title: Inactivation of the lateral habenula reduces anxiogenic behavior and cocaine seeking under conditions of heightened stress.
abstract: Recent anatomical and functional studies have renewed interest in the lateral habenula (LHb), a critical brain region that works in an opponent manner to modulate aversive and appetitive processes. In particular, increased LHb activation is believed to drive anxiogenic states during stressful conditions. Here, we reversibly inactivated the LHb with GABA receptor agonists (baclofen/muscimol) in rats prior to testing in an open field, elevated plus maze, and defensive burying task in the presence or absence of yohimbine, a noradrenergic α2-receptor antagonist that acts as an anxiogenic stressor. In a second set of experiments using a cocaine self-administration and reinstatement model, we inactivated the LHb during extinction responding and cue-induced reinstatement of cocaine seeking in the presence or absence of yohimbine pretreatment. Inactivation of the LHb after yohimbine treatment attenuated anxiogenic behavior by increasing time spent in the open arms and reducing the time spent burying. Inactivation of the LHb also reduced cocaine seeking when cue-induced reinstatement occurred in the presence of yohimbine, but did not affect extinction responding or cue-induced reinstatement by itself. These data demonstrate that the LHb critically regulates states of heightened anxiety during both unconditioned behavior and conditioned appetitive processes.
authors: Department of Neurosciences Medical University of South Carolina Charleston, SC 29425, USA.
authors: Margaret J
authors: MJ
authors: Gill
authors: Shannon M
authors: SM
authors: Ghee
authors: Stiles M
authors: SM
authors: Harper
authors: Ronald E
authors: RE
authors: See
mesh_terms: D000818:Animals; D001007:Anxiety / Q000517:prevention & control*; D003042:Cocaine / Q000008:administration & dosage*; D018755:GABA Agonists / Q000494:pharmacology; D019262:Habenula / Q000187:drug effects*; D008297:Male; D009042:Motivation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological
chemical_list: D018755:GABA Agonists; D003042:Cocaine
keywords: Anxiety; Cocaine; Lateral habenula; Reinstatement; Self-administration; Yohimbine
references: Pharmacol Biochem Behav. 2002 Mar;71(3):407-17
references: 11830175
references: Neuron. 2009 Mar 12;61(5):786-800
references: 19285474
references: Psychopharmacology (Berl). 2001 Mar;154(3):301-10
references: 11351937
references: J Comp Neurol. 2009 Apr 20;513(6):597-621
references: 19235223
references: Neuropharmacology. 2010 Nov;59(6):452-9
references: 20600170
references: Ann N Y Acad Sci. 1990;597:159-74
references: 1974753
references: Pharmacol Biochem Behav. 2008 Apr;89(2):227-33
references: 18230406
references: Neuropsychopharmacology. 2004 Apr;29(4):686-93
references: 14872205
references: Neuropsychopharmacology. 2000 Aug;23(2):138-50
references: 10882840
references: Drug Alcohol Depend. 1995 Apr;38(1):35-43
references: 7648995
references: Behav Brain Res. 2006 Nov 1;174(1):1-8
references: 16920204
references: Neuropharmacology. 2011 Feb-Mar;60(2-3):381-7
references: 20955718
references: Psychopharmacology (Berl). 2011 Jan;213(1):19-27
references: 20827461
references: Nat Neurosci. 2012 Jun 24;15(8):1105-7
references: 22729176
references: J Neurosci. 2004 Feb 18;24(7):1551-60
references: 14973230
references: J Comp Neurol. 2011 Apr 15;519(6):1143-64
references: 21344406
references: Psychopharmacology (Berl). 1979 Oct;65(2):111-8
references: 117478
references: Eur J Neurosci. 2013 Apr;37(8):1340-9
references: 23368289
references: J Neurosci. 1999 Oct 15;19(20):RC35
references: 10516337
references: Psychopharmacology (Berl). 2009 Mar;203(1):121-30
references: 18985323
references: Brain Res. 2006 Feb 16;1073-1074:229-39
references: 16442084
references: Psychopharmacology (Berl). 2011 Jul;216(1):53-62
references: 21308466
references: J Neurosci. 2007 Jun 27;27(26):6923-30
references: 17596440
references: Neuropsychopharmacology. 2010 Jan;35(1):217-38
references: 19710631
references: Nature. 2007 Jun 28;447(7148):1111-5
references: 17522629
references: Psychopharmacology (Berl). 2012 Dec;224(3):431-40
references: 22707255
references: Psychopharmacology (Berl). 1999 Mar;142(4):343-51
references: 10229058
references: Behav Brain Res. 2008 Feb 11;187(1):17-26
references: 17889943
references: Behav Brain Res. 1996 Nov;81(1-2):43-52
references: 8950000
references: J Neurosci. 1986 Mar;6(3):613-9
references: 3958786
references: J Neurosci. 2001 Nov 1;21(21):8655-63
references: 11606653
references: J Neurosci. 1997 Apr 1;17(7):2605-14
references: 9065520
references: CNS Spectr. 2008 Jun;13(6):484-9
references: 18567972
references: J Neurosci Res. 1997 Dec 15;50(6):1040-6
references: 9452019
references: Br J Pharmacol. 2010 Dec;161(8):1677-91
references: 21087442
references: J Neurosci. 1998 Jul 15;18(14):5529-36
references: 9651233
references: J Psychopharmacol. 1988 Jan;2(1):33-8
references: 22159667
references: Neuropsychopharmacology. 2006 Oct;31(10):2188-96
references: 16341025