title: GABA(B) receptor modulation of serotonin neurons in the dorsal raphé nucleus and escalation of aggression in mice.
abstract: 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.
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts 02155, USA.
authors.forename: Aki
authors.initials: A
authors.lastname: Takahashi
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamoto
authors.forename: Christopher O
authors.initials: CO
authors.lastname: Boyson
authors.forename: Joseph F
authors.initials: JF
authors.lastname: DeBold
authors.forename: Klaus A
authors.initials: KA
authors.lastname: Miczek
mesh_terms: 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
chemical_list: D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; D018080:Receptors, GABA-B; D012701:Serotonin
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