title: Loss of the trpc4 gene is associated with a reduction in cocaine self-administration and reduced spontaneous ventral tegmental area dopamine neuronal activity, without deficits in learning for natural rewards.
abstract: Among the canonical transient receptor potential (TRPC) channels, the TRPC4 non-selective cation channel is one of the most abundantly expressed subtypes within mammalian corticolimbic brain regions, but its functional and behavioral role is unknown. To identify a function for TRPC4 channels we compared the performance of rats with a genetic knockout of the trpc4 gene (trpc4 KO) to wild-type (WT) controls on the acquisition of simple and complex learning for natural rewards, and on cocaine self-administration (SA). Despite the abundant distribution of TRPC4 channels through the corticolimbic brain regions, we found trpc4 KO rats exhibited normal learning in Y-maze and complex reversal shift paradigms. However, a deficit was observed in cocaine SA in the trpc4 KO group, which infused significantly less cocaine than WT controls despite displaying normal sucrose SA. Given the important role of ventral tegmental area (VTA) dopamine neurons in cocaine SA, we hypothesized that TRPC4 channels may regulate basal dopamine neuron excitability. Double-immunolabeling showed a selective expression of TRPC4 channels in a subpopulation of putative dopamine neurons in the VTA. Ex vivo recordings of spontaneous VTA dopamine neuronal activity from acute brain slices revealed fewer cells with high-frequency firing rates in trpc4 KO rats compared to WT controls. Since deletion of the trpc4 gene does not impair learning involving natural rewards, but reduces cocaine SA, these data demonstrate a potentially novel role for TRPC4 channels in dopamine systems and may offer a new pharmacological target for more effective treatment of a variety of dopamine disorders.
authors.affiliation: Department of Psychology and Neuroscience, Drake University, Des Moines, IA 50311, USA. Electronic address: william.klipec@drake.edu.
authors.forename: William D
authors.initials: WD
authors.lastname: Klipec
authors.affiliation: Center for Neuroscience, Institute for Behavioral Genetics and Department of Psychology and Neuroscience, University of Colorado at Boulder, Boulder, CO 80309, USA.
authors.forename: Kristin R
authors.initials: KR
authors.lastname: Burrow
authors.affiliation: Center for Neuroscience, Institute for Behavioral Genetics and Department of Psychology and Neuroscience, University of Colorado at Boulder, Boulder, CO 80309, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: O'Neill
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, China; Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, China.
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Cao
authors.affiliation: Biology Department, University of St. Thomas, Saint Paul, MN 55105, USA.
authors.forename: Chloe R
authors.initials: CR
authors.lastname: Lawyer
authors.affiliation: Transposagen Biopharmaceuticals Inc., 535 West Second Street, Lexington, KY 40508, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Ostertag
authors.affiliation: Senomyx, Inc., 4767 Nexus Centre Drive, San Diego, CA 92121, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Fowler
authors.affiliation: Center for Neuroscience, Institute for Behavioral Genetics and Department of Psychology and Neuroscience, University of Colorado at Boulder, Boulder, CO 80309, USA.
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Bachtell
authors.affiliation: Biology Department, University of St. Thomas, Saint Paul, MN 55105, USA; Neuroscience Program, University of St. Thomas, Saint Paul, MN 55105, USA.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Illig
authors.affiliation: Center for Neuroscience, Institute for Behavioral Genetics and Department of Psychology and Neuroscience, University of Colorado at Boulder, Boulder, CO 80309, USA.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Cooper
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage* / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage; D050052:TRPC Cation Channels / Q000172:deficiency* / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects*
chemical_list: D018765:Dopamine Uptake Inhibitors; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; D013395:Sucrose; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine
keywords: Cocaine self-administration; Dopamine; Immunohistochemistry; Mesolimbic; trpc4 knockout