Schizophrenia-like disruptions of sensory gating by serotonin receptor stimulation in rats: Effect of MDMA, DOI and 8-OH-DPAT

Abstract

Schizophrenia pathophysiology is associated with alterations in several neurotransmitter systems, particularly dopamine, glutamate and serotonin (5-HT). Schizophrenia patients also have disruptions in sensory gating, a brain information filtering mechanism in response to repeated sensory stimuli. Dopamine and glutamate have been implicated in sensory gating; however, little is known about the contribution of serotonin. We therefore investigated the effects of several psychoactive compounds that alter serotonergic neuronal activity on event-related potentials (ERP) to paired auditory pulses. Male Sprague-Dawley rats were implanted with cortical surface electrodes to measure ERPs to 150 presentations of two 85 dB bursts of white noise, 500 ms apart (S1 and S2). Saline-treated animals suppressed the response to S2 to less than 50% of S1. In contrast, treatment with the serotonin releaser, MDMA (ecstasy; 2.0mg/kg), the 5-HT2A/2C receptor agonist, DOI (0.5mg/kg), or the 5-HT1A/7 receptor agonist, 8-OH-DPAT (0.5mg/kg), caused an increase in S2/S1 ratios. Analysis of waveform components suggested that the S2/S1 ratio disruption by MDMA was due to subtle effects on the ERPs to S1 and S2; DOI caused the disruption primarily by reducing the ERP to S1; 8-OH-DPAT-induced disruptions were due to an increase in the ERP to S2. These results show that 5-HT receptor stimulation alters S2/S1 ERP ratios in rats. These results may help to elucidate the sensory gating deficits observed in schizophrenia patients.

Pharmacological Mechanisms Involved in Sensory Gating Disruption Induced by (±)-3,4-Methylene- Dioxymethamphetamine (MDMA): Relevance to Schizophrenia

“…A limitation of this study is that, while effects on S2:S1 ratio were highly consistent between the different cohorts and drug studies, there was variability in the amplitude of the individual P and N components of the waveforms, resulting in variability of drug effects on S1 vs. S2. It is unclear why there was this inconsistency although previous studies similarly found some variability of effects on waveform components when comparing MDMA with other serotonergic compounds [25] or following changes in experimental protocol [6,8,52]. Future studies should aim to replicate the present results in larger animal cohorts to reduce experimental variability and more clearly associate drug effects to individual waveform components.…”

“…A 2 mg/kg dose of MDMA ((±) 3,4 methylene-dioxymethamphetamine hydrochloride, Sigma Aldrich, St. Louis, MO, USA) was injected intraperitoneally. This was previously shown to elicit a paired-pulse sensory gating deficit [25]. Pretreatment drugs, haloperidol (Serenace®, Aspen Pharma Pty Ltd, St Leonards, NSW, Australia) 0.25 mg/kg, SCH23390 (Tocris Bioscience, Bristol, UK) 0.1 mg/kg, ketanserin tartrate (Tocris Bioscience, Bristol, UK) 2 mg/kg and WAY100635 maleate (Tocris Bioscience, Bristol, UK) 1 mg/kg, were all injected subcutaneously.…”

“…The reason for the discrepancies between previous results and the current results is unclear but could be related to the behavioural paradigm studied. The fact that both DOI and 8-OH-DPAT can independently disrupt auditory gating [25] suggests that in this paradigm 5-HT2A and 5-HT1A receptors have similar actions to one another. It has also been shown that there is an interdependence of 5 HT1A and 5-HT2A receptors in several other behavioural paradigms.…”

“…The dopamine releaser, amphetamine, caused a disruption of auditory sensory gating in rats, most likely through activation of the dopamine D2 receptor [9] and potentially the D1 receptor [24]. Administration of the 5-HT2A receptor agonist, 1-(2,5 dimethoxy-4-iodophenyl)-2-aminopropane (DOI), or the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), have also been found to cause disruption of auditory sensory gating in rats, suggesting a role for 5-HT2A and 5-HT1A receptors in sensory gating [8,25]. Less is known on the possible interaction of serotonergic and dopaminergic involvement in this mechanism, although one study noted that the 5-HT1A receptor antagonist, UH-301, was able to block the disruption caused by amphetamine [26].…”

“…We previously observed that administration of the serotonin releaser, (±)-3,4 methylenedioxymethamphetamine hydrochloride (MDMA), disrupts sensory gating in rats [25]. This disruption by MDMA was found to be greater than that elicited by DOI or 8-OH-DPAT administration, suggesting that MDMA may be acting upon both 5-HT2A and 5-HT1A receptor subtypes to cause a more robust disruption [25]. MDMA is a potent serotonin releaser, but also affects other neurotransmitter systems, such as dopamine [27].…”