Serotonin releasers increase prepulse inhibition in serotonin 1B knockout mice.

Prepulse inhibition (PPI), a normal reduction of the startle response when a weak stimulus precedes a startling one, is reduced in several neuropsychiatric disorders. The serotonin 1B (5-HT1B) receptor's role in modulating PPI was examined using 5-HT-releasing agents in wild-type (WT) and 5-HT1B knockout (1BKO) mice. MDMA and MBDB increased PPI in 1BKO mice but did not alter PPI in WT mice. In intact mice, the 5-HT1B/1D antagonist GR 127935 (3.0 mg/kg) with MDMA also increased PPI, indicating that the lack of the 5-HT1B receptor, not developmental changes, causes the PPI increase. Activation of 5-HT1B receptors by serotonin disrupts PPI.

Study at a glance

Abstract

Prepulse inhibition (PPI) is the normal reduction of the startle response which occurs when an abrupt startling stimulus is preceded by a weak pre-stimulus and is decreased in several neuropsychiatric disorders. The role of the serotonin 1B (5-HT(1B)) receptor in modulating PPI was investigated using 5-HT-releasing agents in wild-type (WT) and 5-HT1B knockout (1BKO) mice. Whether the differential effects of 5-HT-releasing agents on PPI in WT and 1BKO mice resulted from lack of the 5-HT1B receptor or altered development was also assessed. PPI was assessed in WT and 1BKO mice treated with the 5-HT-releasing agents (+)3,4-methylenedioxy-N-methylamphetamine (MDMA: 0, 10 mg/kg) or (+/-)N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB: 0, 10 mg/kg). Additionally, intact 129 Sv mice received pre-treatments of the 5-HT1B/1D antagonist GR 127935 (0, 0.75, 1.5, 3.0 mg/kg) and treatments of MDMA (10 mg/kg). MDMA and MBDB increased PPI in 1BKO mice, but did not alter PPI in WT mice. Intact 129 Sv mice receiving 3.0 mg/kg GR 127935 and 10 mg/kg MDMA exhibited increases in PPI. The ability of GR 127935 to increase PPI in intact MDMA-treated mice suggests that lack of the 5-HT1B receptor, and not altered development, is responsible for the PPI-increasing effects of 5-HT releasers in 1BKO mice. 5-HT release activates multiple 5-HT receptor subtypes, which individually may increase or decrease PPI and together have a combined effect on PPI. Our finding that MDMA and MBDB increase PPI in 1BKO, but not WT mice, indicates that the activation of 5-HT1B receptors by 5-HT disrupts PPI.