1 / 18

Dysregulation of glutamate homeostasis in the NAc core

Dysregulation of glutamate homeostasis in the NAc core underlies relapse (Knackstedt et al., Biol. Psychiatry, 2009). Activation of mGlu2/3 receptors attenuates both stress and cue ethanol seeking (Zhao et al., J. Neurosci. 2006). Orthosteric ligands of mGlu receptors.

ailis
Download Presentation

Dysregulation of glutamate homeostasis in the NAc core

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Dysregulation of glutamate homeostasis in the NAc core underlies relapse (Knackstedt et al., Biol. Psychiatry, 2009)

  2. Activation of mGlu2/3 receptors attenuates both stress and cue ethanol seeking (Zhao et al., J. Neurosci. 2006)

  3. Orthosteric ligands of mGlu receptors DHPG CHPG AIDA LY367385 (mGlu1/5 ago) (mGlu5 ago) (mGlu1 antag) (mGlu1 antag) 2R,4R-APDC LY354740 LY379268 EGlu (mGlu2/3 ago) (mGlu2/3 ago) (mGlu2/3 ago) (mGlu2/3 antag) L-AP4 L-phosphoserine (R,S)-PPG LY341495 (mGlu4/6/7/8 agonists) (pan-antag.; preferential mGlu2/3)

  4. Presynaptic Postsynaptic mGlu4/7/8 Gi PLC AC mGlu2/3 Gq mGlu1/5 Gi AC L-Glu iGluRs Gi mGlu2 Group-III mGlu receptors (except mGlu6) N and P/Q Ca2+channel mGlu4 912 aa mGlu7a 915 aa mGlu7b mGlu8a 908 aa mGlu8b mGlu8c Glutamate - AC Gi/o - cAMP ATP + PI-3-K p-Akt GSK-3ß

  5. mGlu5 receptor antagonists do not affect METH-induced DA release, but prevent the production of ROS induced by METH Salycilic acid (5 mM, added to perfusion fluid) + hydroxyl radicals = 2,3-dyhydroxybenzoic acid 350 200 Saline Saline MPEP, 10 mg/kg MPEP, 10 mg/kg 300 180 250 160 2,3DHBA in the perfusate (% basal) 140 200 Dopamine in the perfusate (% basal) * * 120 150 * 100 100 80 50 0 20 40 60 80 100 120 140 160 180 200 220 0 20 40 60 80 100 120 140 160 180 200 220 Time (min) Time (min) MPEP (10 mg/kg, i.p.) MPEP (10 mg/kg, i.p.) METH (5 mg/kg, i.p.) METH (5 mg/kg, i.p.)

  6. Negative allosteric modulators inhibit receptor function independently of the concentrations of ambient glutamate mGlu1 negative modulators Fenobam mGlu5 negative modulators ADX100159

  7. Activation of mGlu2/3 receptors in the NAc reduces context-dependent heroin relapse (Bossert et al., Neuropsychopharmacol., 2006) LY379268

  8. 3. mGlu5 stimulates gliotransmission in the NAc (D’Ascenzo et al., PNAS 2000) mGlu2 Glut NR2A mGlu4/7/8 mGlu2/3 i mGlu3 NR2B mGlu3 mGlu3 Glut Glia mGlu5 Glia mGlu5

  9. DNA methylation and histone acetylation are two critical epigenetic mechanisms controlling chromatin structure and function in mammalian neurons Or methylation Korzus Nat. Neurosc. 13,405,2010

  10. Renthal and Nestler Dialog. Clin Neurosci 11, 2009

  11. Class C G-protein coupled receptors Metabotropic Glu (mGlu1-8) - GABAB – Ca2+ sensing – pheromone – Taste receptors: T1R1/T1R3 (umami) – T1R2/T1R3 (sweet) Antagonist Agonist Venus Fly Trap

  12. Changes in synaptic plasticity in medium spiny neurons of NAcc associated with drug addiction

More Related