title: Blockade of nucleus accumbens 5-HT2A and 5-HT2C receptors prevents the expression of cocaine-induced behavioral and neurochemical sensitization in rats.
abstract: BACKGROUND
  The serotonin 5-HT(2A) and 5-HT(2C) receptors regulate the capacity of acute cocaine to augment behavior and monoamine levels within the nucleus accumbens (NAC), a brain region involved in cocaine's addictive and psychotogenic properties.
  
  
  OBJECTIVE
  In the present study, we tested the hypothesis that NAC 5-HT(2A) and 5-HT(2C) receptor activation is involved in the expression of cocaine-induced neuroplasticity following protracted withdrawal from a sensitizing repeated cocaine regimen (days 1 and 7, 15 mg/kg; days 2-6, 30 mg/kg, i.p.).
  
  
  METHODS
  The effects of intra-NAC infusions of the 5-HT(2A) antagonist R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methanol (MDL 100907; 0, 50, 100, 500 nM) or the 5-HT(2C) antagonist [6-chloro-5-methyl-1-(6-(2-methylpiridin-3-yloxy)pyridine-3-yl carbamoyl] inodoline dihydrochloride (SB 242084; 0, 50, 100, 500 nM) were first assessed upon the expression of locomotor activity elicited by a 15-mg/kg cocaine challenge injection administered at 3-week withdrawal. A follow-up in vivo microdialysis experiment then compared the effects of the local perfusion of 0, 50, or 100 nM of each antagonist upon cocaine-induced dopamine and glutamate sensitization in the NAC.
  
  
  RESULTS
  Although neither MDL 100907 nor SB 242084 altered acute cocaine-induced locomotion, SB 242084 reduced acute cocaine-elevated NAC dopamine and glutamate levels. Intra-NAC perfusion with either compound blocked the expression of cocaine-induced locomotor and glutamate sensitization, but only MDL 100907 pretreatment prevented the expression of cocaine-induced dopamine sensitization.
  
  
  CONCLUSIONS
  These data provide the first evidence that NAC 5-HT(2A) and 5-HT(2C) receptors are critical for the expression of cocaine-induced neuroplasticity following protracted withdrawal, which has relevance for their therapeutic utility in the treatment of addiction.
authors.affiliation: Department of Psychology, University of California at Santa Barbara, Santa Barbara, CA 93106-9660, USA.
authors.forename: Avi E
authors.initials: AE
authors.lastname: Zayara
authors.forename: Gregor
authors.initials: G
authors.lastname: McIver
authors.forename: Paola N
authors.initials: PN
authors.lastname: Valdivia
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Lominac
authors.forename: Andrew C
authors.initials: AC
authors.lastname: McCreary
authors.forename: Karen K
authors.initials: KK
authors.lastname: Szumlinski
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D009473:Neuronal Plasticity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D005464:Fluorobenzenes; D007211:Indoles; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D058830:Serotonin 5-HT2 Receptor Antagonists; D018698:Glutamic Acid; C079049:volinanserin; D003042:Cocaine; D004298:Dopamine
references.citation: Psychopharmacology (Berl). 2003 Feb;165(4):329-36
references.pmid: 12451437
references.citation: Psychopharmacology (Berl). 2000 May;150(1):45-51
references.pmid: 10867975
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2004 May;28(3):547-57
references.pmid: 15093963
references.citation: Can J Psychiatry. 2002 Feb;47(1):27-38
references.pmid: 11873706
references.citation: Neuropharmacology. 1997 Apr-May;36(4-5):609-20
references.pmid: 9225286
references.citation: J Neurosci Res. 2006 Nov 15;84(7):1528-42
references.pmid: 17016851
references.citation: J Pharmacol Exp Ther. 2000 Dec;295(3):1183-91
references.pmid: 11082456
references.citation: Neurosci Lett. 2006 Aug 7;403(3):256-60
references.pmid: 16759803
references.citation: J Neurosci. 2001 Dec 15;21(24):9856-66
references.pmid: 11739593
references.citation: Neuropsychopharmacology. 2002 Mar;26(3):311-24
references.pmid: 11850146
references.citation: Eur J Pharmacol. 1994 Jul 1;259(2):137-41
references.pmid: 7957607
references.citation: Cell Tissue Res. 2006 Nov;326(2):553-72
references.pmid: 16896947
references.citation: Synapse. 2000 Jan;35(1):53-61
references.pmid: 10579808
references.citation: Neuropsychopharmacology. 2002 Oct;27(4):576-86
references.pmid: 12377394
references.citation: Curr Opin Investig Drugs. 2002 Jan;3(1):106-12
references.pmid: 12054060
references.citation: Neuropharmacology. 1997 Apr-May;36(4-5):589-99
references.pmid: 9225284
references.citation: J Neurosci. 2002 Nov 15;22(22):10039-45
references.pmid: 12427861
references.citation: Neuropsychopharmacology. 2008 May;33(6):1402-12
references.pmid: 17653111
references.citation: Addiction. 2000 Aug;95 Suppl 2:S91-117
references.pmid: 11002906
references.citation: Psychopharmacology (Berl). 2006 Sep;187(4):515-25
references.pmid: 16832658
references.citation: Neuropharmacology. 1997 Apr-May;36(4-5):621-9
references.pmid: 9225287
references.citation: Eur J Neurosci. 2004 Dec;20(11):3073-84
references.pmid: 15579162
references.citation: J Neurosci. 2000 Mar 1;20(5):1952-63
references.pmid: 10684896
references.citation: J Neurosci. 2001 Oct 1;21(19):7781-7
references.pmid: 11567068
references.citation: Neuropsychopharmacology. 2004 Sep;29(9):1675-87
references.pmid: 15127081
references.citation: J Neurosci. 2000 Dec 1;20(23):8846-52
references.pmid: 11102493
references.citation: J Neurochem. 1999 Sep;73(3):1033-42
references.pmid: 10461892
references.citation: Brain Res. 2000 Apr 28;863(1-2):254-8
references.pmid: 10773215
references.citation: Brain Res. 1998 May 18;793(1-2):103-11
references.pmid: 9630549
references.citation: J Neurosci Methods. 1980 Dec;3(2):129-49
references.pmid: 6110810
references.citation: J Neurochem. 2000 Oct;75(4):1625-33
references.pmid: 10987844
references.citation: Curr Top Med Chem. 2006;6(18):1971-85
references.pmid: 17017968
references.citation: Neuropsychopharmacology. 2004 Feb;29(2):308-18
references.pmid: 14666118
references.citation: Neuropharmacology. 1999 Aug;38(8):1195-205
references.pmid: 10462132
references.citation: J Pharmacol Exp Ther. 1995 Sep;274(3):1414-24
references.pmid: 7562516
references.citation: Neuropharmacology. 1998;37(2):265-72
references.pmid: 9680252
references.citation: Neuropsychopharmacology. 2008 May;33(6):1365-78
references.pmid: 17568396
references.citation: Neuropharmacology. 2000;39(1):123-32
references.pmid: 10665825
references.citation: J Pharmacol Exp Ther. 2001 Apr;297(1):357-63
references.pmid: 11259563
references.citation: Neuroscience. 1999;92(2):601-11
references.pmid: 10408609
references.citation: Pharmacol Biochem Behav. 1999 Jun;63(2):237-43
references.pmid: 10371652
references.citation: J Neurochem. 1993 Nov;61(5):1611-9
references.pmid: 7693863
references.citation: Eur J Pharmacol. 1992 Nov 13;223(1):65-74
references.pmid: 1362159
references.citation: Synapse. 2000 Dec 1;38(3):328-37
references.pmid: 11020236
references.citation: Behav Pharmacol. 2007 Dec;18(8):791-800
references.pmid: 17989517
references.citation: J Pharmacol Exp Ther. 2004 Apr;309(1):109-18
references.pmid: 14722316
references.citation: Pharmacol Biochem Behav. 2002 Apr;71(4):745-56
references.pmid: 11888566
references.citation: Psychopharmacology (Berl). 2000 Aug;151(2-3):99-120
references.pmid: 10972458
references.citation: J Pharmacol Exp Ther. 2003 Aug;306(2):734-43
references.pmid: 12721337
references.citation: Synapse. 2000 Jun 1;36(3):205-21
references.pmid: 10819900
references.citation: J Neurosci. 2002 May 1;22(9):3312-20
references.pmid: 11978805
references.citation: Brain Res. 1998 Jun 8;795(1-2):264-76
references.pmid: 9622647
references.citation: Neurosci Lett. 2003 Aug 7;346(3):137-40
references.pmid: 12853103
references.citation: Neuroscience. 2001;105(2):379-92
references.pmid: 11672605
references.citation: Synapse. 2005 Mar 1;55(3):156-63
references.pmid: 15602751
references.citation: Brain Res. 1989 Dec 18;504(2):231-7
references.pmid: 2598025
references.citation: J Psychopharmacol. 1998;12(1):49-53
references.pmid: 9584968
references.citation: J Neurochem. 2004 Oct;91(2):318-26
references.pmid: 15447665
references.citation: Brain Res. 2000 May 19;865(1):85-90
references.pmid: 10814735
references.citation: J Neurosci. 2002 Sep 1;22(17):7509-17
references.pmid: 12196574
references.citation: J Pharmacol Exp Ther. 2004 Sep;310(3):1246-54
references.pmid: 15131246
references.citation: J Neurochem. 2004 Apr;89(2):418-29
references.pmid: 15056285
references.citation: Brain Res. 2000 Aug 4;873(1):34-45
references.pmid: 10915808
references.citation: J Pharmacol Exp Ther. 1996 May;277(2):968-81
references.pmid: 8627580
references.citation: Dialogues Clin Neurosci. 2007;9(4):389-97
references.pmid: 18286799
references.citation: Neuroscience. 1999;91(2):587-97
references.pmid: 10366016
references.citation: Synapse. 2001 Oct;42(1):12-26
references.pmid: 11668587
references.citation: Eur J Pharmacol. 1999 Feb 19;367(2-3):197-206
references.pmid: 10078993
references.citation: Neuropharmacology. 2008 Nov;55(6):969-76
references.pmid: 18602407
references.citation: Curr Top Med Chem. 2006;6(18):1909-25
references.pmid: 17017966
references.citation: Neuropsychopharmacology. 2008 Jan;33(2):237-46
references.pmid: 17429406
references.citation: J Comp Neurol. 1997 Jul 28;384(2):233-47
references.pmid: 9215720
references.citation: Neuropsychopharmacology. 2004 Feb;29(2):319-26
references.pmid: 14560323