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

Although central serotonergic systems are known to influence responses to noxious stimuli, mechanisms underlying serotonergic modulation of pain responses are unclear. We pro-posed that serotonin 2C receptors (5-HT2CRs), which are expressed within brain regions implicated in sensory and affective responses to pain, contribute to the serotonergic modu-lation of pain responses. In mice constitutively lacking 5-HT2CRs (2CKOmice) we found normal baseline sensory responses to noxious thermal, mechanical and chemical stimuli. In contrast, 2CKOmice exhibited a selective enhancement of affect-related ultrasonic after-discharge vocalizations in response to footshock. Enhanced affect-related responses to noxious stimuli were also exhibited by 2CKOmice in a fear-sensitized startle assay. The extent to which a brief series of unconditioned footshocks produced enhancement of acous-tic startle responses was markedly increased in 2CKOmice. As mesolimbic dopamine path-ways influence affective responses to noxious stimuli, and these pathways are disinhibited in 2CKOmice, we examined the sensitivity of footshock-induced enhancement of startle to dopamine receptor blockade. Systemic administration of the dopamine D2/D3 recepto