the basis of previous behavioral and CREB expression studies in C57BL/6 mice (35, 54), Rp-8Br-cAMPS was dissolved in aCSF to be delivered at the concentration of 0.4 nmol/0.5 μl per hemisphere. Bilateral infusions were performed before the last Y-maze session to avoid disruption of encoding during the water-maze task that was run 72 h after.…”

Heads for learning, tails for memory: reward, reinforcement and a role of dopamine in determining behavioral relevance across multiple timescales

“…Recently, Baudonnat et al (2011) also investigated how different types of reward influence the selection and acquisition of learning strategies. Initially, they showed that mice were able to learn whether to use spatial location or intramaze visual cues to guide decision-making in a Y-maze when correct choices were reinforced with natural (food) reward (Figures 2A,B).…”

“…However, drugs of abuse can also pharmacologically hijack the dopamine system and result in maladaptive patterns of behavior. To determine how an excess of dopamine might affect learning strategies, Baudonnat and colleagues carried out the same Y-maze experiment except that instead of receiving food reward for correct responses, the mice received intra-VTA injections of morphine, which has been shown to disinhibit dopamine neurons and induce dopamine release in target structures (Matthews and German, 1984; Johnson and North, 1992; Nugent et al, 2007; Baudonnat et al, 2011). While the animals learned the cued version of the task at a comparable rate with either natural or pharmacological reward, mice reinforced with morphine were unable to acquire the spatial strategy (Figure 2B).…”