Estrogen Prevents 5-HT1A Receptor-Induced Disruptions of Prepulse Inhibition in Healthy Women

Abstract

The sex steroid hormone, estrogen, has been proposed to be protective against schizophrenia. This study examined the effects of estrogen treatment on modulation of prepulse inhibition (PPI) by the serotonin-1A (5-HT 1A ) receptor partial agonist, buspirone. PPI is a model of sensorimotor gating, which is deficient in schizophrenia and other mental illnesses. A total of 11 healthy women were tested following four acute treatment conditions: placebo, buspirone (Buspar; 5 mg), estradiol (Estrofem; 2 mg), and combined buspirone and estradiol. Electromyogram activity was measured across three interstimulus intervals (ISI): 30, 60, and 120 ms. There was no significant effect of either drug treatment on startle amplitude or habituation. At 120 ms ISI, buspirone caused a significant disruption of PPI and pretreatment with estrogen prevented this disruption. Estrogen treatment, administered in the appropriate experimental conditions, prevented PPI deficits induced by 5-HT 1A receptor activation and may therefore also play a protective role in sensorimotor gating deficits in schizophrenia.

Differential Effects of Acute Serotonin and Dopamine Depletion on Prepulse Inhibition and P50 Suppression Measures of Sensorimotor and Sensory Gating in Humans

“…Following ATD we observed impairments in sensorimotor gating, as evidenced by a reduction in PPI. This finding directly supports a number of studies that have similarly found a decrease in PPI following a reduction in serotonergic neurotransmission in healthy humans, with ATD (Phillips et al, 2000a), the 5-HT 2 receptor antagonist ketanserin (Graham et al, 2002), and the 5-HT 1A partial agonist buspirone (Gogos et al, 2006). The findings also concur with a number of studies that report the opposite effect (ie an increase in PPI with enhancement of serotonergic neurotransmission) with MDMA (Liechti et al, 2001) and the 5-HT 2A/1A agonist psilocybin (Gouzoulis-Mayfrank et al, 1998;Vollenweider et al, 1999).…”

“…It could be argued that the positive effects of MDMA and psilocybin may be mediated by their effects on other neurotransmitter systems, including dopamine or noradrenaline, rather than their serotonergic actions. However, this is unlikely as we and others have shown a decrease in PPI following ATD (in this study and Phillips et al, 2000a) and with the 5-HT 1A agonist, buspirone (Gogos et al, 2006). It is more likely that effects are related to the potency of serotonergic modulation.…”

“…EMG activity was digitized continuously at 2000 Hz, amplified and band-pass filtered (0.05-500 Hz) using a Neuroscan Synamps system. Acoustic startle testing was similar to the procedure used by Gogos et al (2006) and comprised a total of 24 trials consisting 8 trials of the startle stimuli (ie pulse alone (PA)), to allow for habituation in order to obtain an accurate measure of startle amplitude (Gogos et al, 2006), 8 trials of PA stimuli, and 8 trials each of PA and prepulse stimuli (ie prepulse-PA (PP)), with the trials of PA and PP presented in a pseudo-random order. The inter-trial intervals ranged from 16 to 24 s (M ¼ 20 s).…”

“…%PPI was calculated as (PA-PP/ PA) Â 100, with higher percentages indicating greater inhibition (ie more sensorimotor gating). Following methods used in our previous studies (Gogos et al, 2006), two participants were classified as 'non-responders' and excluded from further statistical analysis, as the peak startle amplitude was less than 0.3 (arbitrary units) in the placebo treatment condition. A third participant was also classified as a non-responder as they did not demonstrate PPI in the placebo treatment condition (ie subjects needed to demonstrate pre-pulse inhibition in the placebo treatment condition to examine the effects of dopamine and serotonin depletion on prepulse inhibition).…”

“…However, the effects of psilocybin on PPI may be dependant on the ISI, with another study finding a decrease in PPI at ISIs of 30 ms, no effects at ISIs of 60 ms, and an increase in PPI at 120-2000 ms (Vollenweider et al, 2007). On the other hand, reducing serotonergic neurotransmission with ketanserin (a non-selective 5-HT 2 receptor antagonist) (Graham et al, 2002) or buspirone (a 5-HT 1A partial agonist acting presynaptically) (Gogos et al, 2006) has been found to reduce PPI. Nevertheless, other studies have found no effects on PPI following enhancement of central serotonin levels with the administration of serotonin reuptake inhibitors, fenfluramine (Abel et al, 2007), fluvoxamine (Phillips et al, 2000b), citalopram (Liechti et al, 2001), and escitalopram (Jensen et al, 2007).…”