Disruption Of Prepulse Inhibition Research Articles

Assessing the Cntnap2 knockout rat prepulse inhibition deficit through prepulse scaling of the baseline startle response curve

Many neurodevelopmental disorders, including autism spectrum disorder (ASD), are associated with changes in sensory processing and sensorimotor gating. The acoustic startle response and prepulse inhibition (PPI) of startle are widely used translational measures for assessing sensory processing and sensorimotor gating, respectively. The Cntnap2 knockout (KO) rat has proven to be a valid model for ASD, displaying core symptoms, including sensory processing perturbations. Here, we used a novel method to assess startle and PPI in Cntnap2 KO rats that allows for the identification of separate scaling components: startle scaling, which is a change in startle amplitude to a given sound, and sound scaling, which reflects a change in sound processing. Cntnap2 KO rats show increased startle due to both an increased overall response (startle scaling) and a left shift of the sound/response curve (sound scaling). In the presence of a prepulse, wildtype rats show a reduction of startle due to both startle scaling and sound scaling, whereas Cntnap2 KO rats show normal startle scaling, but disrupted sound scaling, resulting in the reported PPI deficit. These results validate that startle and sound scaling by a prepulse are indeed two independent processes, with only the latter being impaired in Cntnap2 KO rats. As startle scaling is likely related to motor output and sound scaling to sound processing, this novel approach reveals additional information on the possible cause of PPI disruptions in preclinical models.

Interaction of Brain-Derived Neurotrophic Factor with the Effects of Chronic Methamphetamine on Prepulse Inhibition in Mice Is Independent of Dopamine D3 Receptors.

The aim of the present study was to gain a better understanding of the role of brain-derived neurotrophic factor (BDNF) and dopamine D3 receptors in the effects of chronic methamphetamine (METH) on prepulse inhibition (PPI), an endophenotype of psychosis. We compared the effect of a three-week adolescent METH treatment protocol on the regulation of PPI in wildtype mice, BDNF heterozygous mice (HET), D3 receptor knockout mice (D3KO), and double-mutant mice (DM) with both BDNF heterozygosity and D3 receptor knockout. Chronic METH induced disruption of PPI regulation in male mice with BDNF haploinsufficiency (HET and DM), independent of D3 receptor knockout. Specifically, these mice showed reduced baseline PPI, as well as attenuated disruption of PPI induced by acute treatment with the dopamine receptor agonist, apomorphine (APO), or the glutamate NMDA receptor antagonist, MK-801. In contrast, there were no effects of BDNF heterozygosity or D3 knockout on PPI regulation in female mice. Chronic METH pretreatment induced the expected locomotor hyperactivity sensitisation, where female HET and DM mice also showed endogenous sensitisation. Differential sex-specific effects of genotype and METH pretreatment were observed on dopamine receptor and dopamine transporter gene expression in the striatum and frontal cortex. Taken together, these results show a significant involvement of BDNF in the long-term effects of METH on PPI, particularly in male mice, but these effects appear independent of D3 receptors. The role of this receptor in psychosis endophenotypes therefore remains unclear.

Effects of total sleep deprivation on sensorimotor gating in humans

Sensorimotor gating is a measure of pre-attentional information processing and can be measured by prepulse inhibition (PPI) of the startle reflex. Sleep deprivation has been shown to disrupt PPI in animals and humans, and has been proposed as an early phase 2 model to probe antipsychotic efficacy in heathy humans. To further investigate the reliability and efficacy of sleep deprivation to produce PPI deficits we tested the effects of total sleep deprivation (TSD) on PPI in healthy controls in a highly controlled sleep laboratory environment. Participants spent 4 days and nights in a controlled laboratory environment with their sleep monitored with polysomnography. Participants were randomly assigned to either normal sleep on all 4 nights (N = 17) or 36 h of TSD on the 3rd or 4th night (N = 40). Participants were assessed for sleepiness using the Karolinska Sleepiness Scale (KSS) and underwent a daily PPI task (interstimlulus intervals 30–2000 ms) in the evening. Both within-subject effects (TSD vs. normal sleep in TSD group alone) and between-subject effects (TSD vs. no TSD group) of TSD on PPI were assessed. TSD increased subjective sleepiness measured with the KSS, but did not significantly alter overall startle, habituation or PPI. Sleep measures including duration, rapid eye movement and slow wave sleep duration were also not associated with PPI performance. The current results show that human sensorimotor gating may not be reliably sensitive to sleep deprivation. Further research is required for TSD to be considered a dependable model of PPI disruption for drug discovery in humans.

Quinpirole, but not muscimol, infused into the nucleus accumbens disrupts prepulse inhibition of the acoustic startle in rhesus macaques

Sensorimotor gating is the ability to suppress motor responses to irrelevant sensory inputs. This response is disrupted in a range of neuropsychiatric disorders. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is a form of sensorimotor gating in which a low-intensity prepulse immediately precedes a startling stimulus, resulting in an attenuation of the startle response. PPI is conserved across species and the underlying circuitry mediating this effect has been widely studied in rodents. However, recent work from our laboratories has shown an unexpected divergence between the circuitry controlling PPI in rodents as compared to macaques. The nucleus accumbens, a component of the basal ganglia, has been identified as a key modulatory node for PPI in rodents. The role of the nucleus accumbens in modulating PPI in primates has yet to be investigated. We measured whole-body PPI of the ASR in six rhesus macaques following (1) pharmacological inhibition of the nucleus accumbens using the GABAA agonist muscimol, and (2) focal application of the dopamine D2/3 agonist quinpirole (at 3 doses). We found that quinpirole, but not muscimol, infused into the nucleus accumbens disrupts prepulse inhibition in monkeys. These results differ from those observed in rodents, where both muscimol and quinpirole disrupt prepulse inhibition.

TAAR1 dependent and independent actions of the potential antipsychotic and dual TAAR1/5-HT1A receptor agonist SEP-363856

SEP-363856 (SEP-856) is a novel antipsychotic under clinical development. It displays a unique pattern of receptor interaction, with only weak (partial agonist) activity at dopamine D2 receptors, yet more potent agonist activity at the trace amine associated receptor (TAAR1) and 5-hydroxytryptamine 1 A receptor (5-HT1A). Nonetheless, these observations await independent confirmation and more detailed characterization of the in vitro and in vivo actions of SEP-856 at TAAR1 and 5-HT1A receptors would be instructive. Herein, we employed luminescence complementation technology in heterologous live cell systems, confocal microscopy, voltage clamp electrophysiology, behavioral readouts and TAAR1 knockout (KO) mice to study SEP-856 in further detail. We provide evidence for the ability of SEP-856 to activate TAAR1 at the surface plasma membrane, and show that this interaction results in Gαs recruitment (pEC50: 6.08 ± 0.22 EMAX: 96.41% ± 15.26) and by extension, to G-protein inwardly rectifying potassium (GIRK) channel activation. Using TAAR1-KO mice, we find TAAR1 to be indispensable for SEP-856 control of body temperature, baseline locomotion reduction and for “antipsychotic-like” efficacy as characterized by a reversal of dizocilipine (MK-801) mediated disruption of pre-pulse inhibition. Conversely, the inhibition by SEP-856 of MK-801 induced locomotion was unaffected in TAAR1 KO mice. SEP-856 behaved as a low-potency, partial agonist at the 5-HT1A receptor, while it partially inhibited recruitment of D2 receptor-coupled Gα and GIRK by DA and acted as a weak partial agonist with low potency at the same receptor when applied alone. Our findings corroborate and extend previous observations on the molecular substrates engaged by this unique, dual TAAR1/5-HT1A receptor agonist and potential antipsychotic that could prove to have major advantages in the treatment of schizophrenia and other psychotic disorders.

Targeting α6GABAA receptors as a novel therapy for schizophrenia: A proof-of-concept preclinical study using various animal models.

GABAA receptors containing α6 subunits (α6GABAARs) in the cerebellum have -been implicated in schizophrenia. It was reported that the GABA synthesizing enzymes were downregulated whereas α6GABAARs were upregulated in postmortem cerebellar tissues of patients with schizophrenia and in a rat model induced by chronic phencyclidine (PCP). We have previously demonstrated that pyrazoloquinolinone Compound 6, an α6GABAAR-highly selective positive allosteric modulator (PAM), can rescue the disrupted prepulse inhibition (PPI) induced by methamphetamine (METH), an animal model mimicking the sensorimotor gating deficit based on the hyper-dopaminergic hypothesis of schizophrenia. Here, we demonstrate that not only Compound 6, but also its structural analogues, LAU463 and LAU159, with similarly high α6GABAAR selectivity and their respective deuterated derivatives (DK-I-56-1, DK-I-58-1 and DK-I-59-1) can rescue METH-induced PPI disruption. Besides, Compound 6 and DK-I-56-I can also rescue the PPI disruption induced by acute administration of PCP, an animal model based on the hypo-glutamatergic hypothesis of schizophrenia. Importantly, Compound 6 and DK-I-56-I, at doses not affecting spontaneous locomotor activity, can also rescue impairments of social interaction and novel object recognition in mice induced by chronic PCP treatments. At similar doses, Compound 6 did not induce sedation but significantly suppressed METH-induced hyperlocomotion. Thus, α6GABAAR-selective PAMs can rescue not only disrupted PPI but also hyperlocomotion, social withdrawal, and cognitive impairment, in both METH- and PCP-induced animal models mimicking schizophrenia, suggesting that they are a potential novel therapy for the three core symptoms, i.e. positive symptoms, negative symptoms, and cognitive impairment, of 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.

Clozapine Increases Nestin Concentration in the Adult Male Rat Hippocampus: A Preliminary Study.

Patients with schizophrenia, and rodent models of the disease, both exhibit suppressed neurogenesis, with antipsychotics possibly enhancing neurogenesis in pre-clinical models. Nestin, a cytoskeletal protein, is implicated in neuronal differentiation and adult neurogenesis. We hypothesized that schizophrenia pathogenesis involves nestin downregulation; however, few studies have related nestin to schizophrenia. We assessed nestin protein concentration, prepulse inhibition (PPI), and social interaction in the MK-801 model of schizophrenia, with or without antipsychotic (clozapine) treatment. Adult male Sprague–Dawley rats were intraperitoneally administered saline or MK-801 (0.1 mg/kg) to produce a schizophrenia-like phenotype, with concomitant subcutaneous injections of vehicle or clozapine (5 mg/kg). PPI was assessed on days 1, 8, and 15, and social interaction was assessed on day 4. Hippocampus tissue samples were dissected for Western blotting of nestin concentration. MK-801 alone did not alter nestin concentration, while clozapine alone enhanced hippocampal nestin concentration; this effect was not apparent in animals with MK-801 and clozapine co-administration. MK-801 also produced schizophrenia-like PPI disruptions, some of which were reversed by clozapine. Social interaction deficits were not detected in this model. This is the first report of clozapine-induced enhancements of hippocampal nestin concentration that might be mediated by NMDA receptors. Future studies will explore the impact of neurodevelopmental nestin concentration on symptom onset and antipsychotic treatment.

Distinct sex-dependent behavioral responses induced by two positive allosteric modulators of alpha 5 subunit-containing GABAA receptors

Dysregulation of GABAergic neurotransmission has long been implicated in several psychiatric disorders, including schizophrenia, depression, and anxiety disorders. Alpha 5 subunit-containing GABAA receptors (α5-GABAAR), which are expressed mainly by pyramidal neurons in the hippocampus, have been proposed as a potential target to treat these psychiatric disorders. Here, we evaluated the effects produced by GL-II-73 and SH-053–2′F-R-CH3 (1, 5, and 10 mg/kg), two positive allosteric modulators of α5-GABAAR in behavioral tests sensitive to drugs with anxiolytic, antidepressant, and antipsychotic properties in male and female C57BL/6 mice. In both males and females, GL-II-73 produced an anxiolytic-like effect in the elevated plus-maze (EPM) and novelty-suppressed feeding and a rapid and sustained antidepressant-like effect in the forced swim test. GL-II-73 also induced antipsychotic-like effects in males indicated by attenuating MK-801-induced hyperlocomotion and prepulse inhibition (PPI) disruption. However, GL-II-73 per se increased locomotor activity and impaired fear memory extinction in males and females and PPI in males. On the other hand, SH-053–2′F-R-CH3 induced anxiolytic-like effects in the EPM and facilitated fear memory extinction in males. Contrary to GL-II-73, SH-053–2′F-R-CH3 attenuated MK-801-induced hyperlocomotion and PPI disruption in females but not in males. Neither of these drugs induced rewarding effects or impaired motor coordination. These findings suggest that GL-II-73 and SH-053–2′F-R-CH3 cause distinct sex-dependent behavioral responses and support continued preclinical research on the potential of positive allosteric modulators of α5-GABAAR for the treatment of psychiatric disorders.

Novel D2/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment

Schizophrenia is a serious mental disorder without a fully understood pathomechanism, but which involves dysregulation of neurotransmitters and their receptors. The best option for the management of schizophrenia comprises so-called multi-target ligands, similar to the third generation of neuroleptics. Dopamine type 2 receptors (D2Rs) are the main target in the treatment of schizophrenia, in particular for mitigation of the positive symptoms. Due to the high expression of 5-hydroxytryptamine type 3 receptors (5-HT3Rs) in human brain areas responsible for emotional behavior, motivation, and cognitive function, 5-HT3Rs represent a potential target for modulating the cognitive and negative symptoms of schizophrenia. Here we present the design, synthesis, and both in vitro and in vivo biological evaluation of 1,4-disubstituted aromatic piperazines. Screening of in vitro properties revealed the two most promising drug candidates (21 and 24) which were found to be potent D2Rs and moderate 5-HT3R antagonists, and which were forwarded to in vivo studies in Wistar rats. Considering toxicity, administration of the maximal feasible dose of 21 (2 mg/kg) did not produce any side effects. By contrast, the higher solubility of 24 led to revelation of mild and temporary side effects at the dose of 20 mg/kg. Importantly, both 21 and 24 showed facile crossing of the blood-brain barrier, even exerting higher levels in the brain in comparison to plasma. In a behavioral study using the acute amphetamine model of psychosis, we showed that compound 24 ameliorated both positive and negative effects of amphetamine including hyperlocomotion, social impairments, and disruption of prepulse inhibition. The effect of the highest dose (10 mg/kg) was comparable to the effect of the reference dose of aripiprazole (1 mg/kg).

Sex Differences in Psychosis: Focus on Animal Models.

Most psychiatric illnesses, such as schizophrenia, show profound sex differences in incidence, clinical presentation, course, and outcome. Fortunately, more recently the literature on sex differences and (to a lesser extent) effects of sex steroid hormones is expanding, and in this review we have focused on such studies in psychosis, both from a clinical/epidemiological and preclinical/animal model perspective. We begin by briefly describing the clinical evidence for sex differences in schizophrenia epidemiology, symptomatology, and pathophysiology. We then detail sex differences and sex hormone effects in behavioral animal models of psychosis, specifically psychotropic drug-induced locomotor hyperactivity and disruption of prepulse inhibition. We expand on the preclinical data to include developmental and genetic models of psychosis, such as the maternal immune activation model and neuregulin transgenic animals, respectively. Finally, we suggest several recommendations for future studies, in order to facilitate a better understanding of sex differences in the development of psychosis.

<i>p</i>-Hydroxyamphetamine induced prepulse inhibition disruptions is modulated by serotonergic and adrenergic receptors

<i>p</i>-Hydroxyamphetamine induced prepulse inhibition disruptions is modulated by serotonergic and adrenergic receptors

The effects of galangin in prepulse inhibition test and experimental schizophrenia models.

Acetylcholinesterase inhibitors are the focus of interest in the management of schizophrenia. We aimed to investigate the effects of acute galangin administration, a flavonoid compound with acetylcholinesterase inhibiting activity, on schizophrenia-associated cognitive deficits in rats and schizophrenia models in mice. Apomorphine-induced prepulse inhibition (PPI) disruption for cognitive functions, nicotinic, muscarinic, and serotonergic mechanism involvement, and brain acetylcholine levels were investigated in Wistar rats. Apomorphine-induced climbing, MK-801-induced hyperlocomotion, and catalepsy tests were used as schizophrenia models in Swiss albino mice. The effects of galangin were compared with acetylcholinesterase inhibitor donepezil, and typical and atypical antipsychotics haloperidol and olanzapine, respectively. Galangin (50,100 mg/kg) enhanced apomorphine-induced PPI disruption similar to donepezil, haloperidol, and olanzapine (p < 0.05). This effect was not altered in the combination of galangin with the nicotinic receptor antagonist mecamylamine (1 mg/kg), the muscarinic receptor antagonist scopolamine (0.05 mg/kg), or the serotonin-1A receptor antagonist WAY-100635 (1 mg/kg) (p > 0.05). Galangin (50,100 mg/kg) alone increased brain acetylcholine concentrations (p < 0.05), but not in apomorphine-injected rats (p > 0.05). Galangin (50 mg/kg) decreased apomorphine-induced climbing and MK-801-induced hyperlocomotion similar to haloperidol and olanzapine (p < 0.05), but did not induce catalepsy, unlike them. We suggest that galangin may help enhance schizophrenia-associated cognitive deficits, and nicotinic, muscarinic cholinergic, and serotonin-1A receptors are not involved in this effect. Galangin also exerted an antipsychotic-like effect without inducing catalepsy and may be considered as an advantageous antipsychotic agent.

LSD-stimulated behaviors in mice require \u03b2-arrestin 2 but not \u03b2-arrestin 1

Recent evidence suggests that psychedelic drugs can exert beneficial effects on anxiety, depression, and ethanol and nicotine abuse in humans. However, their hallucinogenic side-effects often preclude their clinical use. Lysergic acid diethylamide (LSD) is a prototypical hallucinogen and its psychedelic actions are exerted through the 5-HT2A serotonin receptor (5-HT2AR). 5-HT2AR activation stimulates Gq- and β-arrestin- (βArr) mediated signaling. To separate these signaling modalities, we have used βArr1 and βArr2 mice. We find that LSD stimulates motor activities to similar extents in WT and βArr1-KO mice, without effects in βArr2-KOs. LSD robustly stimulates many surrogates of psychedelic drug actions including head twitches, grooming, retrograde walking, and nose-poking in WT and βArr1-KO animals. By contrast, in βArr2-KO mice head twitch responses are low with LSD and this psychedelic is without effects on other surrogates. The 5-HT2AR antagonist MDL100907 (MDL) blocks the LSD effects. LSD also disrupts prepulse inhibition (PPI) in WT and βArr1-KOs, but not in βArr2-KOs. MDL restores LSD-mediated disruption of PPI in WT mice; haloperidol is required for normalization of PPI in βArr1-KOs. Collectively, these results reveal that LSD’s psychedelic drug-like actions appear to require βArr2.

Sodium valproate improves sensorimotor gating deficit induced by sleep deprivation at low doses

Background/aim Sleep deprivation disrupts prepulse inhibition of acoustic startle reflex and can be used to mimic psychosis in experimental animals. On the other hand, it is also a model for other disorders of sensory processing, including migraine. This study aims to assess the effects of sodium valproate, a drug that is used in a variety of neuropsychiatric disorders, on normal and disrupted sensorimotor gating in rats.Materials and methods Sixty-two Wistar albino rats were randomly distributed into 8 groups. Subchronic and intraperitoneal sodium valproate were administrated to the sleep-deprived and nonsleep-deprived rats by either 50–100 or 200 mg/kg/day. Prepulse inhibition test and locomotor activity test were performed. Sleep deprivation induced by the modified multiple platform method.Results Sleep deprivation impaired prepulse inhibition, decreased startle amplitude, and increased locomotor activity. Sodium valproate did not significantly alter prepulse inhibition and locomotor activity in nonsleep-deprived and sleep-deprived groups. On the other hand, all doses decreased locomotor activity in drug-treated groups, and low dose improved sensorimotor gating and startle amplitude after sleep deprivation.Conclusion Low-dose sodium valproate improves sleep deprivation-disrupted sensorimotor gating, and this finding may rationalize the use of sodium valproate in psychotic states and other sensory processing disorders. Dose-dependent effects of sodium valproate on sensorimotor gating should be investigated in detail.

Juvenile social isolation leads to schizophrenia-like behaviors via excess lactate production by astrocytes

Repeated early environmental deprivation is regarded as a typical paradigm to mimic the behavioral abnormalities and brain dysfunction that occur in psychiatric disorders. Previously, we reported that social isolation could disrupt prepulse inhibition (PPI) in Sprague-Dawley (SD) rats, producing the typical characteristics of a schizophrenia animal model. Based on further analysis of previous proteomic and transcriptomic data, a disrupted balance of glucose metabolism was found in the prefrontal cortex (PFC) of isolated rats. Subsequently, in the first experiment of this study, we investigated the effects of juvenile social isolation (postnatal days (PND) 21–34) on PPI and lactate levels in PND56 rats. Compared with the social rearing group, rats in the isolated rearing group showed disrupted PPI and increased lactate levels in the PFC. In the second experiment, at PND55, the model rats were acutely injected with a glycogen phosphorylase inhibitor (4-dideoxy-1,4-imino-darabinitol, DAB) or control saline in the bilateral PFC. Our data showed that acute DAB administration (50 pmol, 0.5 μl) significantly improved the disrupted PPI and decreased the levels of oxidative phosphorylation (OXPHOS)-related mRNAs as well as lactate. In summary, our results suggested that excess astrocytic lactate production was involved in the impairment of auditory sensory gating of isolated rats, which may contribute to the metabolic pathogenesis of schizophrenia.

Cannabidiol prevents disruptions in sensorimotor gating induced by psychotomimetic drugs that last for 24-h with probable involvement of epigenetic changes in the ventral striatum

Cannabidiol (CBD), a major non-psychotomimetic component of the Cannabis sativa plant, shows therapeutic potential in several psychiatric disorders, including schizophrenia. The molecular mechanisms underlying the antipsychotic-like effects of CBD are not fully understood. Schizophrenia and antipsychotic treatment can modulate DNA methylation in the blood and brain, resulting in altered expression of diverse genes associated with this complex disorder. However, to date, the possible involvement of DNA methylation in the antipsychotic-like effects of CBD has not been investigated. Therefore, this study aimed at evaluating in mice submitted to the prepulse inhibition (PPI) model: i) the effects of a single injection of CBD or clozapine followed by AMPH or MK-801 on PPI and global DNA methylation changes in the ventral striatum and prefrontal cortex (PFC); and ii). if the acute antipsychotic-like effects of CBD would last for 24-h. AMPH (5 mg/kg) and MK-801 (0.5 mg/kg) impaired PPI. CBD (30 and 60 mg/kg), similar to clozapine (5 mg/kg), attenuated AMPH- and MK801-induced PPI disruption. AMPH, but not MK-801, increased global DNA methylation in the ventral striatum, an effect prevented by CBD. CBD and clozapine increased, by themselves, DNA methylation in the prefrontal cortex. The acute effects of CBD (30 or 60 mg/kg) on the PPI impairment induced by AMPH or MK-801 was also detectable 24 h later. Altogether, the results show that CBD induces acute antipsychotic-like effects that last for 24-h. It also modulates DNA methylation in the ventral striatum, suggesting a new potential mechanism for its antipsychotic-like effects.

GRK3 deficiency elicits brain immune activation and psychosis

The G protein-coupled receptor kinase (GRK) family member protein GRK3 has been linked to the pathophysiology of schizophrenia and bipolar disorder. Expression, as well as protein levels, of GRK3 are reduced in post-mortem prefrontal cortex of schizophrenia subjects. Here, we investigate functional behavior and neurotransmission related to immune activation and psychosis using mice lacking functional Grk3 and utilizing a variety of methods, including behavioral, biochemical, electrophysiological, molecular, and imaging methods. Compared to wildtype controls, the Grk3−/− mice show a number of aberrations linked to psychosis, including elevated brain levels of IL-1β, increased turnover of kynurenic acid (KYNA), hyper-responsiveness to D-amphetamine, elevated spontaneous firing of midbrain dopamine neurons, and disruption in prepulse inhibition. Analyzing human genetic data, we observe a link between psychotic features in bipolar disorder, decreased GRK expression, and increased concentration of CSF KYNA. Taken together, our data suggest that Grk3−/− mice show face and construct validity relating to the psychosis phenotype with glial activation and would be suitable for translational studies of novel immunomodulatory agents in psychotic disorders.

Disruption of prepulse inhibition is associated with compulsive behavior severity and nucleus accumbens dopamine receptor changes in Sapap3 knockout mice

Obsessive compulsive disorder (OCD) is associated with disruption of sensorimotor gating, which may contribute to difficulties inhibiting intrusive thoughts and compulsive rituals. Neural mechanisms underlying these disturbances are unclear; however, striatal dopamine is implicated in regulation of sensorimotor gating and OCD pathophysiology. The goal of this study was to examine the relationships between sensorimotor gating, compulsive behavior, and striatal dopamine receptor levels in Sapap3 knockout mice (KOs), a widely used preclinical model system for OCD research. We found a trend for disruption of sensorimotor gating in Sapap3-KOs using the translational measure prepulse inhibition (PPI); however, there was significant heterogeneity in both PPI and compulsive grooming in KOs. Disruption of PPI was significantly correlated with a more severe compulsive phenotype. In addition, PPI disruption and compulsive grooming severity were associated with reduced dopamine D1 and D2/3 receptor density in the nucleus accumbens core (NAcC). Compulsive grooming progressively worsened in Sapap3-KOs tested longitudinally, but PPI disruption was first detected in high-grooming KOs at 7 months of age. Through detailed characterization of individual differences in OCD-relevant behavioral and neurochemical measures, our findings suggest that NAcC dopamine receptor changes may be involved in disruption of sensorimotor gating and compulsive behavior relevant to OCD.

The α6 GABAA Receptor Positive Allosteric Modulator DK-I-56-1 Reduces Tic-Related Behaviors in Mouse Models of Tourette Syndrome.

Tourette syndrome (TS) is a disabling neurodevelopmental disorder characterized by multiple, recurrent tics. The pharmacological treatment of TS is currently based on dopaminergic antagonists; however, these drugs are associated with extrapyramidal symptoms and other serious adverse events. Recent evidence suggests that positive allosteric modulators (PAMs) of GABAA receptors containing α6 subunits (α6 GABAARs) oppose the behavioral effects of dopamine. Building on this evidence, in the present study, we tested the efficacy of DK-I-56-1, a highly selective PAM for α6 GABAARs, in mouse models of TS exhibiting tic-related responses. DK-I-56-1 significantly reduced tic-like jerks and prepulse inhibition (PPI) deficits in D1CT-7 transgenic mice, a well-documented mouse model of TS. DK-I-56-1 also prevented the exacerbation of spontaneous eyeblink reflex induced by the potent dopamine D1 receptor agonist SKF 82958, a proxy for tic-like responses. We also showed that both systemic and prefrontal cortical administration of DK-I-56-1 countered the PPI disruption caused by SKF 82958. Although the effects of DK-I-56-1 were akin to those elicited by dopaminergic antagonists, this drug did not elicit extrapyramidal effects, as measured by catalepsy. These results point to α6 GABAAR PAMs as promising TS therapies with a better safety profile than dopaminergic antagonists.