title: Effects of chronic cocaine self-administration on norepinephrine transporters in the nonhuman primate brain.
abstract: BACKGROUND
  While cocaine blocks dopamine and serotonin transporters, considerably less emphasis has been placed on its effects following blockade of the norepinephrine transporter (NET). To date, no studies have made a systematic investigation of the effects of chronic cocaine on primate NET density.
  
  
  OBJECTIVE
  We previously reported increases in NET density in portions of the monkey bed nucleus of stria terminalis after 100 days of cocaine self-administration. In the present study we extend these findings and assess the changes in [3H]nisoxetine binding in additional brain regions of rhesus monkeys chronically self-administrating cocaine.
  
  
  RESULTS
  [3H]Nisoxetine binding sites in the A1 noradrenergic cell group were significantly higher after 5 days of cocaine exposure. One hundred days of self-administration also induced a higher density of NET binding within the A1 cell group; however, in addition, the effects extended to the nucleus prepositus, as well as forebrain regions such as hypothalamic nuclei, basolateral amygdala, parasubiculum, and entorhinal cortex.
  
  
  CONCLUSIONS
  These data demonstrate that cocaine self-administration alters the noradrenergic system of nonhuman primates. Although cocaine affected NET binding sites in the forebrain projections of both the ventral (VNAB) and dorsal (DNAB) noradrenergic bundles, the alteration in the A1 cell group at the early time-point suggests that the VNAB appears to be more sensitive than the DNAB to the effects of cocaine. Given the role of norepinephrine in arousal and attention, as well as mediating responses to stress, long-term exposure to cocaine is likely to result in significant changes in the way in which information is perceived and processed by the central nervous system of long-term cocaine users.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors.forename: Thomas J R
authors.initials: TJ
authors.lastname: Beveridge
authors.forename: Hilary R
authors.initials: HR
authors.lastname: Smith
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nader
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Porrino
mesh_terms: D000818:Animals; D001345:Autoradiography / Q000379:methods; D001522:Behavior, Animal; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D001931:Brain Mapping; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D003042:Cocaine / Q000008:administration & dosage*; D003847:Deoxyglucose / Q000493:pharmacokinetics; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D008253:Macaca mulatta; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D012646:Self Administration; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D002247:Carbon Isotopes; D018765:Dopamine Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D005473:Fluoxetine; D014316:Tritium; C011386:nisoxetine; D003847:Deoxyglucose; D003042:Cocaine
references.citation: Brain Res. 1993 Nov 19;628(1-2):17-25
references.pmid: 8313144
references.citation: J Pharmacol Exp Ther. 1999 Sep;290(3):1347-55
references.pmid: 10454513
references.citation: J Neurosci. 1999 Oct 15;19(20):RC35
references.pmid: 10516337
references.citation: Life Sci. 1988;43(4):309-15
references.pmid: 2969443
references.citation: Neuroscience. 1988 Oct;27(1):1-39
references.pmid: 3059226
references.citation: Brain Res. 1994 Feb 28;638(1-2):182-8
references.pmid: 7515319
references.citation: Nature. 2000 Jan 27;403(6768):430-4
references.pmid: 10667795
references.citation: Brain Res. 1990 Jun 4;518(1-2):227-43
references.pmid: 1697208
references.citation: J Pharmacol Exp Ther. 1996 Apr;277(1):225-34
references.pmid: 8613924
references.citation: J Comp Neurol. 1993 Jun 1;332(1):105-22
references.pmid: 7685779
references.citation: Nature. 1997 Apr 24;386(6627):827-30
references.pmid: 9126740
references.citation: J Pharmacol Exp Ther. 1995 Mar;272(3):1176-86
references.pmid: 7891330
references.citation: J Pharmacol Exp Ther. 1991 Nov;259(2):495-500
references.pmid: 1658300
references.citation: J Pharmacol Exp Ther. 1992 Jan;260(1):427-36
references.pmid: 1731049
references.citation: Neuropsychopharmacology. 2002 Jul;27(1):35-46
references.pmid: 12062905
references.citation: J Pharmacol Exp Ther. 1994 Sep;270(3):1134-8
references.pmid: 7932162
references.citation: Brain Res. 1996 Oct 14;736(1-2):287-96
references.pmid: 8930335
references.citation: J Neurosci. 1999 Jun 15;19(12):5119-23
references.pmid: 10366644
references.citation: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11642-7
references.pmid: 10500230
references.citation: Neuroscience. 1998 Jun;84(4):967-96
references.pmid: 9578390
references.citation: Nature. 1996 Feb 15;379(6566):606-12
references.pmid: 8628395
references.citation: Neurosci Biobehav Rev. 2004 Jan;27(8):813-20
references.pmid: 15019430
references.citation: Neurosci Lett. 2004 Nov 11;370(2-3):201-5
references.pmid: 15488323
references.citation: Brain Res Mol Brain Res. 2000 Nov 10;83(1-2):107-20
references.pmid: 11072100
references.citation: J Neurosci. 2002 Jul 1;22(13):5713-8
references.pmid: 12097523
references.citation: J Pharmacol Exp Ther. 1992 May;261(2):476-83
references.pmid: 1578363
references.citation: Ann N Y Acad Sci. 1999 Jun 29;877:486-98
references.pmid: 10415666
references.citation: Neuropsychopharmacology. 2000 Aug;23(2):138-50
references.pmid: 10882840
references.citation: Curr Opin Neurobiol. 2001 Apr;11(2):250-7
references.pmid: 11301247
references.citation: J Comp Neurol. 1991 Jul 22;309(4):445-85
references.pmid: 1918444
references.citation: Mol Cell Neurosci. 1994 Apr;5(2):189-95
references.pmid: 8032687
references.citation: J Neurosci. 2002 Sep 1;22(17):7687-94
references.pmid: 12196592
references.citation: Life Sci. 1990;46(9):635-45
references.pmid: 2308472
references.citation: J Pharmacol Exp Ther. 1995 Oct;275(1):53-62
references.pmid: 7562595
references.citation: J Neurosci. 2001 Apr 15;21(8):2799-807
references.pmid: 11306632
references.citation: Neuropsychopharmacology. 2004 Apr;29(4):686-93
references.pmid: 14872205
references.citation: Brain Res. 1995 Feb 20;672(1-2):289-97
references.pmid: 7749750
references.citation: J Comp Neurol. 1986 Sep 22;251(4):451-73
references.pmid: 2431009
references.citation: Psychopharmacology (Berl). 2001 Dec;158(4):360-5
references.pmid: 11797056
references.citation: Drug Alcohol Depend. 2001 Jun 1;63(1):69-78
references.pmid: 11297832
references.citation: J Pharmacol Exp Ther. 1998 Mar;284(3):1015-25
references.pmid: 9495862
references.citation: J Pharmacol Exp Ther. 2000 Dec;295(3):951-9
references.pmid: 11082428
references.citation: Brain Res. 1989 Dec 25;505(1):7-11
references.pmid: 2611679
references.citation: Brain Res Mol Brain Res. 1997 Oct 3;49(1-2):95-102
references.pmid: 9387868
references.citation: Drug Alcohol Depend. 1991 Jan;27(1):51-61
references.pmid: 1709403
references.citation: Psychopharmacology (Berl). 1992;106(4):459-62
references.pmid: 1579620
references.citation: Psychoneuroendocrinology. 2002 Jan-Feb;27(1-2):13-33
references.pmid: 11750768
references.citation: Psychopharmacology (Berl). 1997 Jun;131(3):307-12
references.pmid: 9203242
references.citation: Eur J Pharmacol. 1990 Sep 4;186(1):1-8
references.pmid: 2282931
references.citation: Arch Gen Psychiatry. 1994 Sep;51(9):713-9
references.pmid: 8080348
references.citation: J Neurochem. 2002 Apr;81(2):292-300
references.pmid: 12064476
references.citation: J Neurosci. 2003 Jan 1;23(1):12-6
references.pmid: 12514195
references.citation: Can J Psychol. 1977 Dec;31(4):195-203
references.pmid: 608135
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5300-5
references.pmid: 11320258