title: 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.
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.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, 835 S. Wolcott, Chicago, IL 60612-7342, USA.
authors.forename: Sudarat
authors.initials: S
authors.lastname: Nimitvilai
authors.forename: Maureen A
authors.initials: MA
authors.lastname: McElvain
authors.forename: Mark S
authors.initials: MS
authors.lastname: Brodie
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology*; D034281:Dynamins / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D019257:Quinpirole / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D018028:Receptors, Neurotensin / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects*
chemical_list: D002227:Carbazoles; D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; D018377:Neurotransmitter Agents; D010455:Peptides; D017448:Receptors, Dopamine D2; D018028:Receptors, Neurotensin; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; C445259:beta-adrenergic receptor kinase inhibitory peptide; C081021:Go 6976; D019257:Quinpirole; D011493:Protein Kinase C; D054769:G-Protein-Coupled Receptor Kinase 2; D034281:Dynamins