title: Mechanisms of activation of nucleus accumbens neurons by cocaine via sigma-1 receptor-inositol 1,4,5-trisphosphate-transient receptor potential canonical channel pathways.
abstract: Cocaine promotes addictive behavior primarily by blocking the dopamine transporter, thus increasing dopamine transmission in the nucleus accumbens (nAcc); however, additional mechanisms are continually emerging. Sigma-1 receptors (σ1Rs) are known targets for cocaine, yet the mechanisms underlying σ1R-mediated effects of cocaine are incompletely understood. The present study examined direct effects of cocaine on dissociated nAcc neurons expressing phosphatidylinositol-linked D1 receptors. Endoplasmic reticulum-located σ1Rs and inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) were targeted using intracellular microinjection. IP3 microinjection robustly elevated intracellular Ca(2+) concentration, [Ca(2+)]i. While cocaine alone was devoid of an effect, the IP3-induced response was σ1R-dependently enhanced by cocaine co-injection. Likewise, cocaine augmented the [Ca(2+)]i increase elicited by extracellularly applying an IP3-generating molecule (ATP), via σ1Rs. The cocaine-induced enhancement of the IP3/ATP-mediated Ca(2+) elevation occurred at pharmacologically relevant concentrations and was mediated by transient receptor potential canonical channels (TRPC). IP3 microinjection elicited a slight, transient depolarization, further converted to a greatly enhanced, prolonged response, by cocaine co-injection. The cocaine-triggered augmentation was σ1R-dependent, TRPC-mediated and contingent on [Ca(2+)]i elevation. ATP-induced depolarization was similarly enhanced by cocaine. Thus, we identify a novel mechanism by which cocaine promotes activation of D1-expressing nAcc neurons: enhancement of IP3R-mediated responses via σ1R activation at the endoplasmic reticulum, resulting in augmented Ca(2+) release and amplified depolarization due to subsequent stimulation of TRPC. In vivo, intra-accumbal blockade of σ1R or TRPC significantly diminished cocaine-induced hyperlocomotion and locomotor sensitization, endorsing a physio-pathological significance of the pathway identified in vitro.
authors.affiliation: Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Barr
authors.affiliation: Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Deliu
authors.affiliation: Department of Pharmaceutical Sciences, Thomas Jefferson University, Jefferson School of Pharmacy, Philadelphia, PA 19107, USA.
authors.forename: G Cristina
authors.initials: GC
authors.lastname: Brailoiu
authors.affiliation: Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Pingwei
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutical Sciences, Thomas Jefferson University, Jefferson School of Pharmacy, Philadelphia, PA 19107, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Yan
authors.affiliation: Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Abood
authors.affiliation: Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA. Electronic address: ellen.unterwald@temple.edu.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Unterwald
authors.affiliation: Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA. Electronic address: ebrailou@temple.edu.
authors.forename: Eugen
authors.initials: E
authors.lastname: Brailoiu
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D000255:Adenosine Triphosphate; D002118:Calcium; D003042:Cocaine; D007093:Imidazoles; D015544:Inositol 1,4,5-Trisphosphate; D053496:Inositol 1,4,5-Trisphosphate Receptors; D017480:Receptors, sigma; D050052:TRPC Cation Channels; D000097605:Sigma-1 Receptor; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole
keywords: Calcium; Endoplasmic reticulum; Imaging; Nucleus accumbens; Sigma receptors; Transient receptor potential channels