Glycogen synthase kinase 3 beta alters anxiety-, depression-, and addiction-related behaviors and neuronal activity in the nucleus accumbens shell.

Autor: Crofton EJ; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA., Nenov MN; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA., Zhang Y; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA., Scala F; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA; Biophysics Graduate Program, Institute of Human Physiology, Universita Cattolica, Rome, Italy., Page SA; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA., McCue DL; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA., Li D; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA., Hommel JD; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA., Laezza F; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA., Green TA; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA. Electronic address: tom.green@utmb.edu.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2017 May 01; Vol. 117, pp. 49-60. Date of Electronic Publication: 2017 Jan 23.
DOI: 10.1016/j.neuropharm.2017.01.020
Abstrakt: Psychiatric disorders such as anxiety, depression and addiction are often comorbid brain pathologies thought to share common mechanistic biology. As part of the cortico-limbic circuit, the nucleus accumbens shell (NAcSh) plays a fundamental role in integrating information in the circuit, such that modulation of NAcSh circuitry alters anxiety, depression, and addiction-related behaviors. Intracellular kinase cascades in the NAcSh have proven important mediators of behavior. To investigate glycogen-synthase kinase 3 (GSK3) beta signaling in the NAcSh in vivo we knocked down GSK3beta expression with a novel adeno-associated viral vector (AAV2) and assessed changes in anxiety- and depression-like behavior and cocaine self-administration in GSK3beta knockdown rats. GSK3beta knockdown reduced anxiety-like behavior while increasing depression-like behavior and cocaine self-administration. Correlative electrophysiological recordings in acute brain slices were used to assess the effect of AAV-shGSK3beta on spontaneous firing and intrinsic excitability of tonically active interneurons (TANs), cells required for input and output signal integration in the NAcSh and for processing reward-related behaviors. Loose-patch recordings showed that TANs transduced by AAV-shGSK3beta exhibited reduction in tonic firing and increased spike half width. When assessed by whole-cell patch clamp recordings these changes were mirrored by reduction in action potential firing and accompanied by decreased hyperpolarization-induced depolarizing sag potentials, increased action potential current threshold, and decreased maximum rise time. These results suggest that silencing of GSK3beta in the NAcSh increases depression- and addiction-related behavior, possibly by decreasing intrinsic excitability of TANs. However, this study does not rule out contributions from other neuronal sub-types.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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