Chronic coadministration of olanzapine and fluoxetine activates locus coeruleus neurons in rats: implications for bipolar disorder.
BACKGROUND
The depressive phase of bipolar disorder (bipolar depression) is a difficult-to-treat form of depression. The olanzapine/fluoxetine combination (Symbyax) is the only medication approved to treat this disorder. The precise neural mechanisms responsible for its efficacy are not clearly understood.


OBJECTIVE
In order to further elucidate the neurobiological mechanisms responsible for the beneficial clinical effects of the olanzapine/fluoxetine combination, the current experiment was designed to investigate the effects of chronic coadministration of olanzapine and fluoxetine on electrophysiological activity in the locus coeruleus (LC).


METHODS
Rats received olanzapine for 3 weeks via subcutaneous osmotic pumps while simultaneously receiving daily intraperitoneal injections of fluoxetine. These chronically treated rats were anesthetized, and single-unit recordings of LC neurons were made.


RESULTS
Chronic administration of olanzapine alone significantly increased firing of LC neurons, while, as reported previously, chronic administration of fluoxetine alone significantly reduced firing of LC neurons. However, in the combination condition, olanzapine was able to block the fluoxetine-induced suppression of the LC, and a significant increase in LC activity was observed.


CONCLUSIONS
The observed increase in firing of LC neurons could lead to enhanced levels of norepinephrine release in projection areas and amelioration of the clinical symptoms of bipolar depression.
Seager
Matthew A
MA
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Barth
Vanessa N
VN
Phebus
Lee A
LA
Rasmussen
Kurt
K
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001569:Benzodiazepines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D001714:Bipolar Disorder / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D001921:Brain / Q000378:metabolism; D004357:Drug Synergism; D005473:Fluoxetine / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D007260:Infusion Pumps; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D000077152:Olanzapine; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
D014150:Antipsychotic Agents; D001569:Benzodiazepines; D005473:Fluoxetine; D000077152:Olanzapine; D017367:Selective Serotonin Reuptake Inhibitors
Arch Gen Psychiatry. 2000 Sep;57(9):841-9
10986547
J Clin Psychiatry. 2004;65 Suppl 4:11-24
15046537
J Pharmacol Exp Ther. 2002 Sep;302(3):983-91
12183655
J Clin Psychiatry. 2003 Nov;64(11):1349-56
14658950
J Clin Psychiatry. 2002 Dec;63(12 ):1164-70
12523877
J Pharmacol Exp Ther. 1996 Feb;276(2):658-66
8632334
J Clin Psychiatry. 2003;64 Suppl 1:19-23
12625801
Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8047-51
7520174
Naunyn Schmiedebergs Arch Pharmacol. 2000 Sep;362(3):266-75
10997729
Biol Psychiatry. 2004 Jun 1;55(11):1103-9
15158430
J Comp Neurol. 1998 Mar 9;392(2):227-51
9512271
Eur J Pharmacol. 2000 Apr 21;395(1):31-6
10781670
Drug Saf. 2003;26(5):337-51
12650634
Lancet. 2002 Jan 19;359(9302):241-7
11812578
J Clin Psychiatry. 2003;64 Suppl 2:14-8
12625794
Neurosci Lett. 2003 Oct 9;349(3):196-200
12951202
Am J Psychiatry. 1995 Aug;152(8):1130-8
7625459
J Clin Psychiatry. 2003;64 Suppl 1:5-12
12625799
AAPS PharmSci. 2002;4(2):E11
12102620
J Neurosci. 1984 Nov;4(11):2877-90
6150071
Nat Neurosci. 2003 Sep;6(9):968-73
12897785
Nature. 1971 Nov 12;234(5324):100-2
4942887
Proc Natl Acad Sci U S A. 2004 May 25;101(21):8186-91
15148402
Pharmacol Biochem Behav. 1979 Jan;10(1):5-9
441095
Clin Ther. 2004 Jan;26(1):125-34
14996525
Brain Res. 1986 Jan 1;362(1):165-70
2867813
Psychopharmacology (Berl). 2003 Apr;167(1):79-84
12632247
Brain Res. 2001 Dec 13;922(1):9-20
11730697
Am J Psychiatry. 1994 Nov;151(11):1642-5
7943454
Neuropharmacology. 2004 Feb;46(2):232-42
14680761
J Neural Transm Gen Sect. 1993;93(1):11-25
8373553
Int J Neuropsychopharmacol. 2004 Sep;7(3):321-7
15228643
Biol Psychiatry. 2004 Oct 15;56(8):570-80
15476686
J Pharmacol Exp Ther. 1990 May;253(2):833-40
2338658
Br J Clin Pharmacol. 1992 Sep;34(3):262-5
1389951
J Clin Psychiatry. 2002 Sep;63(9):826-37
12363125
Eur J Pharmacol. 2000 Apr 7;394(1):67-73
10771036
J Clin Psychiatry. 2000;61 Suppl 1:26-32
10703760
Brain Res. 1984 Jul 30;307(1-2):359-62
6147177
J Pharmacol Exp Ther. 2001 Aug;298(2):651-7
11454927
Biol Psychiatry. 2004 Jun 1;55(11):1095-102
15158429
Int Clin Psychopharmacol. 1995 Dec;10 Suppl 4:11-7
8930005
Brain Res. 1996 Dec 2;742(1-2):89-97
9117425
Biol Psychiatry. 2001 Jan 15;49(2):117-29
11164758
Am J Psychiatry. 2001 Jan;158(1):131-4
11136647
Biol Psychiatry. 2001 Oct 1;50(7):510-20
11600104
Neuropsychopharmacology. 2000 Sep;23 (3):250-62
10942849
J Neurochem. 1992 Feb;58(2):494-502
1345939
Arch Gen Psychiatry. 2003 Nov;60(11):1079-88
14609883
Drug Metab Dispos. 1997 Jan;25(1):81-93
9010634
Biol Psychiatry. 2003 Apr 15;53(8):671-9
12706953