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 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.

A novel method for automatic quantification of psychostimulant-evoked route-tracing stereotypy: application to Mus musculus.

RATIONALE: Route-tracing stereotypy is a powerful behavioral correlate of striatal function that is difficult to quantify. Measurements of route-tracing stereotypy in an automated, high throughput, easily quantified, and replicable manner would facilitate functional studies of this central nervous system region. OBJECTIVE: We examined how t-pattern sequential analysis (Magnusson Behav Res Meth Instrum Comput 32:93-110, 2000) can be used to quantify mouse route-tracing stereotypies. This method reveals patterns by testing whether particular sequences of defined states occur within a specific time interval at a probability greater than chance. RESULTS: Mouse home-cage locomotor patterns were recorded after psychostimulant administration (GBR 12909, 0, 3, 10, and 30 mg/kg; d-amphetamine, 0, 2.5, 5, and 10 mg/kg). After treatment with GBR 12909, dose-dependent increases in the number of found patterns and overall pattern length and depth were observed. Similar findings were seen after treatment with d-amphetamine up to the dosage where focused stereotypies dominated behavioral response. For both psychostimulants, detected patterns displayed similar morphological features. Pattern sets containing a few frequently repeated patterns of greater length/depth accounted for a greater percentage of overall trial duration in a dose-dependant manner. This finding led to the development of a t-pattern-derived route-tracing stereotypy score. Compared to scores derived by manual observation, these t-pattern-derived route-tracing stereotypy scores yielded similar results with less within-group variability. These findings remained similar after reanalysis with removal of patterns unmatched after human scoring and after normalization of locomotor speeds at low and high ranges. CONCLUSIONS: T-pattern analysis is a versatile and robust pattern detection and quantification algorithm that complements currently available observational phenotyping methods.