Prepulse Inhibition Of Startle Response Research Articles

Prepulse inhibition of startle response and working memory are affected by acute stress induction: results from a psychophysiological approach

Prepulse inhibition of startle response and working memory are affected by acute stress induction: results from a psychophysiological approach

Pharmacokinetics, systemic toxicity, thermoregulation and acute behavioural effects of 25CN-NBOMe.

N-(2-methoxybenzyl)phenethylamines (NBOMes) are a family of potent 5-HT2A agonists containing substances emerging on the illicit drug market as a replacement for N,N-diethyllysergamide (LSD). Despite the increasing use of NBOMes for diagnostic, research and recreational purposes, only a limited number of studies have focussed on their in vivo effect. Here, we investigated pharmacokinetics, systemic toxicity, thermoregulation in individually and group-housed animals, and acute behavioural effects after subcutaneous administration of 2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)benzonitrile (25CN-NBOMe; 0.2, 1, and 5 mg/kg) in Wistar rats. Drug concentration peaked 1 h after the administration of 5 mg/kg in both blood serum and brain tissue with a half-life of 1.88 and 2.28 h, respectively. According to Organisation for Economic Co-operation and Development 423 toxicity assay, the drug is classified into category 3 with a lethal dose of 300 mg/kg and an estimated LD50 value of 200 mg/kg. Histological examination of organs collected from rats injected with the lethal dose revealed subtle pathological changes, highly suggestive of acute cardiovascular arrest due to malignant arrhythmia. Altered thermoregulation after 5 mg/kg was demonstrated by reduced body temperature in individually housed rats (p < 0.01). Behavioural effects assessed by the Open Field test and Prepulse Inhibition of Startle Response revealed that the two lower doses (0.2 and 1 mg/kg) caused a reduction in locomotor activity (p < 0.01), increased anxiety (p < 0.05) and 5 mg/kg additionally impaired sensorimotor gating (p < 0.001). In summary, 25CN-NBOMe readily passes the blood-brain barrier and exhibits a moderate level of toxicity and behavioural effect comparable with other NBOMes.

Structure-activity relationships of dually-acting acetylcholinesterase inhibitors derived from tacrine on N-methyl-d-Aspartate receptors.

Tacrine is a classic drug whose efficacy against neurodegenerative diseases is still shrouded in mystery. It seems that besides its inhibitory effect on cholinesterases, the clinical benefit is co-determined by NMDAR-antagonizing activity. Our previous data showed that the direct inhibitory effect of tacrine, as well as its 7-methoxy derivative (7-MEOTA), is ensured via a "foot-in-the-door" open-channel blockage, and that interestingly both tacrine and 7-MEOTA are slightly more potent at the GluN1/GluN2A receptors when compared with the GluN1/GluN2B receptors. Here, we report that in a series of 30 novel tacrine derivatives, designed for assessment of structure-activity relationship, blocking efficacy differs among different compounds and receptors using electrophysiology with HEK293cells expressing the defined types of NMDARs. Selected compounds (4 and 5) potently inhibited both GluN1/GluN2A and GluN1/GluN2B receptors; other compounds (7 and 23) more effectively inhibited the GluN1/GluN2B receptors; or the GluN1/GluN2A receptors (21 and 28). QSAR study revealed statistically significant model for the data obtained for inhibition of GluN1/Glu2B at-60 mV expressed as IC50 values, and for relative inhibition of GluN1/Glu2A at+40mV caused by a concentration of 100μM. The models can be utilized for a ligand-based virtual screening to detect potential candidates for inhibition of GluN1/Glu2A and/or GluN1/Glu2B subtypes. Using invivo experiments in rats we observed that unlike MK-801, the tested novel compounds did not induce hyperlocomotion in open field, and also did not impair prepulse inhibition of startle response, suggesting minimal induction of psychotomimetic side effects. We conclude that tacrine derivatives are promising compounds since they are centrally available subtype-specific inhibitors of the NMDARs without detrimental behavioral side-effects.

Rats with elevated genetic risk for metabolic syndrome exhibit cognitive deficiencies when young

Metabolic syndrome (MetS) is a known risk factor for cognitive decline. Using polygenic rat models selectively bred for high and low intrinsic exercise capacity and simultaneously modelling as low and high innate risk factor for MetS respectively, we have previously shown that adult animals with lower exercise capacity/higher MetS risk perform poorly in tasks requiring flexible cognition. However, it is not known whether these deficits in cognition are present already at young age. Also, it is unclear whether the high risk genome is related also to lower-level cognition, such as sensory gating measured as prepulse inhibition. In this study, young and adult (5-8 weeks and ~9 months) rats selectively bred for 36 generations as High-Capacity Runners (HCR) or Low-Capacity Runners (LCR) were tested for behavior in an open field task, modulation of startle reflex, and spatial learning in a T-maze. HCR rats were more active in the open field than LCR rats independent of age. Responses to the startle stimulus habituated to the same extent in LCR compared to HCR rats when young, but as adults, stronger habituation was seen in the HCR animals. The prepulse inhibition of startle response was equally strong in young HCR and LCR animals but the effect was shorter lasting in HCR animals. In T-maze, adult HCR animals unexpectedly showed attenuated learning, but we interpret this finding to stem from differences in motivation rather than learning ability. Overall, in the LCR rats with the risk genome for poor aerobic fitness and MetS, indications of compromised cognitive function are present already at a young age.

A Methyltransferase Inhibitor (Decitabine) Alleviates Intergenerational Effects of Paternal Neonatal Exposure to Anesthesia With Sevoflurane.

Neonatal exposure to sevoflurane induces neurobehavioral and neuroendocrine abnormalities in exposed male rats (generation F0) and neurobehavioral, but not neuroendocrine, abnormalities in their male, but not female, offspring (generation F1). These effects of sevoflurane are accompanied by a hypermethylated neuron-specific K-2Cl (Kcc2) Cl exporter gene in the F0 spermatozoa and the F1 male hypothalamus, while the gene's expression is reduced in the F0 and F1 hypothalamus. We investigated whether inhibition of deoxyribonucleic acid methyltransferases (DNMTs) before paternal sevoflurane exposure could alleviate the anesthetic's F0 and F1 effects. Sprague-Dawley male rats were anesthetized with 2.1% sevoflurane for 5 hours on postnatal day (P) 5 and mated with control females on P90 to generate offspring. The nonselective DNMT inhibitor decitabine (0.5 mg/kg, intraperitoneally) was administered 30 minutes before sevoflurane exposure. The F0 and F1 male rats were evaluated in in vivo and in vitro tests in adulthood. Paternal exposure to sevoflurane induced impaired prepulse inhibition of the acoustic startle response and exacerbated corticosterone responses to stress in F0 males and impaired prepulse inhibition of the startle responses in F1 males. These effects were accompanied in both generations by reduced and increased expressions of hypothalamic Kcc2 and Dnmt3a/b, respectively. Decitabine deterred the effects of paternal exposure to sevoflurane in F0 and F1 males. These results suggest that similar decitabine-sensitive mechanisms regulating expression of multiple genes are involved in the mediation of neurobehavioral abnormalities in sires neonatally exposed to sevoflurane and in their future unexposed male offspring.

Pharmacological Validation of the Prepulse Inhibition of Startle Response in Larval Zebrafish using a Commercial Automated System and Software.

While there is an abundance of commercial and standardized automated systems and software for performing the prepulse inhibition (PPI) assay in rodents, to the best of our knowledge, all PPI assays performed in the zebrafish have, until now, been done using custom made systems which were only available to individual groups. This has thereby presented challenges, particularly with regard to issues of data reproducibility and standardization. In the present work, we generated a protocol that utilizes commercially available automated systems to pharmacologically validate the PPIassay in larval zebrafish. Consistent with published findings, we were able to replicate the results of apomorphine, haloperidol and ketamine on the PPI response of 6 days post-fertilization zebrafish larvae.

Quetiapine lipid core nanocapsules restore prepulse inhibition deficits in a neurodevelopmental model of schizophrenia in male and female rats

Lipid core nanocapsules (LNC) have been extensively studied as a new treatment strategy to improve therapeutic effects of antipsychotic drugs. We investigated the efficacy of quetiapine LNCs (QLNCs) on the poly(i:c) model of schizophrenia in both male and female rats using the pre-pulse inhibition of startle response (PPI) test paradigm after evaluating the outcomes of three different poly(i:c) doses administered to pregnant damns at GD15 on neurodevelopmental outcomes of maternal immune activation (MIA) in adult offspring. QTP solution was not capable of producing a reversal in the sensorimotor gating-disruptive effect caused by the prenatal poly(i:c) exposure. The same dose of QTP given as QLNCs significantly improved PPI-impairment. This is the first study reporting the restoration of the PPI deficits in a neurodevelopmental model of SCZ using LNCs. This is a promising delivery system strategy to improve antipsychotic effects contributing to the development of better SCZ pharmacological treatments.

Chitosan-coated nanocapsules ameliorates the effect of olanzapine in prepulse inhibition of startle response (PPI) in rats following oral administration

In this study, olanzapine-loaded lipid-core nanocapsules were successfully developed and coated with two different chitosan solutions (same concentration of chitosan but either in 1% acetic acid solution or in acetate buffer pH 5.5) aiming to increase the mucoadhesion and the brain delivery of olanzapine in order to improve the antipsychotic effect after oral administration. These nanoformulations underwent a full physicochemical characterization followed by efficacy evaluation in PPI in rats. The formulation selected for the PPI study (nanocapsules coated with chitosan solution in sodium acetate buffer pH 5.5, NCOLA-B) showed pH of 5.9 ± 0.2, diameter of 162 ± 12 nm with polydispersity index of 0.24 ± 0.01, zeta potential of +6.9 ± 0.7 mV, drug content of 1.06 mg.mL−1 with 42.2% of encapsulation efficiency. Moreover, the nanocapsules showed spherical shape by transmission electron microscopy, suitable physical stability by multiple light scattering, control of drug release (dialysis bag method), low viscosity with Newtonian behavior and great mucin adhesion capacity. Unlike olanzapine solution (10 mg.mL−1), NCOLA-B (1 mg.mL−1) prevented the PPI disruption induced by apomorphine (4 mg.kg−1, s.c.) when administered by the oral route. In conclusion, these findings open new possibilities for the nanoformulation composed of nanocapsules coated with chitosan as a novel strategy for olanzapine delivery.

Targeting Glia with N-Acetylcysteine Modulates Brain Glutamate and Behaviors Relevant to Neurodevelopmental Disorders in C57BL/6J Mice.

An imbalance between excitatory (E) glutamate and inhibitory (I) GABA transmission may underlie neurodevelopmental conditions such as autism spectrum disorder (ASD) and schizophrenia. This may be direct, through alterations in synaptic genes, but there is increasing evidence for the importance of indirect modulation of E/I balance through glial mechanisms. Here, we used C57BL/6J mice to test the hypothesis that striatal glutamate levels can be shifted by N-acetylcysteine (NAC), which acts at the cystine-glutamate antiporter of glial cells. Striatal glutamate was quantified in vivo using proton magnetic resonance spectroscopy. The effect of NAC on behaviors relevant to ASD was examined in a separate cohort. NAC induced a time-dependent decrease in striatal glutamate, which recapitulated findings of lower striatal glutamate reported in ASD. NAC-treated animals were significantly less active and more anxious in the open field test; and NAC-treated females had significantly impaired prepulse inhibition of startle response. This at least partly mimics greater anxiety and impaired sensorimotor gating reported in neurodevelopmental disorders. Thus glial mechanisms regulate glutamate acutely and have functional consequences even in adulthood. Glial cells may be a potential drug target for the development of new therapies for neurodevelopmental disorders across the life-span.

Sensory processing dysfunction in the personal experience and neuronal machinery of schizophrenia.

Sensory processing deficits, first investigated by Kraepelin and Bleuler as possible pathophysiological mechanisms in schizophrenia, are now being recharacterized in the context of our current understanding of the molecular and neurobiological brain mechanisms involved. The National Institute of Mental Health Research Domain Criteria position these deficits as intermediaries between molecular and cellular mechanisms and clinical symptoms of schizophrenia, such as hallucinations. The prepulse inhibition of startle responses by a weaker preceding tone, the inhibitory gating of response to paired sensory stimuli characterized using the auditory P50 evoked response, and the detection of slight deviations in patterns of sensory stimulation eliciting the cortical mismatch negativity potential demonstrate deficits in early sensory processing mechanisms, whose molecular and neurobiological bases are increasingly well understood. Deficits in sensory processing underlie more complex cognitive dysfunction and are in turn affected by higher-level cognitive difficulties. These deficits are now being used to identify genes involved in familial transmission of schizophrenia and to monitor potentially therapeutic drug effects for both treatment and prevention. This research also provides a clinical reminder that patients' sensory perception of the surrounding world, even during treatment sessions, may differ considerably from others' perceptions. A person's ability to understand and interact effectively with the surrounding world ultimately depends on an underlying sensory experience of it.

Auditory cortex is required for fear potentiation of gap detection.

Auditory cortex is necessary for the perceptual detection of brief gaps in noise, but is not necessary for many other auditory tasks such as frequency discrimination, prepulse inhibition of startle responses, or fear conditioning with pure tones. It remains unclear why auditory cortex should be necessary for some auditory tasks but not others. One possibility is that auditory cortex is causally involved in gap detection and other forms of temporal processing in order to associate meaning with temporally structured sounds. This predicts that auditory cortex should be necessary for associating meaning with gaps. To test this prediction, we developed a fear conditioning paradigm for mice based on gap detection. We found that pairing a 10 or 100 ms gap with an aversive stimulus caused a robust enhancement of gap detection measured 6 h later, which we refer to as fear potentiation of gap detection. Optogenetic suppression of auditory cortex during pairing abolished this fear potentiation, indicating that auditory cortex is critically involved in associating temporally structured sounds with emotionally salient events.

Prepulse Inhibition of Startle Response: Recent Advances in Human Studies of Psychiatric Disease

Prepulse inhibition (PPI) is considered to be one of the most promising neurophysiological indexes for translational research in psychiatry. Impairment of PPI has been reported in several psychiatric diseases, particularly schizophrenia, where PPI is considered a candidate intermediate phenotype (endophenotype) of the disease. Recent findings from a variety of research areas have provided important evidence regarding PPI impairment. Human brain imaging studies have demonstrated the involvement of the striatum, hippocampus, thalamus and frontal and parietal cortical regions in PPI. In addition, several genetic polymorphisms, including variations in the genes coding for Catechol O-methyltransferase, Neuregulin 1, nuclear factor kappa-B subunit 3 and serotonin-2A receptor were related to PPI; and these findings support PPI as a polygenetic trait that involves several neurotransmitter pathways. Early psychosis studies suggest that PPI disruption is present before the onset of psychosis. Also, discrepancy of PPI impairment between children and adults can be found in other psychiatric diseases, such as autistic spectrum disorders and posttraumatic stress disorder, and comprehensive investigation of startle response might contribute to understand the impairment of the neural circuitry in psychiatric diseases. Finally, recent studies with both Asian and Caucasian subjects indicate that patients with schizophrenia exhibit impaired PPI, and impaired sensorimotor gating might be a global common psychophysiological feature of schizophrenia. In conclusion, studies of PPI have successfully contributed to a better understanding of the fundamental neural mechanisms underlying sensorimotor gating and will certainly be most valuable in devising future approaches that aim to investigate the complex pathogenesis of psychiatric diseases.

Allopregnanolone infused into the dorsal (CA1) hippocampus increases prepulse inhibition of startle response in Wistar rats

The hippocampus is a brain structure that has traditionally been associated with the pathophysiology and neuropathology of schizophrenia. Also, one of the animal models of schizophrenia most widely accepted and validated is the deterioration of prepulse inhibition (PPI). The hippocampus (both dorsal and ventral) seems to be a brain structure important for the PPI since it appears to contribute to sensorimotor gating. A possible role of neurosteroids in schizophrenia has recently been suggested, as clozapine and olanzapine treatments increase brain and plasma levels of the neurosteroid allopregnanolone (AlloP). The aim of the present work is to investigate the effects of the intrahippocampal administration of neurosteroids on prepulse inhibition. For this purpose, we have bilaterally injected AlloP (0.2 μg/0.5 μl) and pregnenolone sulphate (PregS, 5 ng/0.5 μl) into the dorsal CA1 hippocampus, and we have evaluated PPI behavior. Results show that intrahippocampal AlloP increases PPI ability regardless of prepulse intensity (5, 10 or 15 db above background). Intrahippocampal PregS administration, at the dose tested, does not significantly affect PPI performance. The increase in PPI due to intrahippocampal AlloP administration points out the important role of the hippocampus in central sensorimotor gating mechanisms and on the effects of neurosteroids on this behavior. The present findings may contribute to the study of the neurobiological basis of schizophrenia.

Interactions between corticotropin-releasing factor and the serotonin 1A receptor system on acoustic startle amplitude and prepulse inhibition of the startle response in two rat strains

Both the neuropeptide, corticotropin-releasing factor (CRF) and the serotonin 1A (5-HT1A) receptor systems have been implicated in anxiety disorders and there is evidence that the two systems interact with each other to affect behavior. Both systems have individually been shown to affect prepulse inhibition (PPI) of the acoustic startle response. PPI is a form of sensorimotor gating that is reduced in patients with anxiety disorders including post-traumatic stress and panic disorder. Here, we examined whether the two systems interact or counteract each other to affect acoustic startle amplitude, PPI and habituation of the startle response. In experiment 1, Brown Norway (BN) and Wistar-Kyoto (WKY) rats were administered ether an intraperitoneal (IP) injection of saline or the 5-HT1A receptor agonist, 8-OH-DPAT 10 min prior to receiving an intracerebroventricular (ICV) infusion of either saline or CRF (0.3 μg). In a second experiment, rats were administered either an IP injection of saline or the 5-HT1A receptor antagonist, WAY 100,635 10 min prior to receiving an ICV infusion of saline or CRF. Thirty min after the ICV infusion, the startle response and PPI were assessed. As we have previously shown, the dose of CRF used in these experiments reduced PPI in BN rats and had no effect on PPI in WKY rats. Administration of 8-OH-DPAT alone had no effect on PPI in either rat strain when the data from the two strains were examined separately. Administration of 8-OH-DPAT added to the effect of CRF in BN rats, and the combination of 8-OH-DPAT and CRF significantly reduced PPI in WKY rats. CRF alone had no effect on baseline startle amplitude in either rat strain, but CRF enhanced the 8-OH-DPAT-induced increase in startle in both strains. Administration of WAY 100,635 did not affect the CRF-induced change in PPI and there were no interactions between CRF and WAY 100,635 on baseline startle. The results suggest that activation of the 5-HT1A receptor can potentiate the effect of CRF on endophenotypes of anxiety disorders in animal models.This article is part of a Special Issue entitled ‘Anxiety and Depression’.

AFQ056, a new mGluR5 antagonist for treatment of fragile X syndrome

Fragile X syndrome, the most common form of inherited intellectual disability, is caused by a lack of FMRP, which is the product of the Fmr1 gene. FMRP is an RNA-binding protein and a component of RNA-granules found in the dendrites of neurons. At the synapse, FMRP is involved in regulation of translation of specific target mRNAs upon stimulation of mGluR5 receptors.In this study, we test the effects of a new mGluR5 antagonist (AFQ056) on the prepulse inhibition of startle response in mice. We show that Fmr1 KO mice have a deficit in inhibition of the startle response after a prepulse and that AFQ056 can rescue this phenotype. We also studied the effect of AFQ056 on cultured Fmr1 KO hippocampal neurons; untreated neurons showed elongated spines and treatment resulted in shortened spines. These results suggest that AFQ056 might be a potent mGluR5 antagonist to rescue various aspects of the fragile X phenotype.

Behavioural and cognitive abnormalities in an imprinting centre deletion mouse model for Prader–Willi syndrome

The genes in the imprinted cluster on human chromosome 15q11-q13 are known to contribute to psychiatric conditions such as schizophrenia and autism. Major disruptions of this interval leading to a lack of paternal allele expression give rise to Prader-Willi syndrome (PWS), a neurodevelopmental disorder with core symptoms of a failure to thrive in infancy and, on emergence from infancy, learning disabilities and over-eating. Individuals with PWS also display a number of behavioural problems and an increased incidence of neuropsychiatric abnormalities, which recent work indicates involve aspects of frontal dysfunction. To begin to examine the contribution of genes in this interval to relevant psychological and behavioural phenotypes, we exploited the imprinting centre (IC) deletion mouse model for PWS (PWS-IC(+/-)) and the five-choice serial reaction time task (5-CSRTT), which is primarily an assay of visuospatial attention and response control that is highly sensitive to frontal manipulations. Locomotor activity, open-field behaviour and sensorimotor gating were also assessed. PWS-IC(+/-) mice displayed reduced locomotor activity, increased acoustic startle responses and decreased prepulse inhibition of startle responses. In the 5-CSRTT, the PWS-IC(+/-) mice showed deficits in discriminative response accuracy, increased correct reaction times and increased omissions. Task manipulations confirmed that these differences were likely to be due to impaired attention. Our data recapitulate several aspects of the PWS clinical condition, including findings consistent with frontal abnormalities, and may indicate novel contributions of the imprinted genes found in 15q11-q13 to behavioural and cognitive function generally.

Allopregnanolone has no effect on startle response and prepulse inhibition of startle response in patients with premenstrual dysphoric disorder or healthy controls

Background Allopregnanolone is an endogenous neuroactive steroid which, through the binding to the GABA A receptor, enhances inhibitory neurotransmission and exerts anxiolytic, sedative and antiepileptic effects. Following acute administration, allopregnanolone reliably acts as an anxiolytic compound. The primary aim of this study was to investigate if allopregnanolone, administered to healthy women and women with premenstrual dysphoric disorder (PMDD), would have an anxiolytic effect, expressed as a decreased startle response. Materials and methods Sixteen PMDD patients and twelve healthy controls completed the study. The participants were scheduled for the startle tests twice in the luteal phase. During the test sessions an intravenous allopregnanolone and placebo bolus injection was administered in double-blinded, randomized order at intervals of 48 h. Following the allopregnanolone/placebo injections startle response and prepulse inhibition of startle response (PPI) were assessed by electromyography. Results Following the intravenous allopregnanolone administration the serum concentrations of allopregnanolone increased to 50–70 nmol/l, corresponding to levels that are seen during pregnancy. The obtained serum concentrations of allopregnanolone were significantly lower in PMDD patients than among the healthy controls, p < 0.05. The allopregnanolone injection resulted in significant increases of self-rated sedation in both groups, p < 0.01. Allopregnanolone did not induce any changes in startle response or prepulse inhibition of startle response in comparison to placebo. No differences in allopregnanolone-induced changes in startle response or PPI could be detected between PMDD patients and controls subjects. Conclusion Startle response and PPI were unaffected by acute intravenous administration of allopregnanolone in PMDD patients and healthy controls.

Reversal of sensorimotor gating abnormalities in Fmr1 knockout mice carrying a human Fmr1 transgene.

Fragile X syndrome is caused by a CGG trinucleotide repeat expansion of the FMR1 gene. Individuals with fragile X display several behavioral abnormalities including hyperactivity, social anxiety, autistic-like features, impaired cognitive processing, and impaired sensorimotor gating. The Fmr1KO mouse model of fragile X exhibits several related behavioral phenotypes such as increased activity and altered social interactions. Individuals with fragile X also have impaired sensorimotor gating as measured using the prepulse inhibition of startle response. The authors have recently shown that Fmr1KO mice with a yeast artificial chromosome containing the human FMR1 gene have corrected or overcorrected abnormal behaviors including hyperactivity and altered social interactions. Here the authors present results from a study examining abnormal sensorimotor gating in Fmr1KO mice. Consistent with previous findings, Fmr1KO mice have increased prepulse inhibition. The KO mice with the yeast artificial chromosome containing the human FMR1 gene had levels of prepulse inhibition comparable to WT mice, indicating not only a correction of this phenotype, but also clearly demonstrating that in mice levels of the fragile X mental retardation protein regulate sensorimotor gating.

Lower levels of prepulse inhibition of startle response in pregnant women compared to postpartum women

During the postpartum period, estradiol and progesterone levels decline from very high levels during late pregnancy to low levels within 48h of parturition. This period is associated with dysphoric states such as the postpartum blues. Animal studies have suggested an enhanced acoustic startle response and deficient prepulse inhibition (PPI) of startle response following progesterone withdrawal and during the postpartum period. The aim of the current study was to compare acoustic startle response and PPI in healthy third trimester pregnant women and healthy postpartum women. Twenty-eight healthy pregnant and 21 healthy postpartum women (examined between 48h and 1 week after delivery) were recruited for the study. In addition, to evaluate the time-course of postpartum changes 11 early postpartum women (examined within 48h following delivery) were included in the study. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of m. Orbicularis Oculi. Twenty pulse-alone trials (115dB 40ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115dB 40ms noise burst preceded at a 100ms interval by 20ms prepulses that were 72, 74, 78 or 86dB. Pregnant women exhibited lower levels of PPI compared to late postpartum women, p<0.05. There was no difference between pregnant women and postpartum women examined within 48h of delivery. There was no difference in startle response or habituation to startle response between pregnant women and either of the two groups of postpartum women. Healthy women display lower levels of PPI during late pregnancy when estradiol and progesterone levels are high compared to the late postpartum period when ovarian steroid levels have declined.

Effects of mood stabilizers on the disruption of prepulse inhibition induced by apomorphine or dizocilpine in mice

The prepulse inhibition of the startle response provides an operational measure of sensorimotor gating in which a weak stimulus presented prior to a startling stimulus reduces the startle response. Prepulse inhibition deficits were observed in patients with several neuropsychiatric disorders, including schizophrenia and acute manic bipolar patients. Valproic acid, carbamazepine and lithium carbonate are frequently used as mood stabilizers in patients with bipolar affective disorder and schizophrenia. However, little is known about the mechanisms of action of mood stabilizers on prepulse inhibition deficits. In this study, we investigated the effects of mood stabilizers on the disruption of prepulse inhibition of the acoustic startle response induced by either apomorphine or dizocilpine in mice. Valproate (30–300 mg/kg, i.p.), carbamazepine (3–30 mg/kg, i.p.) and lithium carbonate (10–100 mg/kg, p.o.) had any effect on prepulse inhibition by itself. Valproate, carbamazepine and lithium carbonate reversed the disruption of prepulse inhibition induced by apomorphine (1 mg/kg, s.c.). Although valproate and carbamazepine had no effect on the disruption of prepulse inhibition induced by dizocilpine (0.3 mg/kg, s.c.), lithium carbonate exacerbated the dizocilpine-induced disruption. These results suggest that valproate, carbamazepine and lithium carbonate reverse the disruption of prepulse inhibition through the dopaminergic system.