title: Metabotropic glutamate 2/3 receptors in the ventral tegmental area and the nucleus accumbens shell are involved in behaviors relating to nicotine dependence.
abstract: The motivation to maintain nicotine self-administration and dependence may involve alterations in glutamatergic neurotransmission. Metabotropic glutamate (mGlu) 2/3 receptors regulate glutamate and dopamine release in the ventral tegmental area (VTA) and the nucleus accumbens (NAc) shell, two brain areas critically involved in reward and motivational processes. We found that acute systemic, as well as intra-VTA or intra-NAc, administration of the mGlu2/3 receptor agonist LY379268 [(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate] decreased nicotine, but not food, self-administration in rats. In addition, nicotine self-administration downregulated mGlu2/3 receptor function in corticolimbic rat brain sites including the VTA and the NAc, demonstrated by decreased coupling of mGlu2/3 receptors to G-proteins in the [35S]GTPgammaS binding assay. Furthermore, repeated treatment with LY379268 reduced nicotine self-administration at the beginning of a 14 d treatment period; however, the number of nicotine infusions earned gradually returned to baseline levels, indicating tolerance to the effects of repeated LY379268 treatment. Finally, LY379268 administration decreased both cue-induced reinstatement of nicotine- and food-seeking behavior. Together, these findings indicate an important role for mGlu2/3 receptors in the posterior VTA and the NAc shell in the mediation of the rewarding effects of nicotine and potentially in cue-induced nicotine-seeking behavior.
authors: Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors: Matthias E
authors: ME
authors: Liechti
authors: Loic
authors: L
authors: Lhuillier
authors: Klemens
authors: K
authors: Kaupmann
authors: Athina
authors: A
authors: Markou
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003463:Cues; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005518:Food Preferences / Q000502:physiology / Q000523:psychology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D008297:Male; D009538:Nicotine / Q000008:administration & dosage; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D012054:Reinforcement, Psychology; D012646:Self Administration / Q000379:methods; D014029:Tobacco Use Disorder / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018690:Excitatory Amino Acid Agonists; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009538:Nicotine
references: J Neurosci. 1998 Sep 15;18(18):7502-10
references: 9736668
references: Annu Rev Pharmacol Toxicol. 1997;37:205-37
references: 9131252
references: J Pharmacol Exp Ther. 2002 Nov;303(2):608-15
references: 12388642
references: J Neurochem. 2000 Sep;75(3):889-907
references: 10936169
references: J Pharmacol Exp Ther. 1999 Apr;289(1):412-6
references: 10087032
references: J Pharmacol Exp Ther. 2003 Sep;306(3):1068-76
references: 12805481
references: Neuropharmacology. 1999 Oct;38(10):1431-76
references: 10530808
references: J Comp Neurol. 2005 Jun 20;487(1):15-27
references: 15861463
references: J Pharmacol Exp Ther. 2006 Aug;318(2):922-31
references: 16675638
references: Am J Psychiatry. 2005 Aug;162(8):1403-13
references: 16055761
references: Curr Opin Pharmacol. 2004 Feb;4(1):23-9
references: 15018835
references: J Neurosci. 2003 Apr 15;23(8):3531-7
references: 12716962
references: Neuron. 2000 Aug;27(2):349-57
references: 10985354
references: J Neurosci. 2002 Aug 15;22(16):7225-33
references: 12177217
references: J Pharmacol Exp Ther. 1999 Oct;291(1):161-70
references: 10490900
references: Neurosci Lett. 2006 Jan 30;393(2-3):127-30
references: 16233956
references: Neuroscience. 2001;106(3):481-503
references: 11591452
references: Synapse. 2000 Dec 15;38(4):375-83
references: 11044884
references: Behav Brain Res. 2006 Oct 2;173(1):148-52
references: 16834996
references: J Neurosci. 2002 May 1;22(9):3338-41
references: 11978809
references: Eur J Pharmacol. 2007 Jan 12;554(2-3):164-74
references: 17113075
references: J Pharmacol Exp Ther. 2002 Jan;300(1):162-71
references: 11752112
references: J Comp Neurol. 1993 Sep 8;335(2):252-66
references: 8227517
references: Neuropsychopharmacology. 2006 Oct;31(10):2197-209
references: 16341024
references: Psychopharmacology (Berl). 2006 Mar;184(3-4):417-25
references: 16163522
references: J Neurosci. 2005 Jul 6;25(27):6389-93
references: 16000629
references: J Neurosci. 2006 Jan 18;26(3):723-30
references: 16421292
references: J Neurosci. 2004 Nov 24;24(47):10726-30
references: 15564590
references: Psychopharmacology (Berl). 2006 Mar;184(3-4):435-46
references: 16397746
references: Psychopharmacology (Berl). 2001 Mar;154(3):311-8
references: 11351938
references: J Neurosci Methods. 1980 Dec;3(2):129-49
references: 6110810
references: J Neurosci. 1996 May 1;16(9):3112-22
references: 8622141
references: J Neurosci. 2004 May 19;24(20):4723-7
references: 15152032
references: Behav Brain Res. 2006 Aug 10;171(2):207-15
references: 16678921
references: Eur J Pharmacol. 2000 Jul 21;400(2-3):221-4
references: 10988337
references: J Neurosci. 1996 Feb 15;16(4):1550-60
references: 8778304
references: Neuropharmacology. 2005;49 Suppl 1:167-78
references: 16023685
references: Neuroscience. 1993 Apr;53(4):1009-18
references: 8389425
references: Neuropharmacology. 2004 Jul;47(1):1-8
references: 15165829
references: Psychopharmacology (Berl). 1989;99(4):473-8
references: 2594913
references: Psychopharmacology (Berl). 2006 Jun;186(2):143-9
references: 16703399
references: Eur J Neurosci. 2005 Jan;21(1):295-300
references: 15654869
references: J Neurosci. 2006 Sep 27;26(39):9967-74
references: 17005860
references: Neuropsychopharmacology. 2007 Jan;32(1):103-9
references: 16452988
references: J Neurophysiol. 2000 Aug;84(2):759-70
references: 10938303
references: Brain Res Brain Res Rev. 1993 Jan-Apr;18(1):75-113
references: 8096779
references: Neuropsychopharmacology. 2000 Sep;23(3):335-44
references: 10942857
references: Neuropsychopharmacology. 2007 Mar;32(3):710-8
references: 16794568
references: Eur J Neurosci. 2001 Dec;14(11):1843-55
references: 11860480
references: Nat Neurosci. 2003 Jul;6(7):743-9
references: 12778052
references: Neuroreport. 2005 Jun 21;16(9):1013-6
references: 15931079
references: Neuropsychopharmacology. 2005 Jan;30(1):119-28
references: 15266350
references: J Med Chem. 1999 Mar 25;42(6):1027-40
references: 10090786
references: J Neurosci. 2000 Aug 1;20(15):RC89
references: 10899176
references: Eur J Pharmacol. 2005 Dec 28;528(1-3):110-8
references: 16324694
references: Physiol Behav. 2002 Dec;77(4-5):683-7
references: 12527019
references: Psychopharmacology (Berl). 2000 Apr;149(3):217-24
references: 10823401
references: Biol Psychiatry. 2007 Jan 1;61(1):17-22
references: 16876138