title: Dopaminergic dynamics underlying sex-specific cocaine reward.
abstract: Although both males and females become addicted to cocaine, females transition to addiction faster and experience greater difficulties remaining abstinent. We demonstrate an oestrous cycle-dependent mechanism controlling increased cocaine reward in females. During oestrus, ventral tegmental area (VTA) dopamine neuron activity is enhanced and drives post translational modifications at the dopamine transporter (DAT) to increase the ability of cocaine to inhibit its function, an effect mediated by estradiol. Female mice conditioned to associate cocaine with contextual cues during oestrus have enhanced mesolimbic responses to these cues in the absence of drug. Using chemogenetic approaches, we increase VTA activity to mechanistically link oestrous cycle-dependent enhancement of VTA firing to enhanced cocaine affinity at DAT and subsequent reward processing. These data have implications for sexual dimorphism in addiction vulnerability and define a mechanism by which cellular activity results in protein alterations that contribute to dysfunctional learning and reward processing.
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, New York 10029, USA.
authors.forename: Erin S
authors.initials: ES
authors.lastname: Calipari
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, New York 10029, USA.|Department of Pharmacological Sciences, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Juarez
authors.affiliation: Department of Pharmacological Sciences, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Carole
authors.initials: C
authors.lastname: Morel
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, New York 10029, USA.
authors.forename: Deena M
authors.initials: DM
authors.lastname: Walker
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, New York 10029, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cahill
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, New York 10029, USA.
authors.forename: Efrain
authors.initials: E
authors.lastname: Ribeiro
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, New York 10029, USA.
authors.forename: Ciorana
authors.initials: C
authors.lastname: Roman-Ortiz
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California 94305, USA.
authors.forename: Charu
authors.initials: C
authors.lastname: Ramakrishnan
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California 94305, USA.|HHMI, Stanford University, Stanford, California 94305, USA.|Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.affiliation: Department of Pharmacological Sciences, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Ming-Hu
authors.initials: MH
authors.lastname: Han
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, New York 10029, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000818:Animals; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D004594:Electrophysiology / Q000379:methods; D004971:Estrus / Q000187:drug effects* / Q000502:physiology; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D012201:Reward; D012737:Sex Factors; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D003042:Cocaine; D002118:Calcium