title: Group I metabotropic glutamate receptor-mediated activation of PKC gamma in the nucleus accumbens core promotes the reinstatement of cocaine seeking.
abstract: Emerging evidence indicates that type I metabotropic glutamate receptors (mGluRs) in the nucleus accumbens play a critical role in cocaine seeking. The present study sought to determine the role of accumbens core mGluR1, mGluR5 and protein kinase C (PKC) in cocaine priming-induced reinstatement of drug seeking. Here, we show that intra-accumbens core administration of the mGluR1/5 agonist DHPG (250 μM) promoted cocaine seeking in rats. Consistent with these results, administration of an mGluR1 (50.0 μM YM 298198) or mGluR5 (9.0 μM MPEP) antagonist directly into the accumbens core prior to a priming injection of cocaine (10 mg/kg) attenuated the reinstatement of drug seeking. mGluR1/5 stimulation activates a signaling cascade including PKC. Intracore microinjection of PKC inhibitors (10 μM Ro 31-8220 or 30.0 μM chelerythrine) also blunted cocaine seeking. In addition, cocaine priming-induced reinstatement of drug seeking was associated with increased phosphorylation of PKCγ, but not PKCα or PKCβII, in the core. There were no effects of pharmacological inhibition of mGluR1, mGluR5 or PKC in the accumbens core on sucrose seeking. Together, these findings indicate that mGluR1 and mGluR5 activation in the accumbens core promotes cocaine seeking and that these effects are reinforcer specific. Furthermore, stimulation of mGluR1 and mGluR5 in the accumbens core may regulate cocaine seeking, in part, through activation of PKCγ.
authors: Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Heath D
authors: HD
authors: Schmidt
authors: Blake A
authors: BA
authors: Kimmey
authors: Adrian C
authors: AC
authors: Arreola
authors: R Christopher
authors: RC
authors: Pierce
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012118:Resorcinols / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C505455:6-amino-N-cyclohexyl-N,3-dimethylthiazolo(3,2-a)benzimidazole-2-carboxamide; D001562:Benzimidazoles; D018765:Dopamine Uptake Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; D013844:Thiazoles; C104077:metabotropic glutamate receptor type 1; C079215:3,5-dihydroxyphenylglycine; C121465:6-methyl-2-(phenylethynyl)pyridine; C087857:protein kinase C gamma; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D003042:Cocaine; D005998:Glycine
keywords: Addiction; glutamate; psychostimulant; relapse; self-administration; striatum