Mice Lacking Serotonin 2C Receptors Have increased Affective Responses to Aversive Stimuli

• Published in: PloS one Vol. 10; no. 12; p. e0142906
• Main Authors: Bonasera, Stephen J, Schenk, A Katrin, Luxenberg, Evan J, Wang, Xidao, Basbaum, Allan, Tecott, Laurence H
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.12.2015; Public Library of Science (PLoS)
• Subjects: Acids; Animals; Aversive stimuli; Brain; Chemical stimuli; Dopamine; Dopamine Antagonists - pharmacology; Dopamine D2 receptors; Dopamine D3 receptors; Dosage and administration; Fear - physiology; Female; Footshock; Geriatrics; Heat; Laboratory animals; Laboratory rats; Male; Medicine; Mesolimbic system; Mice; Mice, Inbred C57BL; Mice, Knockout; Modulation; Pain; Pain perception; Phenols (Class of compounds); Psychiatry; Raclopride; Raclopride - pharmacology; Receptor, Serotonin, 5-HT2C - physiology; Receptors; Receptors, Dopamine D2 - chemistry; Reflex, Startle - drug effects; Reflex, Startle - physiology; Rodents; Sensitivity enhancement; Serotonin; Serotonin S2 receptors; Startle response; Stimuli; Ultrasonics; Vocalization, Animal - drug effects; Vocalization, Animal - physiology; Vocalization, Animal - radiation effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0142906

Although central serotonergic systems are known to influence responses to noxious stimuli, mechanisms underlying serotonergic modulation of pain responses are unclear. We proposed that serotonin 2C receptors (5-HT2CRs), which are expressed within brain regions implicated in sensory and affective responses to pain, contribute to the serotonergic modulation of pain responses. In mice constitutively lacking 5-HT2CRs (2CKO mice) we found normal baseline sensory responses to noxious thermal, mechanical and chemical stimuli. In contrast, 2CKO mice exhibited a selective enhancement of affect-related ultrasonic afterdischarge vocalizations in response to footshock. Enhanced affect-related responses to noxious stimuli were also exhibited by 2CKO mice in a fear-sensitized startle assay. The extent to which a brief series of unconditioned footshocks produced enhancement of acoustic startle responses was markedly increased in 2CKO mice. As mesolimbic dopamine pathways influence affective responses to noxious stimuli, and these pathways are disinhibited in 2CKO mice, we examined the sensitivity of footshock-induced enhancement of startle to dopamine receptor blockade. Systemic administration of the dopamine D2/D3 receptor antagonist raclopride selectively reduced footshock-induced enhancement of startle without influencing baseline acoustic startle responses. We propose that 5-HT2CRs regulate affective behavioral responses to unconditioned aversive stimuli through mechanisms involving the disinhibition of ascending dopaminergic pathways.