Effects of MDMA (ecstasy) on prepulse inhibition and habituation of startle in humans after pretreatment with citalopram, haloperidol, or ketanserin

Prepulse inhibition (PPI) of the acoustic startle response is an operationa l measure of sensorimotor gating that can be assessed in animals and in hum ans. Serotonin releasers such as MDMA disrupt PPI and reduce startle habitu ation in rodents. These effects are prevented by pretreatment with selectiv e serotonin uptake inhibitors, indicating that the effect of MDMA on startl e plasticity is largely due to carrier-mediated release of serotonin from p resynaptic terminals. In contrast, MDMA has been shown to increase PPI in h umans. It is unclear, however, whether the MDMA-induced increase in PPI in humans is also dependent on carrier-mediated serotonin release and which po stsynaptic receptors are involved. We investigated the effects of three dif ferent pretreatments on the MDMA-induced effects on PPI and habituation in humans. Pretreatments were: (1) the highly selective serotonin uptake inhib itor citalopram (40 mg IV) in 16 subjects, (2) the D-2 antagonist haloperid ol (1.4 mg IV) in 24 subjects, and (3) the 5-HT2A/C antagonist ketanserin ( 50 mg PO) in 14 subjects. Each of the three studies used a double-blind pla cebo-controlled design. All healthy volunteers were examined four times at 2-4-week intervals after placebo, pretreatment, MDMA (1.5 mg/kg PO), and pr etreatment plus MDMA. MDMA increased PPI. Habituation was not altered by MD MA, although MDMA-induced individual differences on habituation and psychol ogical symptoms were inversely correlated. Citalopram attenuated the MDMA-i nduced increase in PPI and most of the psychological effects of MDMA. Neith er haloperidol nor ketanserin had any effect on PPI increases produced by M DMA, although each partially attenuated some MDMA-induced psychological eff ects. Results are consistent with the view that MDMA increases PPI of the a coustic startle reflex in humans via release of presynaptic serotonin. [Neu ropsychopharmacology 24:240-252, 2001] (C) 2001 American College of Neurops ychopharmacology. Published by Elsevier Science Inc.