Increase In Prepulse Inhibition Research Articles

CB2 cannabinoid receptor expression is increased in 129S1/SvImJ mice: behavioral consequences.

Genetic and environmental factors are implicated in the etiology of neuropsychiatric diseases. Inbred mouse strains, including the 129S1/SvImJ (S1), constitute important models to study the influence of genetic factors in these conditions. S1 mice displayed anxiogenic-like behavior, impaired fear extinction, and increased prepulse inhibition (PPI) of startle reflex compared to C57BL/6J (BL6) mice. Given the role played by the endocannabinoid system (ECS) in these responses, we evaluated the expression of the ECS components in different brain regions in S1 mice. Gene expression levels of the cannabinoid type-1 and type-2 receptors (CB1R and CB2R) and the endocannabinoid metabolizing enzymes varied depending on the brain region evaluated. Notably, CB2R expression markedly increased in the amygdala, prefrontal cortex and hippocampus in S1 mice. Moreover, CB2R blockade with SR144528 partially rescued the anxiogenic phenotype in S1 mice, while CB2R activation with JWH133 potentiated the deficits in fear extinction and the PPI of startle reflex in this mouse strain. These data suggest that CB2R is involved in the behavioral alterations observed in S1 mice and underline the importance of this cannabinoid receptor subtype in the regulation of certain central nervous system disorders.

Dorsal striatal dopamine induces fronto-cortical hypoactivity and attenuates anxiety and compulsive behaviors in rats.

Dorsal striatal dopamine transmission engages the cortico-striato-thalamo-cortical (CSTC) circuit, which is implicated in many neuropsychiatric diseases, including obsessive-compulsive disorder (OCD). Yet it is unknown if dorsal striatal dopamine hyperactivity is the cause or consequence of changes elsewhere in the CSTC circuit. Classical pharmacological and neurotoxic manipulations of the CSTC and other brain circuits suffer from various drawbacks related to off-target effects and adaptive changes. Chemogenetics, on the other hand, enables a highly selective targeting of specific neuronal populations within a given circuit. In this study, we developed a chemogenetic method for selective activation of dopamine neurons in the substantia nigra, which innervates the dorsal striatum in the rat. We used this model to investigate effects of targeted dopamine activation on CSTC circuit function, especially in fronto-cortical regions. We found that chemogenetic activation of these neurons increased movement (as expected with increased dopamine release), rearings and time spent in center, while also lower self-grooming. Furthermore, this activation increased prepulse inhibition of the startle response in females. Remarkably, we observed reduced [18F]FDG metabolism in the frontal cortex, following dopamine activation in the dorsal striatum, while total glutamate levels- in this region were increased. This result is in accord with clinical studies of increased [18F]FDG metabolism and lower glutamate levels in similar regions of the brain of people with OCD. Taken together, the present chemogenetic model adds a mechanistic basis with behavioral and translational relevance to prior clinical neuroimaging studies showing deficits in fronto-cortical glucose metabolism across a variety of clinical populations (e.g. addiction, risky decision-making, compulsivity or obesity).

Rhodiola rosea root extract has antipsychotic-like effects in rodent models of sensorimotor gating

Ethnopharmacological relevanceThe plant arctic root (Rhodiola rosea, L.) is growing in northern regions of Europe, Asia and North America. Extracts of R. rosea are used in traditional medicine for various conditions related to nervous system function. According to scientific studies from the last decades, the plant might have potential for use in the treatment of memory impairments, stress and depression, but reports concerning other neuropsychiatric disorders are scarce. Aim of the studyIn this context, our study aimed to examine potential antipsychotic-like effects of R. rosea root extract. Materials and methodsWe tested the effects of R. rosea root extract on prepulse inhibition in rats and mice. Prepulse inhibition is an established operational measure of sensorimotor gating, which is impaired in schizophrenia and other psychotic disorders. ResultsR. rosea root extract increased prepulse inhibition in rats and mice. Interestingly, the R. rosea extract had stronger effects in those individual animals that had low baseline levels of prepulse inhibition. Therefore, we performed further experiments in which we pharmacologically induced a prepulse inhibition deficit by two different psychostimulants, either the dopamine D2 receptor agonist apomorphine or the NMDA receptor antagonist dizocilpine (MK-801). Pre-treatment with the R. rosea extract significantly restored both, apomorphine- and dizocilpine-induced prepulse inhibition deficits. ConclusionsThe present study demonstrates that R. rosea extract robustly reverses prepulse inhibition deficits in rodents. This suggests antipsychotic-like effects of R. rosea extract. Future studies should focus on the pharmacological mechanisms underlying these effects.

Prenatal exposure to TiO2 nanoparticles in mice causes behavioral deficits with relevance to autism spectrum disorder and beyond

Environmental factors are involved in the etiology of autism spectrum disorder (ASD) and may contribute to the raise in its incidence rate. It is currently unknown whether the increasing use of nanoparticles such as titanium dioxide (TiO2 NPs) in consumer products and biomedical applications may play a role in these associations. While nano-sized TiO2 is generally regarded as safe and non-toxic, excessive exposure to TiO2 NPs may be associated with negative health consequences especially when occurring during sensitive developmental periods. To test if prenatal exposure to TiO2 NPs alters fetal development and behavioral functions relevant to ASD, C57Bl6/N dams were subjected to a single intravenous injection of a low (100 µg) or high (1000 µg) dose of TiO2 NPs or vehicle solution on gestation day 9. ASD-related behavioral functions were assessed in the offspring using paradigms that index murine versions of ASD symptoms. Maternal exposure to TiO2 NPs led to subtle and dose-dependent impairments in neonatal vocal communication and juvenile sociability, as well as a dose-dependent increase in prepulse inhibition of the acoustic startle reflex of both sexes. These behavioral alterations emerged in the absence of pregnancy complications. Prenatal exposure to TiO2 NPs did not cause overt fetal malformations or changes in pregnancy outcomes, nor did it affect postnatal growth of the offspring. Taken together, our study provides a first set of preliminary data suggesting that prenatal exposure to nano-sized TiO2 can induce behavioral deficits relevant to ASD and related neurodevelopmental disorders without inducing major changes in physiological development. If extended further, our preclinical findings may provide an incentive for epidemiological studies examining the role of prenatal TiO2 NPs exposure in the etiology of ASD and other neurodevelopmental disorders.

Neuroligin 2 R215H Mutant Mice Manifest Anxiety, Increased Prepulse Inhibition, and Impaired Spatial Learning and Memory.

Neuroligin 2 (NLGN2) is a postsynaptic adhesion protein that plays an essential role in synaptogenesis and function of inhibitory neuron. We previously identified a missense mutation R215H of the NLGN2 in a patient with schizophrenia. This missense mutation was shown to be pathogenic in several cell-based assays. The objective of this study was to better understand the behavioral consequences of this mutation in vivo. We generated a line of transgenic mice carrying this mutation using a recombinant-based method. The mice were subjected to a battery of behavioral tests including open field locomotor activity assay, prepulse inhibition (PPI) assay, accelerated rotarod test, novel location and novel recognition tests, elevated plus-maze (EPM) test, and Morris water maze test. The transgenic animals were viable and fertile, but the Nlgn2 R215H knock-in (KI) homozygous mice showed growth retardation, anxiety-like behavior, increased PPI, and impaired spatial learning and memory. There was no significant interaction between sex and genotype in most behavioral tests; however, we observed a significant interaction between sex and genotype in EPM test in this study. Also, we found that the Nlgn2 R215H homozygous KI mice did not express the NLGN2 protein, resembling Nlgn2 knockout mice. Our results demonstrate that Nlgn2 R215H KI homozygous mice manifest several behavioral abnormalities similar to those found in psychiatric patients carrying NLGN2 mutations, indicating that dysfunction of NLGN2 contributes to the pathogenesis of certain psychiatric symptoms commonly present in various mental disorders, not limited to schizophrenia.

Dexras1 a unique ras-GTPase interacts with NMDA receptor activity and provides a novel dissociation between anxiety, working memory and sensory gating

Dexras1 is a novel GTPase that acts at a confluence of signaling mechanisms associated with psychiatric and neurological disease including NMDA receptors, NOS1AP and nNOS. Recent work has shown that Dexras1 mediates iron trafficking and NMDA-dependent neurodegeneration but a role for Dexras1 in normal brain function or psychiatric disease has not been studied. To test for such a role, mice with germline knockout (KO) of Dexras1 were assayed for behavioral abnormalities as well as changes in NMDA receptor subunit protein expression. Because Dexras1 is up-regulated during stress or by dexamethasone treatment, we included measures associated with emotion including anxiety and depression. Baseline anxiety-like measures (open field and zero maze) were not altered, nor were depression-like behavior (tail suspension). Measures of memory function yielded mixed results, with no changes in episodic memory (novel object recognition) but a significant decrement on working memory (T-maze). Alternatively, there was an increase in pre-pulse inhibition (PPI), without concomitant changes in either startle amplitude or locomotor activity. PPI data are consistent with the direction of change seen following exposure to dopamine D2 antagonists. An examination of NMDA subunit expression levels revealed an increased expression of the NR2A subunit, contrary to previous studies demonstrating down-regulation of the receptor following antipsychotic exposure (Schmitt et al., 2003) and up-regulation after exposure to isolation rearing (Turnock-Jones et al., 2009). These findings suggest a potential role for Dexras1 in modulating a selective subset of psychiatric symptoms, possibly via its interaction with NMDARs and/or other disease-related binding-partners. Furthermore, data suggest that modulating Dexras1 activity has contrasting effects on emotional, sensory and cognitive domains.

Antipsychotic-like effects of a neurotensin receptor type 1 agonist

Although neurotensin (NT) analogs are known to produce antipsychotic-like effects, the therapeutic possibility of a brain penetrant NTS1 agonist in treating psychiatric disorders has not been well studied. Here, we examined whether PD149163, a brain-penetrant NTS1-specific agonist, displays antipsychotic-like effects in C57BL/6J mice by investigating the effect of PD149163 on amphetamine-mediated hyperactivity and amphetamine-induced disruption of prepulse inhibition. In addition, we assessed the effect of PD149163 on glycogen synthase kinase-3 (GSK-3) activity, a downstream molecular target of antipsychotics and mood stabilizers, using phospho-specific antibodies. PD149163 (0.1 and 0.5mg/kg) inhibited amphetamine-induced hyperactivity in mice, indicating that NTS1 activation inhibits psychomotor agitation. PD149163 (0.5mg/kg) also increased prepulse inhibition, suggesting that NTS1 activation reduces prepulse inhibition deficits which often co-occur with psychosis in humans. Interestingly, PD149163 increased the inhibitory serine phosphorylation on both GSK-3α and GSK-3β in a dose- and time-dependent manner in the nucleus accumbens and medial prefrontal cortex of the mice. Moreover, PD149163 inhibited GSK-3 activity in the nucleus accumbens and medial prefrontal cortex in the presence of amphetamine. Thus, like most current antipsychotics and mood stabilizers, PD149163 inhibited GSK-3 activity in cortico-striatal circuitry. Together, our findings indicate that PD149163 may be a novel antipsychotic.

Age-related changes in behavior in C57BL/6J mice from young adulthood to middle age.

BackgroundAging is considered to be associated with progressive changes in the brain and its associated sensory, motor, and cognitive functions. A large number of studies comparing young and aged animals have reported differences in various behaviors between age-cohorts, indicating behavioral dysfunctions related to aging. However, relatively little is known about behavioral changes from young adulthood to middle age, and the effect of age on behavior during the early stages of life remains to be understood. In order to investigate age-related changes in the behaviors of mice from young adulthood to middle age, we performed a large-scale analysis of the behavioral data obtained from our behavioral test battery involving 1739 C57BL/6J wild-type mice at 2–12 months of age.ResultsSignificant behavioral differences between age groups (2–3-, 4–5-, 6–7-, and 8–12-month-old groups) were found in all the behavioral tests, including the light/dark transition, open field, elevated plus maze, rotarod, social interaction, prepulse inhibition, Porsolt forced swim, tail suspension, Barnes maze, and fear conditioning tests, except for the hot plate test. Compared with the 2–3-month-old group, the 4–5- and 6–7-month-old groups exhibited decreased locomotor activity to novel environments, motor function, acoustic startle response, social behavior, and depression-related behavior, increased prepulse inhibition, and deficits in spatial and cued fear memory. For most behaviors, the 8–12-month-old group showed similar but more pronounced changes in most of these behaviors compared with the younger age groups. Older groups exhibited increased anxiety-like behavior in the light/dark transition test whereas those groups showed seemingly decreased anxiety-like behavior measured by the elevated plus maze test.ConclusionsThe large-scale analysis of behavioral data from our battery of behavioral tests indicated age-related changes in a wide range of behaviors from young adulthood to middle age in C57BL/6J mice, though these results might have been influenced by possible confounding factors such as the time of day at testing and prior test experience. Our results also indicate that relatively narrow age differences can produce significant behavioral differences during adulthood in mice. These findings provide an insight into our understanding of the neurobiological processes underlying brain function and behavior that are subject to age-related changes in early to middle life. The findings also indicate that age is one of the critical factors to be carefully considered when designing behavioral tests and interpreting behavioral differences that might be induced by experimental manipulations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0191-9) contains supplementary material, which is available to authorized users.

The Effect of Oxytocin on Social and Non-Social Behaviour and Striatal Protein Expression in C57BL/6N Mice.

Oxytocin has been suggested as a promising new treatment for neurodevelopmental disorders. However, important gaps remain in our understanding of its mode of action, in particular, to what extent oxytocin modulates social and non-social behaviours and whether its effects are generalizable across both sexes. Here we investigated the effects of a range of oxytocin doses on social and non-social behaviours in C57BL/6N mice of both sexes. As the striatum modulates social and non-social behaviours, and is implicated in neurodevelopmental disorders, we also conducted a pilot exploration of changes in striatal protein expression elicited by oxytocin. Oxytocin increased prepulse inhibition of startle but attenuated the recognition memory in male C57BL/6N mice. It increased social interaction time and suppressed the amphetamine locomotor response in both sexes. The striatum proteome following oxytocin exposure could be clearly discriminated from saline controls. With the caveat that these results are preliminary, oxytocin appeared to alter individual protein expression in directions similar to conventional anti-psychotics. The proteins affected by oxytocin could be broadly categorized as those that modulate glutamatergic, GABAergic or dopaminergic signalling and those that mediate cytoskeleton dynamics. Our results here encourage further research into the clinical application of this peptide hormone, which may potentially extend treatment options across a spectrum of neurodevelopmental conditions.

Effects of memantine on hippocampal long-term potentiation, gamma activity, and sensorimotor gating in freely moving rats

Memantine, an uncompetitive N-methyl-D-aspartate receptor antagonist, is used for treatment of patients with Alzheimer's disease. The mechanisms of memantine in relieving cognitive and behavioral symptoms are unclear, and this study attempts to elucidate its action on network and synaptic functions of the hippocampus. The effects of memantine on electrographic activity and hippocampal long-term potentiation (LTP) were investigated in freely moving rats. Basal dendritic excitation on hippocampal CA1 pyramidal cells showed a robust LTP after theta-frequency primed bursts, and the LTP was higher after 5–10 mg/kg intraperitoneal (ip) memantine pretreatment, as compared with saline pretreatment. Injection of scopolamine (5 mg/kg ip) before memantine failed to block the LTP-enhancing effect of memantine. Memantine as compared with saline pretreatment did not affect the LTP after an afterdischarge induced by high-frequency (200-Hz) train stimulation. Memantine (5 or 10 mg/kg ip) significantly enhanced gamma oscillations in the hippocampal local field potentials of 40–100 Hz during walking and awake immobility. Memantine at 10 mg/kg ip, but not at 5 mg/kg ip, increased prepulse inhibition of the acoustic startle response, while both 5 and 10 mg/kg ip memantine enhanced the acoustic startle response as compared with saline-injected rats. These electrophysiological and behavioral effects of memantine are unique among N-methyl-D-aspartate receptor antagonists but are consistent with memantine's effects in improving cognitive and sensorimotor functions of Alzheimer's patients.

The effects of varenicline on sensory gating and exploratory behavior with pretreatment with nicotinic or 5-HT3A receptor antagonists.

Individuals with schizophrenia smoke at high frequency relative to the general population. Despite the harmful effects of cigarette smoking, smoking among schizophrenic patients improves cognitive impairments not addressed or worsened by common neuroleptics. Varenicline, a nonselective neuronal nicotinic receptor (NNR) agonist and full agonist of 5-HT3A receptors, helps reduce smoking among schizophrenic patients. To determine whether varenicline also improves a cognitive symptom of schizophrenia, namely, impaired sensory gating, a transgenic mouse with schizophrenia, th-fgfr1(tk-), was used. Varenicline dose-dependently increased prepulse inhibition (PPI) of the startle response, a measure of sensory gating, in th-fgfr1(tk-) mice and normalized PPI deficits relative to nontransgenic controls. With the highest dose (10 mg/kg), however, there was a robust elevation of PPI and startle response, as well as reduced exploratory behavior in the open field and elevated plus maze. Pretreatment with the nonspecific NNR antagonist mecamylamine attenuated the exaggerated PPI response and, similar to the 5-HT3A receptor antagonist ondansetron, it prevented the reduction in exploratory behavior. Collectively, these results indicate that varenicline at low-to-moderate doses may be beneficial against impaired sensory gating in schizophrenia; however, higher doses may induce anxiogenic effects, which can be prevented with antagonists of NNRs or 5-HT3A receptors.

Repetitive grooming and sensorimotor abnormalities in an ephrin-A knockout model for Autism Spectrum Disorders

EphA receptors and ephrin-A ligands play important roles in neural development and synaptic plasticity in brain regions where expression persists into adulthood. Recently, EPHA3 and EPHA7 gene mutations were linked with Autism Spectrum Disorders (ASDs) and developmental neurological delays, respectively. Furthermore, deletions of ephrin-A2 or ephrin-A3, which exhibit high binding affinity for EphA3 and EphA7 receptors, are associated with subtle deficits in learning and memory behavior and abnormalities in dendritic spine morphology in the cortex and hippocampus in mice. To better characterize a potential role for these ligands in ASDs, we performed a comprehensive behavioral characterization of anxiety-like, sensorimotor, learning, and social behaviors in ephrin-A2/-A3 double knockout (DKO) mice. The predominant phenotype in DKO mice was repetitive and self-injurious grooming behaviors such as have been associated with corticostriatal circuit abnormalities in other rodent models of neuropsychiatric disorders. Consistent with ASDs specifically, DKO mice exhibited decreased preference for social interaction in the social approach assay, decreased locomotor activity in the open field, increased prepulse inhibition of acoustic startle, and a shift towards self-directed activity (e.g., grooming) in novel environments, such as marble burying. Although there were no gross deficits in cognitive assays, subtle differences in performance on fear conditioning and in the Morris water maze resembled traits observed in other rodent models of ASD. We therefore conclude that ephrin-A2/-A3 DKO mice have utility as a novel ASD model with an emphasis on sensory abnormalities and restricted, repetitive behavioral symptoms.

Effects of neonatal treatment with the TRPV1 agonist, capsaicin, on adult rat brain and behaviour

Treatment of neonatal rats with the transient receptor potential vanilloid 1 (TRPV1) channel agonist, capsaicin, produces life-long loss of sensory neurons expressing TRPV1 channels. Previously it was shown that rats treated on day 2 of life with capsaicin had behavioural hyperactivity in a novel environment at 5–7 weeks of age and brain changes reminiscent of those found in subjects with schizophrenia. The objective of the present study was to investigate brain and behavioural responses of adult rats treated as neonates with capsaicin. It was found that the brain changes found at 5–7 weeks in rats treated as neonates with capsaicin persisted into adulthood (12 weeks) but were less in older rats (16–18 weeks). Increased prepulse inhibition (PPI) of acoustic startle was found in these rats at 8 and 12 weeks of age rather than the deficit commonly found in animal models of schizophrenia. Subjects with schizophrenia also have reduced flare responses to niacin and methylnicotinate proposed to be mediated by prostaglandin D2 (PGD2). Flare responses are accompanied by cutaneous plasma extravasation. It was found that the cutaneous plasma extravasation responses to methylnicotinate and PGD2 were reduced in capsaicin-treated rats. In conclusion, several neuroanatomical changes observed in capsaicin-treated rats, as well as the reduced cutaneous plasma extravasation responses, indicate that the role of TRPV1 channels in schizophrenia is worthy of investigation.

Increased Prepulse Inhibition and Sensitization of the Startle Reflex in Autistic Children

The relation between autism spectrum disorders (ASD) and schizophrenia is a subject of intense debate and research due to evidence of common neurobiological pathways in the two disorders. The objective of this study was to explore whether deficits in prepulse inhibition (PPI) of the startle reflex, as usually seen in schizophrenic patients, can be replicated in a group of children with ASD in comparison with a group of matched neuro-typically developed (NTD) controls. An additional aim was to explore possible psychophysiological subgroups within our ASD sample. In a case-control design, 35 ASD patients and 40 matched NTD controls were tested in a psychophysiological test battery. The PPI of the acoustic startle reflex was analyzed in 18 ASD subjects and 34 NTD controls. Habituation and sensitization were analyzed in 23 ASD subjects and 39 NTD controls. In trials with less intense prestimuli (76 dB), patients with ASD did not display the drop in percentage PPI normally found in healthy controls. In addition, ASD patients showed significantly increased sensitization compared with NTD controls. Combined, our results may reflect the hypersensitivity to sensory information in children with ASD. The relation to PPI deficits observed in schizophrenia is not apparent. Future research should study the developmental course of PPI deficits in ASD patients in a longitudinal design.

Effects of intravenous nicotine on prepulse inhibition in smokers and non-smokers: relationship with familial smoking

The reinforcing properties of nicotine may be, in part, derived from its ability to enhance certain forms of cognitive processing. Several animal and human studies have shown that nicotine increases prepulse inhibition (PPI) of the startle reflex. However, it remains unclear whether these effects are related to smoking susceptibility. The current study examined the effects of intravenously delivered nicotine on PPI in smokers and non-smokers, as well as its association with a quantitative index of familial smoking. The sample consisted of 30 non-smokers and 16 smokers, who completed an initial assessment, followed on a separate day by a laboratory assessment of PPI prior to and following each of two intravenous nicotine infusions. Separate doses were used in smoker and non-smoker samples. Analyses indicated that both nicotine infusions acutely enhanced PPI among non-smokers, and this enhancement was positively related to the degree of smoking among first and second-degree relatives. Smokers also displayed PPI enhancement after receiving the first infusion, but this effect was unrelated to familial smoking. These data suggest that the PPI paradigm may have utility as an endophenotype for cognitive processes which contribute to smoking risk.

CEP-26401 (Irdabisant), a Potent and Selective Histamine H3 Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities

CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H₃ receptor (H₃R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H₃R was demonstrated in radioligand binding displacement assays in rat brain membranes (K(i) = 2.7 ± 0.3 nM) and recombinant rat and human H₃R-expressing systems (K(i) = 7.2 ± 0.4 and 2.0 ± 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [³⁵S]guanosine 5'-O-(γ-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H₃R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC₅₀ = 0.1 ± 0.003 mg/kg), and antagonism of the H₃R agonist R-α-methylhistamine- induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED₅₀ = 0.06 mg/kg). CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H₃R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders. CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics.

Behavioral effects of N-desmethylclozapine on locomotor activity and sensorimotor gating function in mice—Possible involvement of muscarinic receptors

N-desmethylclozapine (NDMC), a major circulating metabolite of the atypical antipsychotic drug, clozapine, and has M 1 muscarinic receptor partial agonistic property. The purpose of the present study was to examine whether in vivo behavioral effects of NDMC were elicited through the activation of muscarinic receptors. Both a non-selective muscarinic receptor agonist, oxotremorine (0.01–0.1 mg/kg), and an M 1 and M 4 muscarinic receptor agonist, xanomeline (0.3–3 mg/kg), decreased exploratory locomotor activity in mice. This effect was significantly antagonized by a non-selective muscarinic receptor antagonist, scopolamine, at a dose of 0.3 mg/kg without affecting exploratory locomotor activity by itself. NDMC (3–30 mg/kg) also decreased exploratory locomotor activity in a dose-dependent manner, and the reduced locomotor activity was significantly antagonized by scopolamine at doses of 0.1 and 0.3 mg/kg. These results suggested that NDMC might decrease exploratory locomotor activity at least partly through the activation muscarinic receptors in vivo. NDMC (10–30 mg/kg) and clozapine (0.3–1 mg/kg) dose-dependently increased prepulse inhibition (PPI) in DBA/2J mice, as did xanomeline (1–3 mg/kg). Scopolamine at a dose of 0.3 mg/kg without altering PPI by itself significantly antagonized the increase of PPI caused by NDMC (30 mg/kg), xanomeline (3 mg/kg), and oxotremorine (0.06 mg/kg). These findings suggest that the activation of muscarinic receptors may be at least partly responsible for exerting the antipsychotic-like effects of both NDMC and xanomeline in an animal model for schizophrenia.

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

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

Behavioral effects of clozapine: Involvement of trace amine pathways in C. elegans and M. musculus

Clozapine is an antipsychotic medication with superior efficacy in treatment refractory schizophrenia. The molecular basis of clozapine's therapeutic profile is not well understood. We studied behavioral effects of clozapine in Caenorhabditis elegans to identify novel pathways that modulate clozapine's biological effects. Clozapine stimulated egg laying in C. elegans in a dose-dependent manner. This effect was clozapine-specific, as it was not observed with exposure to a typical antipsychotic, haloperidol or an atypical antipsychotic, olanzapine. A candidate gene screen of biogenic amine neurotransmitter systems identified signaling pathways that mediate this clozapine-specific effect on egg laying. Specifically, we found that clozapine-induced increase in egg laying requires tyramine biosynthesis. To test the implications of this finding across species, we explored whether trace amine systems modulate clozapine's behavioral effects in mammals by studying trace amine-associated receptor 1 (TAAR1) knockout mice. Clozapine increased prepulse inhibition (PPI) in wild-type mice. This increase in PPI was abrogated in TAAR1 knockout mice, implicating TAAR1 in clozapine-induced PPI enhancement. In transfected mammalian cell lines, we found no TAAR activation by antipsychotics, suggesting that modulation of trace amine signaling in mice does not occur directly at the receptor itself. In summary, we report a heretofore-unknown role for trace amine systems in clozapine-mediated effects across two species: C. elegans and mice.

Pharmacological effects of metabotropic glutamate receptor ligands on prepulse inhibition in DBA/2J mice

Schizophrenic patients typically exhibit impairment of sensorimotor gating, which can be modeled in animals using acoustic prepulse inhibition of the startle. Both classical and atypical antipsychotics have been shown to improve prepulse inhibition in DBA/2J mice, a non-pharmacological model for impaired sensorimotor gating. The purpose of the present study was to clarify whether metabotropic glutamate receptors participate in control of sensorimotor gating. We evaluated various metabotropic glutamate receptor ligands on prepulse inhibition in DBA/2J mice. This basal level of prepulse inhibition in DBA/2J mice was increased by only the mGlu 1 receptor antagonists [2-cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1 H-1,2,3-triazol-4-yl]-2,3-dihydro-1 H-isoindol-1-one] (CFMTI), 6-amino- N-cyclohexyl- N,3-dimethylthiazolo[3,2-α]benzimidazole-2-carboxamide hydrochloride (YM-298198), and (3,4-dihydro-2 H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685). There was no effect after treatments with the mGlu 5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), the mGlu 2/3 receptor agonist (−)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), the mGlu 2/3 receptor antagonist (2 S)-2-amino-2-[(1 S,2 S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), the mGlu 7 receptor agonist N,N ′-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), the mGlu 7 receptor antagonist 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5- c]pyridin-4(5 H)-one (MMPIP), or the mGlu 8 receptor agonist ( S)-3,4-dicarboxyphenylglycine (DCPG). These findings indicate that inhibition of mGlu 1 receptor selectively increases prepulse inhibition in DBA/2J mice and suggest that mGlu 1 receptor antagonists could be a novel treatment for some aspects of schizophrenia.