A neurochemical yin and yang: does serotonin activate and norepinephrine deactivate the prefrontal cortex?
BACKGROUND
The prefrontal cortex (PFC) receives serotonergic input from the dorsal raphe nucleus of the brainstem, as well as noradrenergic input from another brainstem nucleus, the locus coeruleus. A large number of studies have shown that these two neurotransmitter systems, and drugs that affect them, modulate the functional properties of the PFC in both humans and animal models.


RESULTS
Here I examine the hypothesis that serotonin (5-HT) plays a general role in activating the PFC, whereas norepinephrine (NE) plays a general role in deactivating this brain region. In this manner, the two neurotransmitter systems may have opposing effects on PFC-influenced behavior. To assess this hypothesis, three primary lines of evidence are examined comprising the effects of 5-HT and NE on impulsivity, cognitive flexibility, and working memory.


CONCLUSIONS
While all of the existing data do not unequivocally support the activation/deactivation hypothesis, there is a large body of support for it.
Fitzgerald
Paul J
PJ
The Zanvyl Krieger Mind/Brain Institute, Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21218, USA. pfitz@mbi.mb.jhu.edu
D000818:Animals; D003071:Cognition / Q000502:physiology; D006801:Humans; D007175:Impulsive Behavior / Q000378:metabolism; D008570:Memory, Short-Term / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*
D012701:Serotonin; D009638:Norepinephrine
Neurology. 2002 Feb 26;58(4):527-36
11865128
J Neurosci. 1988 Nov;8(11):4287-98
2903226
J Neural Transm Suppl. 1987;24:317-24
2824692
Cogn Behav Neurol. 2006 Dec;19(4):204-7
17159617
Prog Brain Res. 2008;169:323-38
18394484
Brain Res. 1993 Jun 18;614(1-2):191-6
8102313
Pharmacol Ther. 2007 Mar;113(3):523-36
17303246
J Trop Pediatr. 2009 Apr;55(2):116-21
19203986
Neuroreport. 1999 Sep 9;10(13):2763-7
10511436
J Psychopharmacol. 2008 Mar;22(2):187-202
18308800
Brain Res. 1996 Dec 2;742(1-2):89-97
9117425
Neuropsychopharmacology. 2001 Apr;24(4):370-8
11182532
Life Sci. 1983 Dec 26;33(26):2609-14
6198573
Psychopharmacology (Berl). 2002 Aug;163(1):42-53
12185399
J Neurosci. 2005 Jan 12;25(2):532-8
15647499
Pharmacol Biochem Behav. 1981 Jun;14(6):849-55
6114497
J Child Adolesc Psychopharmacol. 2005 Apr;15(2):259-69
15910210
Biol Psychiatry. 2006 Jul 1;60(1):66-73
16125144
Cereb Cortex. 2007 Sep;17 Suppl 1:i151-60
17725997
J Clin Psychiatry. 2005 Mar;66(3):294-9
15766294
Int Clin Psychopharmacol. 1994 Spring;9(1):35-40
8195581
Pharmacol Biochem Behav. 2009 Sep;93(3):237-47
19410598
Psychopharmacology (Berl). 1998 Aug;138(3-4):283-94
9725750
Science. 2006 Feb 10;311(5762):861-3
16469930
Psychiatr Genet. 2000 Mar;10(1):39-42
10909127
Neuropsychopharmacology. 2008 Apr;33(5):1028-37
17637611
CNS Drugs. 2009;23 Suppl 1:33-41
19621976
Neuropsychopharmacology. 2002 Nov;27(5):699-711
12431845
Cereb Cortex. 1998 Apr-May;8(3):218-26
9617916
Synapse. 1994 Dec;18(4):294-7
7886621
Brain Behav Evol. 1999 May-Jun;53(5-6):305-12
10473906
Neurobiol Dis. 2007 Jan;25(1):206-16
17064920
Learn Mem. 2003 Nov-Dec;10(6):466-77
14657258
Behav Brain Res. 2008 Jan 10;186(1):23-31
17714800
Brain Res Bull. 1992 Mar;28(3):455-61
1591602
Psychopharmacology (Berl). 2007 Apr;191(2):353-64
17219219
J Psychopharmacol. 2004 Mar;18(1):32-40
15107182
Psychopharmacology (Berl). 1999 Apr;143(2):111-22
10326773
Biol Psychiatry. 2005 May 15;57(10):1209-11
15866563
Brain Res. 1997 Jul 18;763(1):56-62
9272828
Neuroscience. 2009 Feb 18;158(4):1284-91
19041693
Psychopharmacology (Berl). 2006 Jan;183(4):404-12
16307295
Neurobiol Aging. 2008 Jul;29(7):1060-9
17363115
Pharmacol Toxicol. 2003 May;92(5):214-25
12753409
Arch Gen Psychiatry. 1991 Apr;48(4):324-8
2009034
J Med Assoc Thai. 2005 Sep;88 Suppl 4:S357-62
16623055
Neurosci Biobehav Rev. 2009 Jun;33(6):773-83
19111570
Neurosci Biobehav Rev. 2004 Nov;28(7):771-84
15555683
Neuropsychopharmacology. 2003 Jul;28(7):1247-56
12700678
J Psychopharmacol. 2007 Mar;21(2):210-5
17329302
Brain Res Bull. 2006 Jun 15;70(1):81-93
16750486
Pharmacol Biochem Behav. 1992 Mar;41(3):573-9
1350101
Psychopharmacology (Berl). 2009 Oct;206(3):403-14
19629447
Am J Med Genet B Neuropsychiatr Genet. 2009 Jun 5;150B(4):467-75
18655075
Trends Cogn Sci. 2008 Jan;12(1):31-40
18069045
Neuroreport. 2002 Dec 20;13(18):2505-7
12499857
Eur J Neurosci. 2007 Oct;26(7):2066-73
17897403
Life Sci. 2001 Jun 29;69(6):647-57
11476186
Eur J Neurosci. 2000 Jan;12(1):67-79
10651861
Biol Psychiatry. 1999 Jan 1;45(1):26-31
9894572
Science. 2004 May 7;304(5672):878-80
15131308
Biol Psychiatry. 1989 Apr 15;25(8):1049-66
2720017
Neurobiol Aging. 1993 Nov-Dec;14(6):597-603
7905189
Psychopharmacology (Berl). 2009 Aug;205(2):273-83
19404616
Pharmacol Biochem Behav. 1997 Sep;58(1):55-9
9264070
Psychopharmacology (Berl). 2004 Nov;176(3-4):376-85
15232674
Ann N Y Acad Sci. 1997 Dec 29;836:81-105
9616795
Prog Neuropsychopharmacol Biol Psychiatry. 2008 Jan 1;32(1):34-41
17714843
Behav Brain Res. 2003 May 15;141(2):137-45
12742250
Ann N Y Acad Sci. 1999 Apr 30;868:701-15
10414358
Behav Neurosci. 1997 Oct;111(5):883-91
9383511
J Psychiatry Neurosci. 1995 Jul;20(4):271-5
7544158
J Neurosci. 2006 Jul 26;26(30):7870-4
16870732
Psychopharmacology (Berl). 1994 Jun;115(1-2):285-8
7862908
J Psychopharmacol. 2010 Mar;24(3):309-21
19074531
J Neurosci. 2005 Mar 2;25(9):2322-9
15745958
Biol Psychiatry. 1999 Nov 1;46(9):1309-20
10560036
Neuroreport. 1995 Dec 29;7(1):177-82
8742446
Psychol Med. 2003 Jan;33(1):41-9
12537035
Curr Med Chem. 2007;14(28):2989-95
18220735
Psychopharmacology (Berl). 2009 Jan;202(1-3):505-19
18604598
Brain Res. 1987 Aug 4;417(1):59-69
3620979
Am J Psychiatry. 1996 Sep;153(9):1147-53
8780417
J Neural Transm (Vienna). 2008 Aug;115(8):1213-9
18629432
Neuropsychopharmacology. 2008 Sep;33(10):2398-406
18046307
Neurobiol Aging. 1990 Nov-Dec;11(6):583-90
1980719
Cell. 2007 Apr 20;129(2):397-410
17448997
Learn Mem. 2006 Nov-Dec;13(6):770-6
17101879
Biol Psychiatry. 1999 Nov 1;46(9):1259-65
10560031
Am J Phys Anthropol. 2001 Mar;114(3):224-41
11241188
Pharmacol Biochem Behav. 2008 Aug;90(2):250-60
18272211
J Psychopharmacol. 1997;11(1):45-51
9097893
Psychiatry Res. 2002 Dec 15;113(1-2):193-206
12467958
Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):14128-33
17715054
Biol Psychiatry. 2005 Dec 1;58(11):894-900
16043136
Behav Brain Res. 2002 Mar 10;130(1-2):191-6
11864734
Q J Exp Psychol B. 2001 Aug;54(3):247-58
11547514
J Hum Evol. 1999 Aug;37(2):191-223
10444351
Neuropsychopharmacology. 2002 Sep;27(3):421-9
12225699
Psychopharmacology (Berl). 2000 Apr;149(2):147-52
10805609
J Psychopharmacol. 2005 Jan;19(1):21-8
15671125
Neuropsychopharmacology. 2007 May;32(5):1000-10
17077810
Eur J Neurosci. 2007 Jun;25(12):3719-24
17610591
Behav Pharmacol. 2008 Feb;19(1):61-70
18195595
Neuropsychopharmacology. 1999 Nov;21(5):611-21
10516957
Brain Res. 1989 Jan 16;477(1-2):404-7
2539238
J Pharmacol Exp Ther. 1976 Sep;198(3):596-608
185355
Annu Rev Neurosci. 2005;28:403-50
16022602
Psychopharmacology (Berl). 2006 Sep;187(4):486-97
16823591
Schizophr Res. 2007 Sep;95(1-3):158-68
17628435
J Psychopharmacol. 2001 Dec;15(4):219-30
11769814
Neuropsychopharmacology. 1999 Nov;21(5):601-10
10516956
Hum Psychopharmacol. 2009 Aug;24(6):437-46
19637398
Psychiatr Clin North Am. 2000 Mar;23(1):11-25
10729928
Cogn Behav Neurol. 2004 Jun;17(2):93-7
15453517
Neuropsychopharmacology. 2002 Aug;27(2):237-47
12093597
Psychopharmacology (Berl). 2009 Jan;202(1-3):329-41
18587666
Int J Neurosci. 2005 Jan;115(1):47-54
15768851
Neuropsychopharmacology. 2000 Sep;23(3):240-9
10942848
Pharmacol Biochem Behav. 2008 Jan;88(3):222-9
17884154
Neuropsychopharmacology. 1999 May;20(5):460-70
10192826
Psychopharmacology (Berl). 2007 Dec;195(2):223-34
17673981
Physiol Behav. 2007 Aug 15;91(5):652-7
17481676
Pharmacol Biochem Behav. 1993 Feb;44(2):411-8
8446673
J Neurosci. 2002 Oct 1;22(19):8771-7
12351753
Prog Neuropsychopharmacol Biol Psychiatry. 2003 Feb;27(1):147-56
12551738
Biol Psychiatry. 2007 Nov 1;62(9):977-84
17644072