ABSTRACT
RSK2 is a Ser/Thr kinase acting in the Ras/MAPK pathway. Rsk2 gene deficiency leads to the Coffin-Lowry Syndrome, notably characterized by cognitive deficits. We found that mrsk2 knockout mice are unable to associate an aversive stimulus with context in a lithium-induced conditioned place aversion task requiring both high-order cognition and emotional processing. Virally mediated shRNA-RSK2 knockdown in the habenula, whose involvement in cognition is receiving increasing attention, also ablated contextual conditioning. RSK2 signaling in the habenula, therefore, is essential for this task. Our study reveals a novel role for RSK2 in cognitive processes and uncovers the critical implication of an intriguing brain structure in place aversion learning.
Subject(s)
Avoidance Learning/physiology , Habenula/metabolism , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Signal Transduction/physiology , Analysis of Variance , Animals , Antimanic Agents/pharmacology , Avoidance Learning/radiation effects , COS Cells , Chlorocebus aethiops , Conditioning, Operant/drug effects , Habenula/drug effects , Lithium Chloride/pharmacology , Luminescent Proteins/genetics , Mice , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Ribosomal Protein S6 Kinases, 90-kDa/deficiency , Signal Transduction/drug effects , Signal Transduction/genetics , Transfection/methodsABSTRACT
BACKGROUND: Converging experimental data indicate that δ opioid receptors contribute to mediate drug reinforcement processes. Whether their contribution reflects a role in the modulation of drug reward or an implication in conditioned learning, however, has not been explored. In the present study, we investigated the impact of δ receptor gene knockout on reinforced conditioned learning under several experimental paradigms. METHODS: We assessed the ability of δ receptor knockout mice to form drug-context associations with either morphine (appetitive)- or lithium (aversive)-induced Pavlovian place conditioning. We also examined the efficiency of morphine to serve as a positive reinforcer in these mice and their motivation to gain drug injections, with operant intravenous self-administration under fixed and progressive ratio schedules and at two different doses. RESULTS: Mutant mice showed impaired place conditioning in both appetitive and aversive conditions, indicating disrupted context-drug association. In contrast, mutant animals displayed intact acquisition of morphine self-administration and reached breaking-points comparable to control subjects. Thus, reinforcing effects of morphine and motivation to obtain the drug were maintained. CONCLUSION: Collectively, the data suggest that δ receptor activity is not involved in morphine reinforcement but facilitates place conditioning. This study reveals a novel aspect of δ opioid receptor function in addiction-related behaviors.
