Sex-specific effects of psychedelics on prepulse inhibition of startle in 129S6/SvEv mice
Hiba Z. Vohra, J. Saunders, Alaina M. Jaster, M. de la Fuente Revenga, J. Jimenez, A. Fernández-Teruel, J. Wolstenholme, P. Beardsley, J. González-Maeso
Psychopharmacology August 4, 2021 DOI: 10.1007/s00213-021-05913-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled experimental animal study Peer reviewed |
|---|---|
| Population | Male and female 129S6/SvEv mice |
| Interventions | DOI M100 907 LSD apomorphine SKF-82 958 |
| Dose | DOI 0.5 mg/kg i.p.; M100,907 1 mg/kg i.p.; LSD 0.24 mg/kg i.p.; apomorphine 5 mg/kg s.c.; SKF-82,958 0.5 mg/kg i.p. |
| Key findings | DOI increased prepulse inhibition in three of four conditions in male mice and in female mice, with the male effect blocked by the 5-HT2A receptor antagonist M100,907, suggesting receptor-dependent PPI improvement. LSD likewise increased PPI in males, whereas the dopamine agonists apomorphine and SKF-82,958 decreased it. PPI correlated positively with startle amplitude in males and negatively in females. |
Abstract
Prepulse inhibition (PPI) of startle is a sensorimotor gating phenomenon perturbed in a variety of neuropsychiatric conditions. Psychedelics disrupt PPI in rats and humans, but their effects and involvement of the serotonin 5-HT2A receptor (5-HT2AR) in mice remain unexplored. We tested the effect of the psychedelic 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.5 mg/kg, i.p.) on startle amplitude and %PPI in response to acoustic stimuli under up to four different experimental conditions that included changes in background and stimulus intensity, prepulse and pulse duration, and interstimulus interval in male and female 129S6/SvEv mice. We also evaluated the effect of the 5-HT2AR antagonist M100,907 (1 mg/kg, i.p.) on DOI-induced startle amplitude and %PPI, as well as the effect of the psychedelic LSD (0.24 mg/kg, i.p.) and the dopamine agonists apomorphine (5 mg/kg, s.c.) and SKF-82,958 (0.5 mg/kg, i.p.) in male 129S6/SvEv mice. DOI altered startle amplitude with either pulse alone or prepulse + pulse presentations in all PPI conditions, and increased %PPI in three out of four PPI conditions in male mice — an effect that was prevented by M100,907. In female mice, DOI increased %PPI without affecting startle amplitude. %PPI was positively correlated with startle amplitude in males while being negatively correlated in female mice. In male mice, LSD also increased %PPI, although it did not affect startle amplitude, whereas apomorphine and SKF-82,958 induced decreases in %PPI. Our findings highlight a distinct effect of the psychedelic DOI on PPI in 129S6/SvEv mice, suggesting 5-HT2AR-dependent PPI improvement in a paradigm-dependent and sex-dependent manner.