Journal
NEUROPSYCHOPHARMACOLOGY
Volume 33, Issue 12, Pages 2888-2899Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/npp.2008.7
Keywords
microinjection; microdialysis; mouse; CP-94,253; aggressive behavior; 5-H
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Funding
- NIAAA NIH HHS [AA013983, R01 AA013983] Funding Source: Medline
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A significant minority of individuals engages in escalated levels of aggression after consuming moderate doses of alcohol (Alc). Neural modulation of escalated aggression involves altered levels of serotonin (5-HT) and the activity of 5-HT1B receptors. The aim of these studies was to determine whether 5-HT1B receptors in the dorsal raphe (DRN), orbitofrontal (OFC), and medial prefrontal (mPFC) cortex attenuate heightened aggression and regulate extracellular levels of 5-HT. Male mice were trained to self-administer Alc by performing an operant response that was reinforced with a delivery of 6% Alc. To identify Alc-heightened aggressors, each mouse was repeatedly tested for aggression after consuming either 1.0 g/kg Alc or H2O. Next, a cannula was implanted into either the DRN, OFC, or mPFC, and subsets of mice were tested for aggression after drinking either Alc or H2O prior to a microinjection of the 5-HT1B agonist, CP-94,253. Additional mice were implanted with a microdialysis probe into the mPFC, through which CP-94,253 was perfused and samples were collected for 5-HT measurement. Approximately 60% of the mice were more aggressive after drinking Alc, confirming the aggression-heightening effects of 1.0 g/kg Alc. Infusion of 1 mu g CP-94,253 into the DRN reduced both aggressive and motor behaviors. However, infusion of 1 mu g CP-94,253 into the mPFC, but not the OFC, after Alc drinking, increased aggressive behavior. In the mPFC, reverse microdialysis of CP-94,253 increased extracellular levels of 5-HT; levels decreased immediately after the perfusion. This 5-HT increase was attenuated in self-administering mice. These results suggest that 5-HT1B receptors in the mPFC may serve to selectively disinhibit aggressive behavior in mice with a history of Alc self-administration.
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