GABA(B) receptor modulation of serotonin neurons in the dorsal raphé nucleus and escalation of aggression in mice.
The serotonin (5-HT) system in the brain has been studied more than any other neurotransmitter for its role in the neurobiological basis of aggression. However, which mechanisms modulate the 5-HT system to promote escalated aggression is not clear. We here explore the role of GABAergic modulation in the raphé nuclei, from which most 5-HT in the forebrain originates, on escalated aggression in male mice. Pharmacological activation of GABA(B), but not GABA(A), receptors in the dorsal raphé nucleus (DRN) escalated aggressive behaviors. In contrast, GABA agonists did not escalate aggressive behaviors after microinjection into the median raphé nucleus. The aggression-heightening effect of the GABA(B) agonist baclofen depended on the activation of 5-HT neurons in the DRN because it was blocked by coadministration of the 5-HT(1A) agonist 8-OH-DPAT [((+/-)-8-hydroxy-2-(di-n-propylamino)tetralin) hydrobromide] (DPAT), which acts on autoreceptors and inhibits 5-HT neural activity. In vivo microdialysis showed that GABA(B) activation in the DRN increased extracellular 5-HT level in the medial prefrontal cortex. This may be attributable to an indirect action via presynaptic GABA(B) receptors. The presynaptic GABA(B) receptors suppress Ca(2+) channel activity and inhibit neurotransmission, and the coadministration of N-type Ca(2+) channel blocker facilitated the effect of baclofen. These findings suggest that the indirect disinhibition of 5-HT neuron activity by presynaptic GABA(B) receptors on non-5-HT neurons in the DRN is one of the neurobiological mechanisms of escalated aggression.
Takahashi
Aki
A
Department of Psychology, Tufts University, Medford, Massachusetts 02155, USA.
Shimamoto
Akiko
A
Boyson
Christopher O
CO
DeBold
Joseph F
JF
Miczek
Klaus A
KA
D000374:Aggression / Q000187:drug effects / Q000502:physiology* / Q000523:psychology*; D000818:Animals; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology*; D018080:Receptors, GABA-B / Q000502:physiology*; D012701:Serotonin / Q000096:biosynthesis / Q000502:physiology*; D012727:Sex Characteristics
D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; D018080:Receptors, GABA-B; D012701:Serotonin
Brain Res. 1988 Aug 30;459(1):27-36
3139262
Brain Res. 1982 Jan 28;232(2):375-89
7188029
J Neurosci. 2000 Jun 1;20(11):4217-25
10818157
J Neurochem. 2004 Mar;88(6):1373-9
15009637
J Comp Physiol Psychol. 1976 Jan;90(1):102-8
987068
J Neurochem. 2003 Feb;84(4):743-52
12562519
Brain Res. 1983 Sep 26;275(2):329-39
6354359
Psychopharmacology (Berl). 1997 Dec;134(4):392-400
9452182
Eur J Pharmacol. 2005 Dec 5;526(1-3):125-39
16310183
Psychopharmacology (Berl). 1978 Apr 14;57(1):47-55
26933
Psychiatry Res. 2009 Nov 30;174(2):81-8
19833485
Brain Res Mol Brain Res. 1992 Aug;14(4):357-62
1326699
J Comp Neurol. 1978 Jun 1;179(3):641-67
565370
Eur J Pharmacol. 1976 Oct;39(2):357-64
10174
Ann N Y Acad Sci. 2004 Dec;1036:336-55
15817748
Cereb Cortex. 2004 Mar;14(3):281-99
14754868
Behav Brain Res. 2008 Jun 3;189(2):263-72
18281105
Am J Psychiatry. 1997 Oct;154(10):1430-5
9326827
J Physiol. 1987 Mar;384:539-69
3309263
Neuropharmacology. 1997 Apr-May;36(4-5):589-99
9225284
Neurosci Lett. 1992 Mar 16;137(1):101-4
1385646
Br J Pharmacol. 1996 Dec;119(7):1375-84
8968546
Trends Pharmacol Sci. 2005 Jan;26(1):36-43
15629203
J Neurophysiol. 2005 Oct;94(4):2561-74
15944232
Brain Res Brain Res Rev. 2002 Sep;39(2-3):154-80
12423765
Mol Pharmacol. 1990 Sep;38(3):342-7
2169580
Experientia. 1964 Jul 15;20(7):398-9
5856530
J Neurosci Res. 2002 Jan 1;67(1):48-61
11754080
Eur J Pharmacol. 1987 Nov 10;143(2):195-204
2826189
Pharmacol Biochem Behav. 1997 Oct;58(2):425-30
9300602
Psychopharmacology (Berl). 2007 Aug;193(2):295-304
17440711
Brain Res Bull. 1992 Dec;29(6):943-8
1473026
Neuropsychopharmacology. 2008 Nov;33(12):2888-99
18305458
Synapse. 1987;1(1):3-9
3505364
Neuroscience. 2000;98(2):295-300
10854760
Brain Res. 1979 Jan 12;160(2):341-6
570081
Pharmacol Biochem Behav. 1997 Mar;56(3):529-40
9077593
Pharmacol Rev. 2002 Jun;54(2):247-64
12037141
Neuroscience. 1991;40(2):399-412
1851255
Brain Res Rev. 2007 Oct;55(2):329-42
17316819
J Neurosci. 1988 Sep;8(9):3499-506
3171686
J Neurosci. 2001 Nov 1;21(21):8655-63
11606653
J Neurosci. 2000 Dec 15;20(24):9320-5
11125011
Brain Res Bull. 2009 Mar 16;78(4-5):132-8
18955118
Neurosci Lett. 1988 Nov 11;93(2-3):300-6
3241656
J Neurosci. 2007 Oct 31;27(44):11803-6
17978016
J Biol Chem. 2009 Jan 30;284(5):2738-2745
19004821
J Neurophysiol. 2007 Jul;98(1):196-204
17460100
Synapse. 2000 Apr;36(1):21-34
10700023
Synapse. 1994 Jul;17(3):173-81
7974200
Brain Res. 2007 Jul 30;1160:102-12
17588550
Physiol Behav. 1982 Apr;28(4):697-705
7200622
Psychopharmacology (Berl). 2004 Jan;171(2):191-8
13680080
Nat Neurosci. 2004 Feb;7(2):153-9
14745451
Behav Neurosci. 1999 Aug;113(4):804-15
10495088
Science. 2000 Jul 28;289(5479):591-4
10915615
Mol Cell Neurosci. 2000 Oct;16(4):296-312
11085869
Neurochem Int. 2004 Dec;45(7):1057-65
15337305
Nat Neurosci. 2007 Dec;10(12):1559-68
17965710
Physiol Behav. 1986;36(4):653-8
2940609
Neuroscience. 1987 Feb;20(2):365-83
3035421
Ann N Y Acad Sci. 2004 Dec;1036:382-92
15817750
Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13967-72
11087824
J Physiol. 1990 May;424:513-31
2167975
Behav Neurosci. 2003 Aug;117(4):667-74
12931952
Cereb Cortex. 2005 Jan;15(1):1-14
15238448
Brain Res. 1985 Apr 1;331(1):91-103
2985201
J Pharmacol Exp Ther. 2005 Jan;312(1):290-6
15333677
Eur J Pharmacol. 1993 Jul 20;238(2-3):411-5
8405111
J Psychopharmacol. 2000 Jun;14(2):100-13
10890306
Pharmacol Biochem Behav. 1991 Feb;38(2):447-58
1829232
J Neurosci. 2005 Aug 24;25(34):7801-4
16120781
J Neurosci Res. 1996 Dec 15;46(6):697-708
8978504