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

Abstract

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.

Increased fear learning, spatial learning as well as neophobia in Rgs2−/− mice

“…5‐HT 2A and 5‐HT 2C receptors as well as D 2 receptors were previously implicated in memory processes (Bonasera et al . ; Gelao et al . ; Morici et al .…”

“…While these findings link to putative neurobiological targets of Rgs2, dysregulation of GPCR expression by itself may contribute to the observed phenotype of Rgs2 −/− mice. 5-HT 2A and 5-HT 2C receptors as well as D 2 receptors were previously implicated in memory processes (Bonasera et al 2015;Gelao et al 2014;Morici et al 2015;Rocchetti et al 2015;Saab et al 2009;Wang et al 2004;Zhang et al 2013), while the 2A receptor and the NPY 1 receptor were associated with increased anxiety (Bertocchi et al 2011;Karl et al 2006;Lahdesmaki et al 2002;Longo et al 2014;Schramm et al 2001). A dysregulation of 5-HT 1A and 5-HT 1B receptors in the raphe nuclei was previously reported by Lifschytz and coworkers, the same group also noted comparable expression level in cortex and hypothalamus in line with our results of selectively reduced 5-HT 1A expression levels in the amygdala.…”

The grimace scale reliably assesses chronic pain in a rodent model of trigeminal neuropathic pain

“…As described in the Introduction, research into the mechanisms of chronic pain, and studies of potential therapies for chronic pain, have been complicated by the absence of a consensus on reliable, objective and reproducible pain metrics (Mogil, 2009). This shortcoming is particularly acute in studies attempting to quantify ongoing, or “spontaneous” pain, and the affective aspects of pain (Bonasera et al, 2015, Craig, 2009, Mogil, 2009, Tappe-Theodor and Kuner, 2014). Mogil and collaborators addressed these shortcomings by developing the mouse grimace scale (Langford et al, 2010), and, later, the rat grimace scale (Sotocinal et al, 2011).…”

Repetitive Blast Promotes Chronic Aversion to Neutral Cues Encountered in the Peri-Blast Environment

“…There were no statistically significant weight differences between 1x sham (n = 9) and 3x sham (n = 18)-treated mice (24h post-exposure: Student's unpaired t-test, t [25]=0.355, p>0.05;. 72h post-exposure: Student's unpaired t-test, t [25]=0.9368, p>0.05), thus, 1x and 3x sham animals at each time point were pooled together for subsequent weight analyses. A subset of animals was sacrificed 30 minutes following the last exposure and trunk blood was collected.…”

“…To test these ideas, we examined acute physiological and behavioral stress responses to blast exposure and used place conditioning to measure avoidance and examine behavioral (locomotion and vocalizations) and physiological (corticosterone production) stress responses provoked by re-exposure to blast-related cues. Ultrasonic vocalizations (USVs) are thought to vary with behavioral context, with lower kHz USVs primarily seen during aversive scenarios such as restraint stress or social isolation (25)(26)(27), thereby providing a sensitive readout of the animals' affective state.…”