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Reversal of dopamine D2 agonist-induced inhibition of ventral tegmental area neurons by Gq-linked neurotransmitters is dependent on protein kinase C, G protein-coupled receptor kinase, and dynamin.
J Pharmacol Exp Ther 2013; 344(1):253-63JP

Abstract

Dopaminergic neurons of the ventral tegmental area are important components of brain pathways related to addiction. Prolonged exposure of these neurons to moderate concentrations of dopamine (DA) decreases their sensitivity to inhibition by DA, a process called DA-inhibition reversal (DIR). DIR is mediated by phospholipase C and conventional subtype of protein kinase C (cPKC) through concurrent stimulation of D2 and D1-like DA receptors, or by D2 stimulation concurrent with activation of 5-HT(2) or neurotensin receptors. In the present study, we further characterized this phenomenon by use of extracellular recordings in brain slices to examine whether DIR is linked to G protein-coupled receptor kinase-2 (GRK2) or dynamin by assessing DIR in the presence of antagonists of these enzymes. DIR was blocked by β-ARK1 inhibitor, which inhibits GRK2, and by dynasore, which blocks dynamin. Reversal of inhibition by D2 agonist quinpirole was produced by serotonin (50 µM) and by neurotensin (5-10 nM). Serotonin-induced or neurotensin-induced reversal was blocked by β-ARK1 inhibitor, dynasore, or cPKC antagonist 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4c]carbazole-12-propanenitrile (Gö6976). This further characterization of DIR indicates that cPKC, GRK2, and dynamin play important roles in the desensitization of D2 receptors. As drugs of abuse produce persistent increases in DA concentration in the ventral tegmental area, reduction of D2 receptor sensitivity as a result of drug abuse may be a critical factor in the processes of addiction.

Authors+Show Affiliations

Department of Physiology and Biophysics, University of Illinois at Chicago, 835 S. Wolcott, Chicago, IL 60612-7342, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

23019137

Citation

Nimitvilai, Sudarat, et al. "Reversal of Dopamine D2 Agonist-induced Inhibition of Ventral Tegmental Area Neurons By Gq-linked Neurotransmitters Is Dependent On Protein Kinase C, G Protein-coupled Receptor Kinase, and Dynamin." The Journal of Pharmacology and Experimental Therapeutics, vol. 344, no. 1, 2013, pp. 253-63.
Nimitvilai S, McElvain MA, Brodie MS. Reversal of dopamine D2 agonist-induced inhibition of ventral tegmental area neurons by Gq-linked neurotransmitters is dependent on protein kinase C, G protein-coupled receptor kinase, and dynamin. J Pharmacol Exp Ther. 2013;344(1):253-63.
Nimitvilai, S., McElvain, M. A., & Brodie, M. S. (2013). Reversal of dopamine D2 agonist-induced inhibition of ventral tegmental area neurons by Gq-linked neurotransmitters is dependent on protein kinase C, G protein-coupled receptor kinase, and dynamin. The Journal of Pharmacology and Experimental Therapeutics, 344(1), pp. 253-63. doi:10.1124/jpet.112.199844.
Nimitvilai S, McElvain MA, Brodie MS. Reversal of Dopamine D2 Agonist-induced Inhibition of Ventral Tegmental Area Neurons By Gq-linked Neurotransmitters Is Dependent On Protein Kinase C, G Protein-coupled Receptor Kinase, and Dynamin. J Pharmacol Exp Ther. 2013;344(1):253-63. PubMed PMID: 23019137.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reversal of dopamine D2 agonist-induced inhibition of ventral tegmental area neurons by Gq-linked neurotransmitters is dependent on protein kinase C, G protein-coupled receptor kinase, and dynamin. AU - Nimitvilai,Sudarat, AU - McElvain,Maureen A, AU - Brodie,Mark S, Y1 - 2012/09/27/ PY - 2012/9/29/entrez PY - 2012/9/29/pubmed PY - 2013/2/27/medline SP - 253 EP - 63 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 344 IS - 1 N2 - Dopaminergic neurons of the ventral tegmental area are important components of brain pathways related to addiction. Prolonged exposure of these neurons to moderate concentrations of dopamine (DA) decreases their sensitivity to inhibition by DA, a process called DA-inhibition reversal (DIR). DIR is mediated by phospholipase C and conventional subtype of protein kinase C (cPKC) through concurrent stimulation of D2 and D1-like DA receptors, or by D2 stimulation concurrent with activation of 5-HT(2) or neurotensin receptors. In the present study, we further characterized this phenomenon by use of extracellular recordings in brain slices to examine whether DIR is linked to G protein-coupled receptor kinase-2 (GRK2) or dynamin by assessing DIR in the presence of antagonists of these enzymes. DIR was blocked by β-ARK1 inhibitor, which inhibits GRK2, and by dynasore, which blocks dynamin. Reversal of inhibition by D2 agonist quinpirole was produced by serotonin (50 µM) and by neurotensin (5-10 nM). Serotonin-induced or neurotensin-induced reversal was blocked by β-ARK1 inhibitor, dynasore, or cPKC antagonist 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4c]carbazole-12-propanenitrile (Gö6976). This further characterization of DIR indicates that cPKC, GRK2, and dynamin play important roles in the desensitization of D2 receptors. As drugs of abuse produce persistent increases in DA concentration in the ventral tegmental area, reduction of D2 receptor sensitivity as a result of drug abuse may be a critical factor in the processes of addiction. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/23019137/Reversal_of_dopamine_D2_agonist_induced_inhibition_of_ventral_tegmental_area_neurons_by_Gq_linked_neurotransmitters_is_dependent_on_protein_kinase_C_G_protein_coupled_receptor_kinase_and_dynamin_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=23019137 DB - PRIME DP - Unbound Medicine ER -