Cocaine reward and memory after chemogenetic inhibition of distinct serotonin neuron subtypes in mice
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ORIGINAL INVESTIGATION
Cocaine reward and memory after chemogenetic inhibition of distinct serotonin neuron subtypes in mice Britahny M. Baskin 1 & Jia Jia Mai 2 & Susan M. Dymecki 2 & Kathleen M. Kantak 1 Received: 14 January 2020 / Accepted: 18 May 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Rationale We probed serotonin neurons, those denoted by their developmental gene expression as r2Hoxa2-Pet1 (experiment 1) and Drd1a-Pet1 (experiment 2), for differential modulation of cocaine reward and memory as revealed by the expression and development of conditioned place preference (CPP) in transgenic mice. Objectives To query roles in CPP, we inhibited neurons cell autonomously in vivo by activating the transgenically expressed, synthetic DREADD receptor hM4Di (Di) with the exogenous ligand clozapine-N-oxide (CNO). Methods To examine CPP expression, mice were conditioned using behaviorally active doses of cocaine (10.0 or 17.8 mg/kg) vs. saline followed by CPP assessment, first without neuron inhibition (post-conditioning session 1), and then with CNO-mediated neuron inhibition (post-conditioning session 2), followed by 4 more post-conditioning sessions. To examine CPP development, we administered CNO during conditioning sessions and then assayed CPP across 6 postconditioning sessions. Results In r2Hoxa2-Pet1-Di mice, post-conditioning CNO administration did not impact cocaine CPP expression, but after CNO administration during conditioning, cocaine CPP (17.8 mg/kg) persisted across post-conditioning sessions compared with that in controls, suggesting a deficit in extinguishing cocaine memory. Drd1a-Pet1-Di mice, prior to CNO-Di-triggered neuronal inhibition, unexpectedly expressed heightened cocaine CPP (10.0 and 17.8 mg/kg) compared with controls, and this basal phenotype was transiently blocked by acute post-conditioning CNO administration and persistently blocked by repeated CNO administration during conditioning. Conclusion Cocaine reward and memory likely map to distinct serotonergic Pet1 neuron subtypes. r2Hoxa2-Pet1 neurons normally may limit the durability of cocaine memory, without impacting initial cocaine reward magnitude. Drd1a-Pet1 neurons normally may help to promote cocaine reward. Keywords Clozapine-N-oxide . Cocaine . Conditioned place preference . Drd1a-Pet1 neurons . Inhibitory DREADD . Locomotor activity . r2Hoxa2-Pet1 neurons
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00213-020-05560-6) contains supplementary material, which is available to authorized users. * Susan M. Dymecki [email protected] * Kathleen M. Kantak [email protected] 1
Department of Psychological and Brain Sciences, Boston University, 64 Cummington Mall, Boston, MA 02215, USA
2
Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA, USA
In a recent national survey, nearly 1 million Americans met diagnostic criteria for cocaine dependence (Center for Behavioral Health Statistics and Quality,
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