title: Prevention of alcohol-heightened aggression by CRF-R1 antagonists in mice: critical role for DRN-PFC serotonin pathway.
abstract: Alcohol can escalate aggressive behavior in a significant subgroup of rodents, humans, and nonhuman primates. The present study investigated whether blockade of corticotropin-releasing factor receptor type 1 (CRF-R1) could prevent the emergence of alcohol-heightened aggression in mice. The serotonin (5-HT) pathway from the dorsal raphe nucleus (DRN) to the medial prefrontal cortex (mPFC) by CRF-R1 was investigated as a possible target for the prevention of alcohol-heightened aggressive behavior. Male CFW mice that reliably exhibited aggressive behaviors after consuming 1 g/kg of alcohol received systemic or intra-DRN administration of CRF-R1 antagonists, CP-154,526 or MTIP, before a confrontation with a male conspecific. Blockade of DRN CRF-R1 receptors with both antagonists significantly reduced only alcohol-heightened aggression, whereas systemic administration reduced both alcohol-heightened and species-typical aggression. Next, a 5-HT1A agonist, 8-OH-DPAT, was coadministered with CP-154,526 into the DRN to temporarily disrupt 5-HT activity. This manipulation abolished the antiaggressive effects of intra-DRN CP-154,526. In the mPFC, in vivo microdialysis revealed that extracellular 5-HT levels were increased in mice that consumed alcohol and were then injected with CP-154,526, both systemically or intra-DRN. Neither alcohol nor CP-154,526 alone affected 5-HT release in the mPFC. The present results suggest the DRN as a critical site for CRF-R1 to modulate alcohol-heightened aggression via action on the serotonergic DRN-PFC pathway.
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, USA.
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Quadros
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, USA.
authors.forename: Lara S
authors.initials: LS
authors.lastname: Hwa
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamoto
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Carlson
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: DeBold
authors.affiliation: 1] Department of Psychology, Tufts University, Medford, MA, USA [2] Departments of Neuroscience, Psychiatry, and Pharmacology, Tufts University, Boston, MA, USA.
authors.forename: Klaus A
authors.initials: KA
authors.lastname: Miczek
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000374:Aggression / Q000187:drug effects* / Q000502:physiology; D000428:Alcohol Drinking / Q000503:physiopathology / Q000523:psychology; D000818:Animals; D002491:Central Nervous System Agents / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000008:administration & dosage*; D051379:Mice; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012646:Self Administration; D012701:Serotonin / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D000099052:CRF Receptor, Type 1
chemical_list: C518650:3-(4-chloro-2-morpholin-4-ylthiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethylimidazo(1,2-b)pyridazine; C101628:CP 154526; D002491:Central Nervous System Agents; D002492:Central Nervous System Depressants; D011724:Pyridazines; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D058825:Serotonin 5-HT1 Receptor Agonists; D013844:Thiazoles; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D000431:Ethanol; D000099052:CRF Receptor, Type 1; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin