Startle Inhibition Research Articles

Cannabidiol Administered During Peri-Adolescence Prevents Behavioral Abnormalities in an Animal Model of Schizophrenia.

Schizophrenia is considered a debilitating neurodevelopmental psychiatric disorder and its pharmacotherapy remains problematic without recent major advances. The development of interventions able to prevent the emergence of schizophrenia would therefore represent an enormous progress. Here, we investigated whether treatment with cannabidiol (CBD – a compound of Cannabis sativa that presents an antipsychotic profile in animals and humans) during peri-adolescence would prevent schizophrenia-like behavioral abnormalities in an animal model of schizophrenia: the spontaneously hypertensive rat (SHR) strain. Wistar rats and SHRs were treated with vehicle or CBD from 30 to 60 post-natal days. In experiment 1, schizophrenia-like behaviors (locomotor activity, social interaction, prepulse inhibition of startle and contextual fear conditioning) were assessed on post-natal day 90. Side effects commonly associated with antipsychotic treatment were also evaluated: body weight gain and catalepsy throughout the treatment, and oral dyskinesia 48 h after treatment interruption and on post-natal day 90. In experiment 2, serum levels of triglycerides and glycemia were assessed on post-natal day 61. In experiment 3, levels of BDNF, monoamines, and their metabolites were evaluated on post-natal days 61 and 90 in the prefrontal cortex and striatum. Treatment with CBD prevented the emergence of SHRs’ hyperlocomotor activity (a model for the positive symptoms of schizophrenia) and deficits in prepulse inhibition of startle and contextual fear conditioning (cognitive impairments). CBD did not induce any of the potential motor or metabolic side effects evaluated. Treatment with CBD increased the prefrontal cortex 5-HIAA/serotonin ratio and the levels of 5-HIAA on post-natal days 61 and 90, respectively. Our data provide pre-clinical evidence for a safe and beneficial effect of peripubertal and treatment with CBD on preventing positive and cognitive symptoms of schizophrenia, and suggest the involvement of the serotoninergic system on this effect.

Efficacy of stimulus intensity increases and decreases as inhibitors of the acoustic startle response.

The human startle eyeblink response can be inhibited by a change in the stimulus environment briefly before the startling stimulus; both stimulus presentation (prepulse) and cessation of background sound (gap) can result in startle inhibition. More intense prepulses often result in greater inhibition, and this study (N=53 college students) examined whether graded decreases in sound energy relative to a steady background noise (a "partial gap") would follow this same pattern of inhibition. Embedded in a 65dB steady background noise were 100dB white noise startle stimuli preceded at 120ms on some trials by stimulus intensity increases or decreases of 5, 10, or 15dB relative to background. Results showed that startle inhibition was graded by amount of change relative to background, such that greater increases or decreases resulted in greater inhibition. Also, increases were more effective startle inhibitors than decreases at equivalent levels of change from background. These results demonstrate that the neural centers responsible for startle inhibition are responsive to both increases and decreases in stimulus intensity, and are sensitive to amount of change, not simply whether a change occurs. These findings may have implications for the development of a screening method for a hearing disorder called tinnitus.

Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone

Schizophrenia is a neurodevelopmental disorder likely caused by environmental and genetic risk factors but functional interactions between the risk factors are unclear. We tested the hypothesis that dysbindin-1 (Dtnbp1) gene mutation combined with postnatal exposure to viral mimetic polyI:C results in schizophrenia-related behavioural changes in adulthood, and mediates polyI:C-induced inflammation in the subventricular zone (SVZ). Adult Sandy (Sdy, Dtnbp1 mutant) mice given early postnatal polyI:C injections displayed reduced prepulse inhibition of startle, reduced locomotion and deficits in novel object recognition. PolyI:C induced a canonical immune response in the SVZ; it increased mRNA expression of its toll-like receptor 3 (Tlr3) and downstream transcription factors RelA and Sp1. PolyI:C also increased SVZ Dtnbp1 mRNA expression, suggesting dysbindin-1 regulates immune responses. Dysbindin-1 loss in Sdy mice blocked the polyI:C-induced increases in mRNA expression of Tlr3, RelA and Sp1 in the SVZ. Dtnbp1 overexpression in SVZ-derived Sdy neurospheres rescued Tlr3, RelA and Sp1 mRNA expression supporting a functional interaction between dysbindin-1 and polyI:C-induced inflammation. Immunohistochemistry showed higher Iba1+ immune cell density in the SVZ of Sdy mice than in WT postnatally. PolyI:C did not alter SVZ Iba1+ cell density but increased CD45+/Iba1− cell numbers in the SVZ of Sdy mice. Finally, polyI:C injections in Sdy, but not WT mice reduced postnatal and adult SVZ proliferation. Together, we show novel functional interactions between the schizophrenia-relevant dysbindin-1 gene and the immune response to polyI:C. This work sheds light on the molecular basis for amplified abnormalities due to combined genetic predisposition and exposure to environmental schizophrenia risk factors.

Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane exposure to the next generation of male, but not female, rats

BackgroundClinical studies report learning disabilities and attention-deficit/hyperactivity disorders in those exposed to general anaesthesia early in life. Rats, primarily males, exposed to GABAergic anaesthetics as neonates exhibit behavioural abnormalities, exacerbated responses to stress, and reduced expression of hypothalamic K+-2Cl− Cl− exporter (Kcc2). The latter is implicated in development of psychiatric disorders, including male predominant autism spectrum disorders. We tested whether parental early life exposure to sevoflurane, the most frequently used anaesthetic in paediatrics, affects the next generation of unexposed rats. MethodsOffspring (F1) of unexposed or exposed to sevoflurane on postnatal day 5 Sprague-Dawley rats (F0) were subjected to behavioural and brain gene expression evaluations. ResultsMale, but not female, progeny of sevoflurane-exposed parents exhibited abnormalities in behavioural testing and Kcc2 expression. Male F1 rats of both exposed parents exhibited impaired spatial memory and expression of hippocampal and hypothalamic Kcc2. Offspring of only exposed sires had abnormalities in elevated plus maze and prepulse inhibition of startle, but normal spatial memory and impaired expression of hypothalamic, but not hippocampal, Kcc2. In contrast to exposed F0, their progeny exhibited normal corticosterone responses to stress. Bisulphite sequencing revealed increased CpG site methylation in the Kcc2 promoter in F0 sperm and F1 male hippocampus and hypothalamus that was in concordance with the changes in Kcc2 expression in specific F1 groups. ConclusionsNeonatal exposure to sevoflurane can affect the next generation of males through epigenetic modification of Kcc2 expression, while F1 females are at diminished risk.

Antibody-mediated stabilization of NRG1 induces behavioral and electrophysiological alterations in adult mice

Neuregulin 1 (NRG1) is required for development of the central and peripheral nervous system and regulates neurotransmission in the adult. NRG1 and the gene encoding its receptor, ERBB4, are risk genes for schizophrenia, although how alterations in these genes disrupt their function has not been fully established. Studies of knockout and transgenic mice have yielded conflicting results, with both gain and loss of function resulting in similar behavioral and electrophysiological phenotypes. Here, we used high affinity antibodies to NRG1 and ErbB4 to perturb the function of the endogenous proteins in adult mice. Treatment with NRG1 antibodies that block receptor binding caused behavioral alterations associated with schizophrenia, including, hyper-locomotion and impaired pre-pulse inhibition of startle (PPI). Electrophysiological analysis of brain slices from anti-NRG1 treated mice revealed reduced synaptic transmission and enhanced paired-pulse facilitation. In contrast, mice treated with more potent ErbB4 function blocking antibodies did not display behavioral alterations, suggesting a receptor independent mechanism of the anti-NRG1-induced phenotypes. We demonstrate that anti-NRG1 causes accumulation of the full-length transmembrane protein and increases phospho-cofilin levels, which has previously been linked to impaired synaptic transmission, indicating enhancement of non-canonical NRG1 signaling could mediate the CNS effects.

Startling Differences: Using the Acoustic Startle Response to Study Sex Differences and Neurosteroids in Affective Disorders.

Neuroactive steroid hormones, such as estradiol and progesterone, likely play a role in the pathophysiology of female-specific psychiatric disorders such as premenstrual dysphoric disorder (PMDD) and postpartum depression and may contribute to the marked sex differences observed in the incidence and presentation of affective disorders. However, few tools are available to study the precise contributions of these neuroactive steroids (NSs). In this review, we propose that the acoustic startle response (ASR), an objective measure of an organism's response to an emotional context or stressor, is sensitive to NSs. As such, the ASR represents a unique translational tool that may help to elucidate the contribution of NSs to sex differences in psychiatric disorders. Findings suggest that anxiety-potentiated startle (APS) and prepulse inhibition of startle (PPI) are the most robust ASR paradigms for assessing contribution of NSs to affective disorders, while affective startle response modulation (ASRM) appears less diagnostic of sex or menstrual cycle (MC) effects. However, few studies have appropriately used ASR to test a priori hypotheses about sex or MC differences. We recommend that ASR studies account for sex as a biological variable (SABV) and hormonal status to further knowledge of NS contribution to affective disorders.

How do stimulant treatments for ADHD work? Evidence for mediation by improved cognition.

Stimulant medications such as methylphenidate (MPH) are the frontline treatment for Attention-Deficit/Hyperactivity Disorder (ADHD). Despite their well-documented efficacy, the mechanisms by which stimulants improve clinical outcomes are not clear. The current study evaluated whether MPH effects on classroom behavior were mediated by improved cognitive functioning. Children with ADHD (n=82; 9-12years old) participated in a week-long summer research camp, consisting of cognitive testing, classroom periods, and recreational activities. After a baseline day, participants completed a 3-day randomized, double-blind, placebo-controlled trial of MPH (at doses approximating 0.3 and 0.6mg/kg of immediate-release MPH dosed TID). Cognitive domains included inhibitory control (Stop Signal Task and prepulse inhibition of startle), attention (Continuous Performance Task and reaction time variability), and working memory (forward and backward spatial span). Clinical outcomes included math seatwork productivity and teacher-rated classroom behavior. A within-subjects path-analytic approach was used to test mediation. MPH-placebo and dose-response contrasts were used to evaluate drug effects. Methylphenidate improved seatwork productivity and teacher ratings (ds=1.4 and 1.1) and all domains of cognition (ds=0.3-1.1). Inhibitory control (Stop Signal Task, SST) and working memory backward uniquely mediated the effect of MPH (vs. placebo) on productivity. Only working memory backward mediated the impact of MPH on teacher-rated behavior. The dose-response (0.6 vs. 0.3mg/kg) effects were more modest for clinical outcomes (ds=0.4 and 0.2) and cognition (ds=0-0.3); there was no evidence of cognitive mediation of the clinical dose-response effects. These findings are novel in demonstrating that specific cognitive processes mediate clinical improvement with stimulant treatment for ADHD. They converge with work on ADHD theory, neurobiology, and treatment development in suggesting that inhibitory control and working memory may be mechanisms of stimulant treatment response in ADHD. More work is necessary to evaluate the degree to which these findings generalize to chronic treatment, a broader array of clinical outcomes, and nonstimulant treatments.

A schizophrenia-like behavioral trait in the SHR model: Applying confirmatory factor analysis as a new statistical tool

Questionnaires that assess symptoms of schizophrenia patients undergo strict statistical validation, often using confirmatory factor analysis (CFA). CFA allows testing the existence of a trait that both collectively explains the symptoms and gathers the information in a single general index. In rodents, some behaviors are used to model psychiatric symptoms, but no single test or paradigm adequately captures the disorder's phenotype in toto. This work investigated the existence of a behavioral trait in the SHR strain underlying five behavioral tasks used in schizophrenia animal studies and altered in this strain: locomotor activity, rearing behavior, social interaction, prepulse inhibition of startle and contextual fear conditioning. The analysis was conducted on a sample of Wistar (n = 290) and Spontaneously Hypertensive Rats (SHRs, n = 290). CFA showed the existence of a continuous trait in both strains, and higher values among SHRs. This work is the first to demonstrate the existence of a schizophrenia-like trait in an animal model. We suggest that using CFA to evaluate behavioral parameters in animals might facilitate the pre-clinical investigation of psychiatric disorders, diminishing the gap between animal and human studies.

Synthesis of chiral GABAA receptor subtype selective ligands as potential agents to treat schizophrenia as well as depression.

A series of novel imidazobenzodiazepine analogs of the lead chiral ligand SH-053-2'F-S-CH3 (2), an α2/α3/α5 (Bz)GABA (A)ergic receptor subtype selective ligand, which reversed PCP-induced prepulse inhibition (PPI) of acoustic startle, were synthesized. These chiral (S)-CH3 ligands are targeted for the treatment of schizophrenia and depression. These new ligands were designed by modifying the liable ester functionality in 2 to improve the metabolic stability, cytotoxicity, and activity as compared to 2. Based on the data to date, the most promising ligands are the N-cyclopropyl amide GL-I-55 (8c) and the methyl bioisostere GL-I-65 (9a). The in vitro metabolic stability, cytotoxicity and in vivo locomotor effects are described in this report. Based on these results, 8c and 9a are the most promising for further in vivo pharmacology.

Long-term Administration of Salicylate-induced Changes in BDNF Expression and CREB Phosphorylation in the Auditory Cortex of Rats.

Hypothesis:We investigated whether salicylate induces tinnitus through alteration of the expression levels of brain-derived neurotrophic factor (BDNF), proBDNF, tyrosine kinase receptor B (TrkB), cAMP-responsive element-binding protein (CREB), and phosphorylated CREB (p-CREB) in the auditory cortex (AC).Background:Salicylate medication is frequently used for long-term treatment in clinical settings, but it may cause reversible tinnitus. Salicylate-induced tinnitus is associated with changes related to central auditory neuroplasticity. Our previous studies revealed enhanced neural activity and ultrastructural synaptic changes in the central auditory system after long-term salicylate administration. However, the underlying mechanisms remained unclear.Methods:Salicylate-induced tinnitus-like behavior in rats was confirmed using gap prepulse inhibition of acoustic startle and prepulse inhibition testing, followed by comparison of the expression levels of BDNF, proBDNF, TrkB, CREB, and p-CREB. Synaptic ultrastructure was observed under a transmission electron microscope.Results:BDNF and p-CREB were upregulated along with ultrastructural changes at the synapses in the AC of rats treated chronically with salicylate (p < 0.05, compared with control group). These changes returned to normal after 14 days of recovery (p > 0.05).Conclusion:Long-term administration of salicylate increased BDNF expression and CREB activation, upregulated synaptic efficacy, and changed synaptic ultrastructure in the AC. There may be a relationship between these factors and the mechanism of tinnitus.

Characterization of Behavioral, Signaling and Cytokine Alterations in a Rat Neurodevelopmental Model for Schizophrenia, and Their Reversal by the 5-HT6 Receptor Antagonist SB-399885

Post-weaning social isolation of rats produces neuroanatomical, neurochemical and behavioral alterations resembling some core features of schizophrenia. This study examined the ability of the 5-HT6 receptor antagonist SB-399885 to reverse isolation-induced cognitive deficits, then investigated alterations in hippocampal cell proliferation and hippocampal and frontal cortical expression of selected intracellular signaling molecules and cytokines. Male Lister hooded rats (weaned on post-natal days 21–24 and housed individually or in groups of 3–4) received six i.p. injections of vehicle (1% Tween 80, 1 mL/kg) or SB-399885 (5 or 10 mg/kg) over a 2-week period starting 40 days post-weaning, on the days that locomotor activity, novel object discrimination (NOD), pre-pulse inhibition of acoustic startle and acquisition, retention and extinction of a conditioned freezing response (CFR) were assessed. Tissue was collected 24 h after the final injection for immunohistochemistry, reverse-phase protein microarray and western blotting. Isolation rearing impaired NOD and cue-mediated CFR, decreased cell proliferation within the dentate gyrus, and elevated hippocampal TNFα levels and Cdc42 expression. SB-399885 reversed the NOD deficit and partially normalized CFR and cell proliferation. These effects were accompanied by altered expression of several members of the c-Jun N-terminal Kinase (JNK) and p38 MAPK signaling pathways (including TAK1, MKK4 and STAT3). Although JNK and p38 themselves were unaltered at this time point hippocampal TAK1 expression and phosphorylation correlated with visual recognition memory in the NOD task. Continued use of this neurodevelopmental model could further elucidate the neurobiology of schizophrenia and aid assessment of novel therapies for drug-resistant cognitive symptoms.

An Evaluation of Neurotoxicity Following Fluoride Exposure from Gestational Through Adult Ages in Long-Evans Hooded Rats

At elevated levels, fluoride (F−) exposure has been associated with adverse human health effects. In rodents, F− exposure has been reported to induce deficits in motor performance and learning and memory. In this study, we examined Long-Evans hooded male rats maintained on a standard diet (20.5 ppm F−) or a low F− diet (3.24 ppm F−) with drinking water exposure to 0, 10, or 20 ppm F− from gestational day 6 through adulthood. At postnatal day 25, brain F− levels were 0.048 or 0.081 μg/g and femur 235 or 379.8 μg/g for 10 and 20 ppm F−, respectively. Levels increase with age and in adults, levels for plasma were 0.036 or 0.025 μg/ml; for the brain 0.266 or 0.850 μg/g; and for the femur, 681.2 or 993.4 μg/g. At these exposure levels, we observed no exposure-related differences in motor, sensory, or learning and memory performance on running wheel, open-field activity, light/dark place preference, elevated plus maze, pre-pulse startle inhibition, passive avoidance, hot-plate latency, Morris water maze acquisition, probe test, reversal learning, and Y-maze. Serum triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH) levels were not altered as a function of 10 or 20 ppm F− in the drinking water. No exposure-related pathology was observed in the heart, liver, kidney, testes, seminal vesicles, or epididymides. Mild inflammation in the prostate gland was observed at 20 ppm F−. No evidence of neuronal death or glial activation was observed in the hippocampus at 20 ppm F−.

Developmental neurotoxicity in the progeny after maternal gavage with chlorpyrifos

Today, developmental intellectual disorders affect one out of six children in industrialised countries. Intensively used in agriculture, the neurotoxicant pesticide chlorpyrifos (CPF) is known for its environmental persistence and bioaccumulation. Its role has not yet been established in the aetiology of intellectual impairments. Here we assessed whether maternal ingestion of low CPF dose in rats could impair the cerebral function of their progeny.Rat dams received daily CPF exposures (1 mg/kg, per os) during gestation and lactation. Behaviours relevant to mental retardation were measured in the surface righting, negative geotaxis and grip strength at post-natal days (PND) 3 and 7. Open field tests were performed at PND 16, 18 and 20. Fear conditioning was assessed at PND 34. Startle inhibition was tested at PND 31 and 60.According to the results, the progeny of CPF-treated dams showed slower negative geotaxis as neonates, lower novelty exploration as juveniles and faster startle reflex as adolescents and adults.This data suggests that developmental CPF relevant to human exposure may impair novelty-related activity and sensori-motor functions, thus adaptability to the environment. This data supports the hypothesis that CPF may contribute to behavioural disorders including acquisition retardation and consequences as an adult.

Alteration of adaptive behaviors of progeny after maternal mobile phone exposure.

Exposure of pregnant women to radiofrequency (RF) devices raises questions on their possible health consequences for their progeny. We examined the hazard threshold of gestational RF on the progeny's glial homeostasis, sensory-motor gating, emotionality, and novelty seeking and tested whether maternal immune activation would increase RF toxicity. Pregnant dams were daily restrained with loop antennas adjoining the abdomen (fetus body specific absorption rates (SAR): 0, 0.7, or 2.6W/kg) and received three lipopolysaccharide (LPS) intra-peritoneal injections (0 or 80μg/kg). Scores in the prepulse startle inhibition, fear conditioning, open field, and elevated plus maze were assessed at adolescence and adulthood. Glial fibrillary acidic protein (GFAP) and interleukines-1β (ILs) were quantified. LPS induced a SAR-dependent reduction of the prepulse startle inhibition in adults. Activity in the open field was reduced at 2.6W/kg at adolescence. GFAP and ILs, emotional memory, and anxiety-related behaviors were not modified. These data support the hypothesis that maternal immune activation increased the developmental RF exposure-induced long-term neurobiological impairments. These data support the fact that fetuses who receive combined environmental exposures with RF need special attention for protection.

Neural correlates of perceptual separation-induced enhancement of prepulse inhibition of startle in humans

Prepulse inhibition (PPI) is the suppression of the startle reflex when the intense startling stimulus is shortly preceded by a weaker non-startling stimulus (prepulse). In rats, the auditory precedence-effect-induced perceived spatial separation between the fear-conditioned prepulse and a noise masker facilitates selective attention to the prepulse and enhances PPI. However, whether the perceptual separation between the prepulse and a noise masker can also enhance PPI in humans remains unclear. Also, the relationship between the PPI enhancement and the change in early cortical representations of prepulse signals is unclear. This study for the first time reveals that in a sound-attenuated laboratory environment, relative to the listening condition with perceptual co-location between the prepulse stimulus and a noise-masking stimulus, the perceptual separation between the two stimuli significantly enhances the group-mean PPI. More importantly, the early cortical responses (N1/P2 complex) to the prepulse stimulus are also enhanced by the perceptual separation in most listeners, and the perceptual-separation-induced enhancement of the N1 component is positively correlated with the perceptual-separation-induced PPI enhancement. Thus, the perceptual separation enhances PPI through facilitating selective attention to the prepulse, leading to an enhancement of the early cortical representation of the prepulse signal in temporal auditory cortical fields.

Periconceptional folate deficiency leads to autism-like traits in Wistar rat offspring

BackgroundFolates in their role as key one carbon donors, are essential for two major pathways: the synthesis of DNA and RNA precursors and DNA methylation. A growing body of evidence from epidemiological studies indicates a possible association between nutritional and functional deficiency in folates and Autism Spectrum Disorders (ASD). However, there are no available behavioral animal studies on periconceptional one‑carbon donor deficiency during gestation and the autistic phenotype. ObjectiveThe objective of this study was to determine if the periconceptional alteration of one‑carbon metabolism induced with a folate deficient diet would affect the behaviour of rat offspring. MethodsFemale Wistar rats were divided in two groups: control (basal diet, in compliance with standards of regular laboratory diets), or exposed during one month before breeding until Gestational Day 15 to a modified diet with no added folic acid (0.2mg/kg of food), reduced choline (750mg/kg of food), and added 1% SST (a non-absorbable antibiotic used to inhibit folate synthesis by gut bacteria). We administered behavioral tests to offspring, i.e., open field (P20), social interactions (P25), marble burying (P30), elevated plus maze (P35), and prepulse inhibition of the acoustic startle reflex (sensorimotor gating) (P45). Blood homocysteine levels were used to confirm the deficit in one‑carbon donors. ResultsCompared to controls, offspring with the periconceptional deficit in folate showed: (i) congenital body malformations; (ii) reduced social interactions, with a ~30% decrease in social sniffing behavior; (iii) reduced exploration of the open arm by 50% in the elevated plus maze test, indicating increased anxiety; (iv) a ~160% increased number of marbles buried, indicating repetitive behaviors; and (v) altered sensorimotor gating, with a global 50% decrease in startle inhibition. ConclusionMaternal periconceptional deficit in folate provokes alterations in the behavior of offspring relevant to the autistic-like phenotype.

Divergent Responses in the Gap Prepulse Inhibition of the Acoustic Startle Reflex in Two Different Guinea Pig Colonies.

Animal models of tinnitus rely on interpretation of behavioural or reflexive tests to determine the presence of this phantom perception. A commonly used test is the gap prepulse inhibition of acoustic startle (GPIAS), which is often combined with prepulse inhibition (PPI) to ensure that reduced GPIAS suppression is not due to hearing loss caused by the acoustic trauma commonly used to trigger tinnitus development. In our laboratory GPIAS and PPI are routinely used on two colonies of outbred tri-colour guinea pigs. However, our results show that these colonies show divergent results even before any tinnitus-inducing treatment, which impacts their suitability in tinnitus models. Although colony 1 and 2 show similar results in PPI (~95% of animals showing significant suppression), only ~30% of colony 2 also shows significant suppression in GPIAS compared to ~75% of colony 1. Cochlear sensitivity measured using compound action potentials showed no significant differences between colonies. Therefore, peripheral threshold loss was excluded as a possible factor. Our results show that similar strains of laboratory animals can show highly divergent results and GPIAS testing for tinnitus will not work for every animal strain. In addition, our data support the notion that PPI and GPIAS responses may rely on different neural circuitry.

Assessing Prepulse Inhibition of Startle in Mice.

Animal models are an important tool for studying neuropsychiatric disorders. However, a major challenge for researchers working with laboratory rodents is trying to reproduce 'core' symptoms of complex human disorders such as schizophrenia. Despite this challenge, however, it is still conceivable to use animal models designed to reproduce some of the disease's 'endo-phenotypes'. One example is the prepulse inhibition (PPI) of the startle reflex. PPI is a form of startle plasticity and is characterized by a normal reduction in startle magnitude that occurs when an intense startling stimulus (or pulse) is preceded by a weaker pre-stimulus (or prepulse). The PPI paradigm is commonly used to evaluate sensorimotor gating and it has been described in numerous species including humans and rodents. Deficits in PPI have been observed in subjects with schizophrenia and other neuropsychiatric diseases, as well as in established animal models of these disorders. The PPI paradigm is therefore largely used to explore genetic and neurobiological mechanisms underlying the sensorimotor gating phenotypes found in these disorders. Thus, it is necessary to set up reliable and reproducible protocols to study PPI in mice.

Effects of Amphetamine on Sensorimotor Gating and Neurocognition in Antipsychotic-Medicated Schizophrenia Patients.

Prepulse inhibition (PPI) of startle is being explored both as an indicator of target engagement for, and a biomarker predicting the sensitivity to, procognitive effects of drugs. We now report the effects of the pro-attentional drug, d-amphetamine, on PPI and neurocognition in antipsychotic-medicated schizophrenia patients and healthy subjects (HS) who were also tested in a targeted cognitive training (TCT) module. 44 HS and 38 schizophrenia patients completed a double-blind, placebo-controlled crossover study of the effects of a single dose of amphetamine (10 mg po) on PPI and MATRICS Consensus Cognitive Battery (MCCB) performance; TCT results were previously reported from 60 of these subjects. Moderators predicting AMPH sensitivity were assessed, including the rs4680 single-nucleotide polymorphism for catechol-O-methyltransferase (COMT). After placebo, patients exhibited PPI deficits with 60 ms prepulse intervals; these deficits were 'rescued' by amphetamine. The magnitude of amphetamine-enhanced PPI was greater in patients than in HS (p<0.032), and was associated with positive symptoms (p<0.007), antipsychotic load (p<0.015), hedonic effects of AMPH (p<0.003), and with the presence of at least one methionine allele in rs4680 (p<0.008). No significant effects of amphetamine on MCCB performance were detected in either group, though pro-attentional effects of amphetamine in patients were associated with greater amphetamine-enhanced TCT learning. Amphetamine acutely 'normalized' PPI in antipsychotic-medicated schizophrenia patients; no concurrent acute neurocognitive changes were detected by the MCCB. Findings suggest that in the context of appropriate antipsychotic medication, a low dose of amphetamine enhances brain processes associated with higher function in schizophrenia patients, without accompanying changes in MCCB performance.

N-acetyl cysteine reverses bio-behavioural changes induced by prenatal inflammation, adolescent methamphetamine exposure and combined challenges.

Schizophrenia is associated with prenatal inflammation and/or postnatal stressors such as drug abuse, resulting in immune-redox dysfunction. Antioxidants may offer therapeutic benefits. The objective of this study is to investigate N-acetyl cysteine (NAC) as a therapeutic antioxidant to reverse schizophrenia-like bio-behavioural changes in rats exposed to maternal immune activation (MIA), adolescent methamphetamine (MA) or a combination thereof. Sprague-Dawley offspring prenatally exposed to saline/lipopolysaccharide (LPS) received saline or MA (0.2-6mgkg-1 twice daily×16days) during adolescence and divided into LPS, MA and LPS + MA groups. Vehicle/NAC (150mgkg-1×14days) was administered following MA/saline exposure on postnatal day 51-64. Social interaction, novel object recognition and prepulse inhibition (PPI) of startle, as well as regional brain monoamines, lipid peroxidation, plasma reactive oxygen species (ROS) and pro- and anti-inflammatory cytokines (TNF-α; IL-10), were assessed. NAC reversed LPS, MA and LPS + MA-induced anxiety-like social withdrawal behaviours, as well as MA and LPS + MA-induced deficits in recognition memory. PPI deficits were evident in MA, LPS and LPS + MA models, with NAC reversing that following LPS + MA. NAC reversed LPS, MA and LPS + MA-induced frontal cortical dopamine (DA) and noradrenaline (NA) elevations, LPS and LPS + MA-induced frontal cortical 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and striatal NA deficits as well as LPS + MA-induced frontal cortical 5-HT turnover. Decreased IL-10 in the LPS, MA and LPS + MA animals, and increased TNF-α in the LPS and MA animals, was reversed with NAC. NAC also reversed elevated lipid peroxidation and ROS in the LPS and LPS + MA animals. Prenatal LPS, LPS + postnatal MA challenge during adolescence, and to a lesser extent MA alone, promotes schizophrenia-like bio-behavioural changes later in life that are reversed by NAC, emphasizing therapeutic potential for schizophrenia and MA-associated psychosis. The nature and timing of the dual-hit are critical.