Lower Prepulse Inhibition Research Articles

Hypoxic preconditioning in rats with low and high prepulse inhibition of acoustic startle is implemented through topographically different sensory inputs. Working hypothesis

Hypoxic preconditioning in rats with low and high prepulse inhibition of acoustic startle is implemented through topographically different sensory inputs. Working hypothesis

Investigating acoustic startle habituation and prepulse inhibition with silent functional MRI and electromyography in young, healthy adults.

Startle habituation and prepulse inhibition (PPI) are distinct measures of different sensory information processes, yet both result in the attenuation of the startle reflex. Identifying startle habituation and PPI neural mechanisms in humans has mostly evolved from acoustic-focused rodent models. Human functional magnetic resonance imaging (fMRI) studies have used tactile startle paradigms to avoid the confounding effects of gradient-related acoustic noise on auditory paradigms and blood-oxygen-level-dependent (BOLD) measures. This study aimed to examine the neurofunctional basis of acoustic startle habituation and PPI in humans with silent fMRI. Using silent fMRI and simultaneous electromyography (EMG) to measure startle, the neural correlates of acoustic short-term startle habituation and PPI [stimulus onset asynchronies (SOA) of 60 ms and 120 ms] were investigated in 42 healthy adults (28 females). To derive stronger inferences about brain-behaviour correlations at the group-level, models included EMG-assessed measures of startle habituation (regression slope) or PPI (percentage) as a covariate. A linear temporal modulator was modelled at the individual-level to characterise functional changes in neural activity during startle habituation. Over time, participants showed a decrease in startle response (habituation), accompanied by decreasing thalamic, striatal, insula, and brainstem activity. Startle habituation was associated with the linear temporal modulation of BOLD response amplitude in several regions, with thalamus, insula, and parietal lobe activity decreasing over time, and frontal lobe, dorsal striatum, and posterior cingulate activity increasing over time. The paradigm yielded a small amount of PPI (9-13%). No significant neural activity for PPI was detected. Startle habituation was associated with the thalamus, putamen, insula, and brainstem, and with linear BOLD response modulation in thalamic, striatal, insula, parietal, frontal, and posterior cingulate regions. These findings provide insight into the mediation and functional basis of the acoustic primary startle circuit. Instead, whilst reduced compared to conventional MRI, scanner noise may have disrupted prepulse detection and processing, resulting in low PPI and impacting our ability to map its neural signatures. Our findings encourage optimisation of the MRI environment for acoustic PPI-based investigations in humans. Combining EMG and functional neuroimaging methods shows promise for mapping short-term startle habituation in healthy and clinical populations.

The role of prepulse inhibition in predicting new-onset postpartum depression

Predictive measures for postpartum depression (PPD), which affects around 12% of childbearing women, would enable early, targeted support. Here we explore prepulse inhibition (PPI), a measure of sensorimotor processing, as a biological tool for prediction of women at risk for PPD. Using data from the longitudinal BASIC study in Uppsala, Sweden, we used PPI measures from late pregnancy and reports on depressive symptoms assessed 6 weeks postpartum with the Edinburgh Postnatal Depression Scale to determine the association between pregnancy PPI and PPD. Lower PPI was associated with PPD onset in women who were not depressed during pregnancy. Further studies are encouraged to validate these promising results suggesting PPI as a predictive marker of new-onset PPD.

Stressing out! Effects of acute stress on prepulse inhibition and working memory.

Prepulse inhibition (PPI) of the startle reflex serves as a pre-cognitive marker of sensorimotor gating, and its deficit may predict cognitive impairments. Startle reflex is modulated by many factors. Among them, stress has been a topic of interest, but its effects on both pre-cognitive and cognitive variables continue to yield divergent results. This study aims to analyze the effect of acute stress on PPI of the startle reflex and cognitive function (working memory, attention, inhibition, and verbal fluency). Participants were exposed to the MAST stress induction protocol or a stress-neutral task: stress group (n = 54) or control group (n = 54). Following stress induction, participants' startle responses were recorded, and cognition was assessed. The results revealed that participants in the stress group exhibited greater startle magnitude, lower PPI, and lower scores in working memory tests compared with the control group. Additionally, a correlation was found between working memory and PPI across all the participants, independent of stress group. These findings support the notion that after stress, both greater startle magnitude and diminished PPI could play an adaptive role by allowing for increased processing of stimuli potentially dangerous and stress-related. Similarly, our results lend support to the hypothesis that lower PPI may be predictive of cognitive impairment. Considering the impact of stress on both pre-cognitive (PPI) and cognitive (working memory) variables, we discuss the possibility that the effect of stress on PPI occurs through motivational priming and emphasize the relevance of considering stress in both basic and translational science.

Tobacco withdrawal-induced changes in sensorimotor filtering as a predictor of smoking lapse in trauma-exposed individuals

Prepulse inhibition (PPI) is a measure of sensorimotor filtering thought to shield the processing of initial weaker auditory stimuli from interruption by a later startle response. Previous studies have shown smoking withdrawal to have a negative impact on sensorimotor filtering, particularly in individuals with psychopathology. Because tobacco use may alleviate sensory and sensorimotor filtering deficits, we examined whether smoking withdrawal-induced changes in PPI were associated with maintenance of smoking abstinence in trauma-exposed individuals with and without PTSD who were attempting to quit smoking. Thirty-eight individuals (n = 24 with current or past PTSD; 14 trauma-exposed healthy controls) made an acute biochemically-verified smoking cessation attempt supported by 8 days of contingency management (CM) and cognitive behavioral therapy (CBT) for smoking. Participants completed a PPI task at the pre-quit baseline, 2 days post-quit, and 5 days post-quit. Post-quit changes in PPI were compared between those who remained abstinent for the first 8-days of the quit attempt and those who lapsed back to smoking. PPI changes induced by biochemically-verified smoking abstinence were associated with maintenance of abstinence across the 8-day CM/CBT-supported quit attempt. As compared to those who maintained tobacco abstinence, participants who lapsed to smoking had significantly lower PPI at 2 and 5 days post-quit relative to baseline. Thus, among trauma-exposed individuals, decreases in PPI during acute smoking cessation supported by CM/CBT are associated with lapse back to smoking. Interventions that improve PPI during early smoking abstinence may facilitate smoking cessation among such individuals who are at high risk for chronic, refractory tobacco use.

Low prepulse inhibition predicts lower social interaction, impaired spatial working memory, reference memory and cognitive flexibility in genetically heterogeneous rats

The “Genetically Heterogeneous National Institutes of Health (NIHHS)” stock rat (hereafter HS) shows a wide phenotypic variation, as a result of having been derived from eight inbred rat strains. Thus, these rats may be a conceivable parallel model of a healthy human sample. In order to evaluate whether HS rats have face validity as an animal model of schizophrenia-relevant features, it should be demonstrated that they present behavioural traits that may model negative and cognitive symptoms of the disorder. Previous studies on HS rats have shown that prepulse inhibition (PPI, a measure of sensorimotor gating processes), which is impaired in schizophrenic patients, is correlated with their working memory performance. In this study, we evaluated whether low PPI in the HS stock rat predicts impairments of spatial working memory (SWM), spatial reference memory and cognitive flexibility in the Morris water maze (MWM) test, and we evaluated HS rats for social interaction (SI) in a social investigation task. HS rats were stratified into 2 different groups according to their PPI scores, i.e. low- and high-PPI. In the SI task, low-PPI rats showed decreased social behaviour compared to high-PPI rats. In addition, relative to high-PPI HS rats, the low-PPI group displayed poorer SWM performance, impaired cognitive flexibility (in a reversal task) and worsened long-term spatial memory. Such differential behaviours in social and cognitive paradigms provide evidence on the face validity of low-PPI HS rats as a model of negative-like and cognitive schizophrenia-relevant traits.

Neurobehavioral Profiles of Six Genetically-based Rat Models of Schizophrenia- related Symptoms.

Schizophrenia is a chronic and severe mental disorder with high heterogeneity in its symptoms clusters. The effectiveness of drug treatments for the disorder is far from satisfactory. It is widely accepted that research with valid animal models is essential if we aim at understanding its genetic/ neurobiological mechanisms and finding more effective treatments. The present article presents an overview of six genetically-based (selectively-bred) rat models/strains, which exhibit neurobehavioral schizophrenia-relevant features, i.e., the Apomorphine-susceptible (APO-SUS) rats, the Low-prepulse inhibition rats, the Brattleboro (BRAT) rats, the Spontaneously Hypertensive rats (SHR), the Wisket rats and the Roman High-Avoidance (RHA) rats. Strikingly, all the strains display impairments in prepulse inhibition of the startle response (PPI), which remarkably, in most cases are associated with novelty-induced hyperlocomotion, deficits of social behavior, impairment of latent inhibition and cognitive flexibility, or signs of impaired prefrontal cortex (PFC) function. However, only three of the strains share PPI deficits and dopaminergic (DAergic) psychostimulant-induced hyperlocomotion (together with prefrontal cortex dysfunction in two models, the APO-SUS and RHA), which points out that alterations of the mesolimbic DAergic circuit are a schizophrenia-linked trait that not all models reproduce, but it characterizes some strains that can be valid models of schizophrenia-relevant features and drug-addiction vulnerability (and thus, dual diagnosis). We conclude by putting the research based on these genetically-selected rat models in the context of the Research Domain Criteria (RDoC) framework, suggesting that RDoC-oriented research programs using selectively-bred strains might help to accelerate progress in the various aspects of the schizophrenia-related research agenda.

Methamphetamine-induced locomotor sensitization in mice is not associated with deficits in a range of cognitive, affective and social behaviours: interaction with brain-derived neurotrophic factor Val66Met genotype.

Chronic methamphetamine (Meth) abuse may induce psychosis similar to that observed in schizophrenia. Brain-derived neurotrophic factor (BDNF) has been implicated in the development of psychosis. We have previously shown long-term protein expression changes in mice treated chronically with Meth depending on BDNF Val66Met genotype. The aim of this study was to investigate if these protein expression changes were associated with differential changes in a range of behavioural paradigms for cognition, anxiety, social and other behaviours. Male and female Val/Val, Val/Met and Met/Met mice were treated with an escalating Meth dose protocol from 6 to 9 weeks of age, with controls receiving saline injections. Several overlapping cohorts were tested in the Y-maze for short-term spatial memory, novel-object recognition test, context and cued fear conditioning, sociability and social preference, elevated plus maze for anxiety-like behaviour and prepulse inhibition (PPI) of acoustic startle. Finally, the animals were assessed for spontaneous exploratory locomotor activity and acute Meth-induced locomotor hyperactivity. Acute Meth caused significantly greater locomotor hyperactivity in mice previously treated with the drug than in saline-pretreated controls. Meth-pretreated female mice showed a mild increase in spontaneous locomotor activity. There were no Meth-induced deficits in any of the other behavioural tests. Val/Met mice showed higher overall social investigation time and lower PPI compared with the Val/Val genotype independent of pretreatment. These results show limited long-term effects of chronic Meth on a range of cognitive, affective and social behaviours despite marked drug-induced locomotor sensitization in mice. There was no interaction with BDNF Val66Met genotype.

Prospective longitudinal assessment of sensorimotor gating as a risk/resiliency factor for posttraumatic stress disorder.

Little is understood about cognitive mechanisms that confer risk and resiliency for posttraumatic stress disorder (PTSD). Prepulse Inhibition (PPI) is a measure of pre-attentional response inhibition that is a stable cognitive trait disrupted in many neuropsychiatric disorders characterized by poor behavioral or cognitive inhibition, including PTSD. Differentiating between PTSD-related phenotypes that are pre-existing factors vs. those that emerge specifically after trauma is critical to understanding PTSD etiology and can only be addressed by prospective studies. This study tested the hypothesis that sensorimotor gating performance is associated with risk/resiliency for combat-related PTSD. As part of a prospective, longitudinal study,1226active duty Marines and Navy Corpsman completed a PPI test as well as a clinical interview to assess PTSD symptoms both before, and 3 and 6 months after acombat deployment. Participants that developed PTSD 6 months following deployment (N=46) showed lower PPI across pre and post-deployment time pointscompared to participants who did not develop PTSD(N=1182) . Examination of the distribution of PTSD across PPI performance revealed a lower than expected number of cases in the highest performing quartile compared to the rest of the distribution (p < 0.04). When controlling for other factors that predict PTSD in this population, those in the top 25% of PPI performance showed a >50% reduction in chance to develop PTSD (OR = 0.32). Baseline startle reactivity and startle habituation were not significantly different between PTSD risk and control groups. These findings suggest that robust sensorimotor gating may represent a resiliency factor for development of PTSD following trauma.

Decreased activation of parvalbumin interneurons in the medial prefrontal cortex in intact inbred Roman rats with schizophrenia-like reduced sensorimotor gating

Prepulse inhibition (PPI) allows assessing schizophrenia-like sensorimotor gating deficits in rodents. Previous studies indicate that PPI is modulated by the medial prefrontal cortex (mPFC), which is in agreement with our findings showing that PPI differences in the Roman rats are associated with divergences in mPFC activity. Here, we explore whether differences in PPI and mPFC activity in male Roman rats can be explained by (i) differences in the activation (c-Fos) of inhibitory neurons (parvalbumin (PV) interneurons); and/or (ii) reduced excitatory drive (PSD-95) to PV interneurons. Our data show that low PPI in the Roman high-avoidance (RHA) rats is associated with reduced activation of PV interneurons. Moreover, the RHA rats exhibit decreased density of both PV interneurons and PSD-95 puncta on active PV interneurons. These findings point to reduced cortical inhibition as a candidate to explain the schizophrenia-like features observed in RHA rats and support the role of impaired cortical inhibition in schizophrenia.

Differential effects of chronic adolescent glucocorticoid or methamphetamine on drug-induced locomotor hyperactivity and disruption of prepulse inhibition in adulthood in mice

Sensitization of dopaminergic activity has been suggested as an underlying mechanism in the psychotic symptoms of schizophrenia. Adolescent stress and chronic abuse of methamphetamine (Meth) are well-known risk factors for psychosis and schizophrenia; however it remains unknown how these factors compare in terms of dopaminergic behavioural sensitization in adulthood. In addition, while Brain-Derived Neurotrophic Factor (BDNF) has been implicated in dopaminergic activity and schizophrenia, its role in behavioural sensitization remains unclear. In this study we therefore compared the effect of chronic adolescent treatment with the stress hormone, corticosterone (Cort), or with Meth, on drug-induced locomotor hyperactivity and disruption of prepulse inhibition in adulthood in BDNF heterozygous mice and their wild-type controls, as well as on dopamine receptor gene expression. Between 6 and 9 weeks of age, the animals either received Cort in the drinking water or were treated with an escalating Meth dose protocol. In adulthood, Cort-pretreated mice showed significantly reduced Meth-induced locomotor hyperactivity compared to vehicle-pretreated mice. In contrast, Meth hyperlocomotion was significantly enhanced in animals pretreated with the drug in adolescence. There were no effects of either pretreatment on prepulse inhibition. BDNF Het mice showed greater Meth-induced hyperlocomotion and lower prepulse inhibition than WT mice. There were no effects of either pretreatment on D1 or D2 gene expression in either the dorsal or ventral striatum, while D3 mRNA was shown to be reduced in male mice only irrespective of genotype. These results suggest that in adolescence, chronically elevated glucocorticoid levels, a component of chronic stress, do not cause dopaminergic sensitization adulthood, in contrast to the effect of chronic Meth treatment in the same age period. BDNF does not appear to be involved in the effects of chronic Cort or chronic Meth.

Prepulse inhibition deficits in inbred and outbred rats and between-strain differences in startle habituation do not depend on startle reactivity levels

The acoustic startle response and prepulse inhibition (PPI) of startle are measures related to information processing, which is impaired in schizophrenia. Some studies have provided inconclusive patterns of association between both measures in rodents. We assessed the influence of baseline startle response on PPI in large samples of Roman high-(RHA) and low-avoidance (RLA) rat strains and in genetically heterogeneous stock (HS) rats. Results show that RHAs exhibit a PPI deficit compared to RLA rats, which is present regardless of the startle response levels. HS rats were stratified in two sub-samples according to their high or low PPI (HS-highPPI or HS-lowPPI, respectively) scores, and then they were grouped by their differential baseline startle amplitude (high reactivity –HR- or low reactivity –LR-) within each sub-sample. Differences between high- and low-PPI-stratified HS rats remained regardless of their high or low startle amplitude scores. Thus, the impairments in %PPI found in both RHA and HS-LowPPI rats are present irrespective of the relatively high or low levels of startle amplitude in pulse-alone trials. Another objective of the present study was to evaluate whether habituation to the startling stimulus (i.e., pulse) depends on the initial baseline startle response. RLA rats habituated to the startling stimulus more effectively than RHAs regardless of their baseline startle responses. Conversely, there were no differences in startle habituation in the HS rats grouped by their extreme scores of baseline startle. Altogether, these findings suggest a deficit in information processing in RHA rats, which along with evidence indicating that this strain displays other attentional/cognitive impairments, strengthens the validity of the RHA strain as a putative model of schizophrenia-relevant features.

Prepulse inhibition can predict the motivational effects of cocaine in female mice exposed to maternal separation

The prepulse inhibition (PPI) of the startle response can identify the rodents that are more sensitive to the effects of cocaine. Mice with a lower PPI presented a higher vulnerability to the effects of cocaine and a higher susceptibility to developing a substance use disorder (SUD). Maternal separation with early weaning (MSEW) is a relevant animal model to induce motivational alterations throughout life. Nevertheless, only a few studies on females exist, even though they are more vulnerable to stress- and cocaine-related problems. Hence, the aim of the present study was to evaluate the ability of PPI to identify females with a greater vulnerability to the long-term consequences of early stress on the motivational effects of cocaine. Female mice underwent MSEW and were classified according to their high or low PPI. They were then assessed in the cocaine-induced locomotor sensitization test, the conditioned place preference paradigm or the operant self-administration paradigm. Additionally, they were also evaluated in the passive avoidance task, the tail-suspension and the splash tests. The results revealed that the females with lower PPI presented higher consequences of MSEW on the effects of cocaine and showed an increase in anhedonia-like behaviours. Our findings support that a PPI deficit could represent a biomarker of vulnerability to the effects of cocaine induced by MSEW.

Role of an Atypical Cadherin Gene, Cdh23 in Prepulse Inhibition, and Implication of CDH23 in Schizophrenia.

We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest logarithm of odds score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility.

Associations of multidimensional temperament and character profiles with cognition and sensorimotor gating in individuals at risk for schizophrenia-spectrum disorders: preliminary findings

Cloninger’s biopsychological model for personality distinguishes between Temperament [Novelty Seeking, Harm Avoidance (HA), Reward Dependence (RD), Persistence (PS)], and Character [Self-Directedness (SD), Cooperativeness (CO), Self-Transcendence (ST)] traits. Cloninger has also described three sets of complex interactions among these traits, which can be summarized as a linked network of three cubes. Within each cube, the different combinations of the sub-dimensions formulate multidimensional profiles that describe personality more accurately compared with their individual constituents. The aim of the present study was to examine differences of these multidimensional profiles in cognitive functions and Prepulse Inhibition (PPI) in unaffected relatives of schizophrenia-spectrum patients and control individuals. We assessed 114 unaffected relatives of schizophrenia-spectrum patients and 122 controls for Temperament/Character traits, a wide range of cognitive functions, and PPI of the acoustic startle reflex. The relatives had higher Ηarm Avoidance and Self-Transcendence along with lower Reward Dependence, Persistence, Self-Directedness and Cooperativeness scores as well as lower PPI and poorer cognition compared with controls. We also found a) unequal distribution of relatives and controls in several “disadvantageous” profiles associated with the schizophrenia-spectrum, b) the Schizotypal/Disorganized, Apathetic and Fragile profiles had poorer emotional decision making and attention switching, respectively, compared with their “advantageous” counterparts and c) the Adventurous, Independent, Bossy and Resilient profiles had higher PPI compared with their counterparts. These findings further highlight the significance of personality determinants of cognitive processes and have potential implications in early intervention programs in the schizophrenia-spectrum.

Opposite Pathways of Cholinergic Mechanisms of Hypoxic Preconditioning in the Hippocampus: Participation of Nicotinic α7 Receptors and Their Association with the Baseline Level of Startle Prepulse Inhibition.

(1) Background. A one-time moderate hypobaric hypoxia (HBH) has a preconditioning effect whose neuronal mechanisms are not studied well. Previously, we found a stable correlation between the HBH efficiency and acoustic startle prepulse inhibition (PPI). This makes it possible to predict the individual efficiency of HBH in animals and to study its potential adaptive mechanisms. We revealed a bi-directional action of nicotinic α7 receptor agonist PNU-282987 and its solvent dimethyl sulfoxide on HBH efficiency with the level of PPI > or < 40%. (2) The aim of the present study was to estimate cholinergic mechanisms of HBH effects in different brain regions. (3) Methods: in rats pretested for PPI, we evaluated the activity of synaptic membrane-bound and water-soluble choline acetyltransferase (ChAT) in the sub-fractions of ‘light’ and ‘heavy’ synaptosomes of the neocortex, hippocampus and caudal brainstem in the intact brain and after HBH. We tested the dose-dependent influence of PNU-282987 on the HBH efficiency. (4) Results: PPI level and ChAT activity correlated negatively in all brain structures of the intact animals, so that the values of the latter were higher in rats with PPI < 40% compared to those with PPI > 40%. After HBH, this ChAT activity difference was leveled in the neocortex and caudal brainstem, while for membrane-bound ChAT in the ‘light’ synaptosomal fraction of hippocampus, it was reversed to the opposite. In addition, a pharmacological study revealed that PNU-282987 in all used doses and its solvent displayed corresponding opposite effects on HBH efficiency in rats with different levels of PPI. (5) Conclusion: We substantiate that in rats with low and high PPI two opposite hippocampal cholinergic mechanisms are involved in hypoxic preconditioning, and both are implemented by forebrain projections via nicotinic α7 receptors. Possible causes of association between general protective adaptation, HBH, PPI, forebrain cholinergic system and hippocampus are discussed.

Pre-pulse inhibition deficits in individuals at clinical high-risk for psychosis: A systematic review and meta-analysis.

Neurophysiological markers of schizophrenia may help identify individuals who are at an increased risk of developing psychosis. As an operational measure of sensorimotor gating, pre-pulse inhibition (PPI) deficit has been investigated in clinical high-risk (CHR) individuals. In this study, we performed a systematic review and meta-analysis of studies that investigated PPI in CHR individuals. Relevant studies published as of July 2019 were retrieved from the PubMed, Cochrane, Embase, PscyINFO, EBSCO and Chinese databases. PPI was evaluated by calculating the standard mean differences (SMDs) between CHR individuals and healthy controls (HC) in meta-analysis. Quality of studies was assessed using the Newcastle-Ottawa Scale. I2 index was used to assess heterogeneity and Egger's test was used to assess publication bias. Eight studies were found to be eligible. The meta-analysis included five studies with a combined study population of 184 CHR subjects and 161 HC. CHR individuals showed lower PPI levels compared to HC in 120 ms inter-stimulus interval or stimulus onset asynchrony paradigm (P=.491, SMD=-0.62). No significant heterogeneity was observed in 120 ms PPI paradigm (χ2 =3.41, P=.491, I2 =0.0%). CHR individuals had lower PPI level compared to HC in 120 ms paradigm, which were relatively stable and significant. The results indicate the presence of information processing and inhibitory problems prior to the development of full-blown psychosis. PPI may be clinically used as an objective indicator to supplement the understanding of CHR individuals.

T177. CANNABIDIOL AS A POTENTIAL PREVENTATIVE TREATMENT IN A NEUREGULIN-1 MOUSE MODEL OF SCHIZOPHRENIA

BackgroundSchizophrenia is caused by interactions between genes of predisposition and environmental insults. The main pharmacological treatments for schizophrenia are antipsychotic drugs; however, these are associated with a range of side effects (weight gain, metabolic disease, diabetes), have limited treatment compliance, and do not work for approximately 30% of patients. Cannabidiol (CBD) is a non-psychoactive cannabinoid that has shown promise as an antipsychotic-like drug in both human and rodent studies, however its potential as a preventative drug via anti-inflammatory pathways has not yet been investigated. Brain maturation during adolescent development creates a window where CBD could potentially reverse later behavioural deficits via pathways such as anti-inflammation, and reverse the deficits caused by Δ⁹-tetrahydrocannabinol (THC), a psychoactive compound of the cannabis plant linked to the development of schizophrenia.Here we investigated the therapeutic potential of CBD administered in adolescence to protect against the development of schizophrenia-like behaviours, as well as whether CBD could protect against later sensitivity to THC. For this study we used a well-established genetic mouse model of schizophrenia (Nrg1 TM HET) that shows face, construct, and predictive validity for schizophrenia, and is also more susceptible to the effects of cannabinoids.MethodsIn this study, male Nrg1 TM HET mice and wild type (WT) mice were treated with 30 mg/kg of CBD or vehicle intraperitoneally for three weeks during adolescence (PND 35–60). Mice were tested CBD-free in adulthood (5–6 mo) in the open field task, which measures locomotion and anxiety (related to positive symptoms in schizophrenia); social interaction, which measures mouse interactions (relevant to negative symptoms); pre-pulse inhibition (PPI), which measures sensorimotor gating (deficits also found in schizophrenia patients); and fear conditioning, which measures associative learning and memory. Mice were then treated after one week washout with either 3 mg/kg of THC or vehicle, and run in a battery of open field, social interaction, and PPI tests. Brains and bloods were collected to investigate neuroinflammation after another week of washout. Western blots were used to investigate Iba1 levels, while ELISA was used to investigate levels of cytokines IL-10, IL-1B, and TNF-a.ResultsCBD treatment significantly reduced anxiety in Nrg1 TM HET mice but not WT mice, however it had no effect on locomotion in either group in the open field task. CBD treatment lowered the frequency of total social interaction in both genotypes, and reduced the frequency of social interactions of Nrg1 TM HET to WT levels. CBD reduced PPI in Nrg1 TM HET mice but not WT mice, and Nrg1 TM HET mice had lower overall PPI than WT mice. There was no effect of CBD on fear-associated memory. CBD effects on THC sensitivity in these mice are ongoing, as are brain cytokine and protein analyses.DiscussionThese results suggest that Nrg1 TM HET mice are more susceptible to the effects of chronic CBD in adolescence, despite a significant washout. This confirms previous data from our laboratory demonstrating increased susceptibility of Nrg1 TM HET male mice to cannabinoid constituents, and suggests persistent brain changes following adolescent exposure to CBD. Potential reasons for these persistent changes include an altered neuroinflammatory profile in Nrg1 TM HET mice. CBD has previously been shown to be anxiolytic in other studies and our results confirm its potential as an anxiolytic, particularly in our model of schizophrenia.

Genetic Deciphering of Prepulse Inhibition Reveals the Putative Role of an Atypical Cadherin in Schizophrenia Pathogenesis

Prepulse inhibition (PPI) of the startle response reflects a sensory-motor gating mechanism, and impaired PPI is a characteristic endophenotype of schizophrenia. We have previously localized quantitative trait loci (QTL) for PPI in chromosome 10 by analyzing 1,010 F2 mice derived by crossing C57BL/6N (B6) animals that showed high PPI with C3H/HeN (C3) animals that showed low PPI. However, large number of genes in the QTL hinders delineating precise role of genes in defining PPI.

Prepulse Inhibition of the Startle Reflex as a Predictor of Vulnerability to Develop Locomotor Sensitization to Cocaine.

Prepulse inhibition (PPI) of the startle reflex is a measure of sensory-motor synchronization. A deficit in PPI has been observed in psychiatric patients, especially those with schizophrenia and vulnerable subjects, since the neural bases of this disorder are also involved in the regulation of PPI. Recently, we have reported that baseline PPI levels in mice can predict their sensitivity to the conditioned reinforcing effects of cocaine in the conditioned place preference (CPP) paradigm. Mice with a low PPI presented a lower sensitivity to the conditioned rewarding effects of cocaine; however, once they acquired conditioned preference with a higher dose of the drug, a more persistent associative effect of cocaine with respect to environmental cues was evident in these animals when compared with High-PPI mice. Therefore, we proposed that the PPI paradigm can determine subjects with a higher vulnerability to the effects of cocaine. Developing locomotor sensitization after pre-exposure to cocaine is considered an indicator of transitioning from recreational use to a compulsive consumption of the drug. Thus, the aim of the present study was to evaluate whether subjects with a low PPI display a higher locomotor sensitization induced by cocaine. First, male and female OF1 mice were classified as High- or Low-PPI according to their baseline PPI levels. Subsequently, the motor effects induced by an acute dose of cocaine (Experiments 1 and 2) and the development of locomotor sensitization induced by pre-exposure to this drug (Experiments 3 and 4) were recorded using two apparatuses (Ethovision and actimeter). Low-PPI mice presented low sensitivity to the motor effects of an acute dose of cocaine, but a high increase of activity after repeated administration of the drug, thus suggesting a great developed behavioral sensitization. Differences after pretreatment with cocaine vs. saline were more pronounced among Low-PPI subjects than among High-PPI animals. These results endorse our hypothesis that the PPI paradigm can detect subjects who are more likely to display behaviors induced by cocaine and which can increase the risk of developing a cocaine use disorder. Herein, we further discuss whether a PPI deficit can be considered an endophenotype for cocaine use disorder.