The effects of kappa-opioid receptor ligands on prepulse inhibition and CRF-induced prepulse inhibition deficits in the rat

Rationale  

Kappa-opioid receptor (KOR) agonists produce dysphoria and psychotomimesis in humans. KORs are enriched in the prefrontal cortex and other brain regions that regulate mood and cognitive function. Dysregulation of the dynorphin/KOR system has been implicated in the pathogenesis of schizophrenia, depression, and bipolar disorder. Prepulse inhibition of the acoustic startle reflex (PPI), a sensorimotor gating process, is disrupted in many psychiatric disorders.     

Group II mGluR agonist LY354740 and NAAG peptidase inhibitor effects on prepulse inhibition in PCP and <Emphasis Type="SmallCaps">d</Emphasis>-amphetamine models of schizophrenia

Rationale  

Group II metabotropic glutamate receptor (mGluR) agonists represent a novel approach to the treatment of schizophrenia. Inasmuch as the peptide neurotransmitter N-acetylaspartylglutamate (NAAG) activates these receptors, NAAG peptidase inhibitors conceptually represent a parallel path toward development of new antipsychotic drugs. While group II agonists are effective in several animal models of schizophrenia, they are reported to lack efficacy in moderating the effects of phencyclidine (PCP) on prepulse inhibition of acoustic startle in animal models of sensory processing deficits found in this disorder.     

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

Background

Allopregnanolone is an endogenous neuroactive steroid which, through the binding to the GABA_A receptor, enhances inhibitory neurotransmission and exerts anxiolytic, sedative and antiepileptic effects. Following acute administration, allopregnanolone reliably acts as an anxiolytic compound. The primary aim of this study was to investigate if allopregnanolone, administered to healthy women and women with premenstrual dysphoric disorder (PMDD), would have an anxiolytic effect, expressed as a decreased startle response.

Materials and methods

Sixteen PMDD patients and twelve healthy controls completed the study. The participants were scheduled for the startle tests twice in the luteal phase. During the test sessions an intravenous allopregnanolone and placebo bolus injection was administered in double-blinded, randomized order at intervals of 48 h. Following the allopregnanolone/placebo injections startle response and prepulse inhibition of startle response (PPI) were assessed by electromyography.

Results

Following the intravenous allopregnanolone administration the serum concentrations of allopregnanolone increased to 50-70 nmol/l, corresponding to levels that are seen during pregnancy. The obtained serum concentrations of allopregnanolone were significantly lower in PMDD patients than among the healthy controls, p < 0.05. The allopregnanolone injection resulted in significant increases of self-rated sedation in both groups, p < 0.01. Allopregnanolone did not induce any changes in startle response or prepulse inhibition of startle response in comparison to placebo. No differences in allopregnanolone-induced changes in startle response or PPI could be detected between PMDD patients and controls subjects.

Conclusion

Startle response and PPI were unaffected by acute intravenous administration of allopregnanolone in PMDD patients and healthy controls.     

Sensorimotor gating in neurotensin-1 receptor null mice

BACKGROUND

Converging evidence has implicated endogenous neurotensin (NT) in the pathophysiology of brain processes relevant to schizophrenia. Prepulse inhibition of the startle reflex (PPI) is a measure of sensorimotor gating and considered to be of strong relevance to neuropsychiatric disorders associated with psychosis and cognitive dysfunction. Mice genetically engineered to not express NT display deficits in PPI that model the PPI deficits seen in schizophrenia patients. NT1 receptors have been most strongly implicated in mediating the psychosis relevant effects of NT such as attenuating PPI deficits. To investigate the role of NT1 receptors in the regulation of PPI, we measured baseline PPI in wildtype (WT) and NT1 knockout (KO) mice. We also tested the effects of amphetamine and dizocilpine, a dopamine agonist and NMDA antagonist, respectively, that reduce PPI as well as the NT1 selective receptor agonist PD149163, known to increase PPI in rats.

METHODS

Baseline PPI and acoustic startle response were measured in WT and NT1 KO mice. After baseline testing, mice were tested again after receiving intraperatoneal (IP) saline or one of three doses of amphetamine (1.0, 3.0 and 10.0 mg/kg), dizocilpine (0.3, 1.0 and 3.0 mg/kg) and PD149163 (0.5, 2.0 and 6.0 mg/kg) on separate test days.

RESULTS

Baseline PPI and acoustic startle response in NT1 KO mice were not significantly different from NT1 WT mice. WT and KO mice exhibited similar responses to the PPI-disrupting effects of dizocilpine and amphetamine. PD149163 significantly facilitated PPI (P < 0.004) and decreased the acoustic startle response (P < 0.001) in WT but not NT1 KO mice.

CONCLUSIONS

The data does not support the regulation of baseline PPI or the PPI disruptive effects of amphetamine or dizocilpine by endogenous NT acting at the NT1 receptor, although they support the antipsychotic potential of pharmacological activation of NT1 receptors by NT1 agonists.     

The glutamatergic compounds sarcosine and N-acetylcysteine ameliorate prepulse inhibition deficits in metabotropic glutamate 5 receptor knockout mice

Rationale  

Mice lacking metabotropic glutamate receptors 5 (mGluR5) exhibit reduced glutamatergic function and behavioral abnormalities, including deficits in prepulse inhibition (PPI) of the startle response that may be relevant to schizophrenia. Thus, these mice are an animal model that may be used for preclinical evaluation of potentially new classes of antipsychotic compounds. Recent clinical studies have suggested several compounds that modulate glutamatergic transmission through distinct mechanisms, such as potentiation of the N-methyl-d-aspartate (NMDA) receptor glycine site, activation of group II mGluR, and activation of glutamate-cysteine antiporters, as being efficacious in the treatment of schizophrenia.     

Association between PLA2G12A polymorphism and patients with schizophrenia in a southern Chinese Han population

Background

Elevated phospholipase A2 (PLA2) activity is reported to be involved in the development of schizophrenia. Further study revealed an association between PLA2 groups XIIA (PLA2G12A) polymorphism and patients with schizophrenia in a northeast Chinese Han population.

Objective

This study will further examine whether PLA2G12A rs3087494 polymorphism is associated with patients with schizophrenia in a southern Chinese Han population.

Methods

This polymorphism was genotyped in 438 patients with schizophrenia (diagnosed according to Diagnostic and Statistical Manual of Mental Disorders‐IV) and 876 healthy controls using a case–control design. Demographic and clinical data were collected in all subjects.

Results

The allele and genotype frequencies of PLA2G12A rs3087494 polymorphism significantly differed between groups (both, p < .001). These differences still were significant by adjusting for sex and age. However, there was no difference in age at onset among 3 genotype groups in patients with schizophrenia by adjusting for the variables (F = 0.22, p = .80). Stepwise multivariate regression analysis showed that this polymorphism was not associated with age at onset in patients with schizophrenia (β = .008, t = .07, p = .94).

Conclusions

Our results indicated that even though PLA2G12A rs3087494 polymorphism did not influence age at onset in patients with schizophrenia, it may play an important role in the susceptibility to schizophrenia in a southern Chinese Han population.     

Effect of tandospirone, a serotonin-1A receptor partial agonist, on information processing and locomotion in dizocilpine-treated rats

Rationale  

Augmentation therapy with serotonin-1A receptor (5-HT1A) partial agonists has been suggested to ameliorate psychotic symptoms in patients with schizophrenia.     

Discordant behavioral effects of psychotomimetic drugs in mice with altered NMDA receptor function

Rationale

Enhancement of N-methyl-d-aspartate receptor (NMDAR) activity through its glycine modulatory site (GMS) is a novel therapeutic approach in schizophrenia. Brain concentrations of endogenous GMS agonist d-serine and antagonist N-acetyl-aspartylglutamate are regulated by serine racemase (SR) and glutamic acid decarboxylase 2 (GCP2), respectively. Using mice genetically, under-expressing these enzymes may clarify the role of NMDAR-mediated neurotransmission in schizophrenia.

Objectives

We investigated the behavioral effects of two psychotomimetic drugs, the noncompetitive NMDAR antagonist, phencyclidine (PCP; 0, 1.0, 3.0, or 6.0?mg/kg), and the indirect dopamine receptor agonist, amphetamine (AMPH; 0, 1.0, 2.0, or 4.0?mg/kg), in SR ?/? and GCP2 ?/+ mice. Outcome measures were locomotor activity and prepulse inhibition (PPI) of the acoustic startle reflex. Acute effects of an exogenous GMS antagonist, gavestinel (0, 3.0, or 10.0?mg/kg), on PCP-induced behaviors were examined in wild-type mice for comparison to the mutants with reduced GMS activity.

Results

PCP-induced hyperactivity was increased in GCP2 ?/+ mice, and PCP-enhanced startle reactivity was increased in SR ?/? mice. PCP disruption of PPI was unaffected in either mutant. In contrast, gavestinel attenuated PCP-induced PPI disruption without effect on baseline PPI or locomotor activity. AMPH effects were similar to controls in both mutant strains.

Conclusions

The results of the PCP experiments demonstrate that convergence of pharmacological and genetic manipulations at NMDARs may confound the predictive validity of these preclinical assays for the effects of GMS activation in schizophrenia. The AMPH data provide additional evidence that hyperdopaminergia in schizophrenia may be distinct from NMDAR hypofunction.     

Glutamatergic Neurometabolites in Clozapine-Responsive and -Resistant Schizophrenia

Background:

According to the current schizophrenia treatment guidelines, 3 levels of responsiveness to antipsychotic medication exist: those who respond to first-line antipsychotics, those with treatment-resistant schizophrenia who respond to clozapine, and those with clozapine-resistant or ultra-treatment resistant schizophrenia. Proton magnetic resonance spectroscopy studies indicate that antipsychotic medication decreases glutamate or total glutamate + glutamine in the brains of patients with schizophrenia and may represent a biomarker of treatment response; however, the 3 levels of treatment responsiveness have not been evaluated.

Methods:

Proton magnetic resonance spectroscopy spectra were acquired at 3 Tesla from patients taking a second generation non-clozapine antipsychotic (first-line responders), patients with treatment-resistant schizophrenia taking clozapine, patients with ultra-treatment resistant schizophrenia taking a combination of antipsychotics, and healthy comparison subjects.

Results:

Group differences in cerebrospinal fluid-corrected total glutamate + glutamine levels scaled to creatine were detected in the dorsolateral prefrontal cortex [df(3,48); F = 3.07, P = .04, partial η² = 0.16] and the putamen [df(3,32); F = 2.93, P = .05, partial η² = 0.22]. The first-line responder group had higher dorsolateral prefrontal cortex total glutamate + glutamine levels scaled to creatine than those with ultra-treatment resistant schizophrenia [mean difference = 0.25, standard error = 0.09, P = .04, family-wise error-corrected]. Those with treatment-resistant schizophrenia had higher total glutamate + glutamine levels scaled to creatine in the putamen than the first-line responders (mean difference = 0.31, standard error = 0.12, P = .05, family-wise error-corrected) and those with ultra-treatment-resistant schizophrenia (mean difference = 0.39, standard error = 0.12, P = .02, family-wise error-corrected).

Conclusions:

Total glutamate + glutamine levels scaled to creatine in the putamen may represent a marker of response to clozapine. Future studies should investigate glutamatergic anomalies prior to clozapine initiation and following successful treatment.     

Are DBA/2 mice associated with schizophrenia-like endophenotypes? A behavioural contrast with C57BL/6 mice

Rationale

Due to its intrinsic deficiency in prepulse inhibition (PPI), the inbred DBA/2 mouse strain has been considered as an animal model for evaluating antipsychotic drugs. However, the PPI impairment observed in DBA/2 mice relative to the common C57BL/6 strain is confounded by a concomitant reduction in baseline startle reactivity. In this study, we examined the robustness of the PPI deficit when this confound is fully taken into account.

Materials and methods

Male DBA/2 and C57BL/6 mice were compared in a PPI experiment using multiple pulse stimulus intensities, allowing the possible matching of startle reactivity prior to examination of PPI. The known PPI-enhancing effect of the antipsychotic, clozapine, was then evaluated in half of the animals, whilst the other half was subjected to two additional schizophrenia-relevant behavioural tests: latent inhibition (LI) and locomotor reaction to the psychostimulants—amphetamine and phencyclidine.

Results

PPI deficiency in DBA/2 relative to C57BL/6 mice was essentially independent of the strain difference in baseline startle reactivity. Yet, there was no evidence that DBA/2 mice were superior in detecting the PPI-facilitating effect of clozapine when startle difference was balanced. Compared with C57BL/6 mice, DBA/2 mice also showed impaired LI and a different temporal profile in their responses to amphetamine and phencyclidine.

Conclusion

Relative to the C57BL/6 strain, DBA/2 mice displayed multiple behavioural traits relevant to schizophrenia psycho- and physiopathology, indicative of both dopaminergic and glutamatergic/N-methyl-d-aspartic acid receptor dysfunctions. Further examination of their underlying neurobiological differences is therefore warranted in order to enhance the power of this specific inter-strain comparison as a model of schizophrenia.     

Socio-demographic and clinical characteristics of heavy and non-heavy smokers among schizophrenia inpatients in a Chinese Han population

Objective

Despite higher smoking rates in schizophrenia, few studies have explored the clinical–demographic correlates of different amounts of smoking exposure. Little is known about the association between smoking severity and clinical phenotypes in Chinese patients with schizophrenia.

Materials and methods

We investigated differences between heavy (≥1 pack/day) and non-heavy (<1 pack/day) smoking in 550 male inpatients with schizophrenia using clinician-administered questionnaires and the Fagerstrom Test for Nicotine Dependence. They also were rated on the Positive and Negative Symptom Scale (PANSS), the Simpson and Angus Extrapyramidal Symptom Rating Scale (SAES), and the Abnormal Involuntary Movement Scale (AIMS), as well as were assayed with laboratory tests and an electrocardiogram.

Results

Heavy smoking prevalence was approximately 31 %. Compared to the non-heavy smokers, the heavy smokers were younger, more with paranoid subtype but less with disorganized subtype schizophrenia, smoked at an earlier age, fewer getting clozapine or all atypical antipsychotics together, and were taking larger doses of antipsychotic drugs. The heavy smokers scored significantly lower on the PANSS negative symptom subscore and total score, and also on the SAES and AIMS scores than the non-heavy smokers. In addition, heavy smokers displayed longer rate-corrected electrocardiographic QT intervals, but without any significant differences in other laboratory tests.

Conclusion

Our results suggest several clinical or demographic differences between the heavy and non-heavy smoking patients with schizophrenia in a Chinese population. Heavy smoking remains a general health risk for schizophrenia.     

The effect of nicotine and trauma context on acoustic startle in smokers with and without posttraumatic stress disorder

Rationale  

Exaggerated startle response is a prominent feature of posttraumatic stress disorder (PTSD) although results examining differences in the acoustic startle response (ASR) between those with and without PTSD are mixed. One variable that may affect ASR among persons with PTSD is smoking. Individuals with PTSD are more likely to smoke and have greater difficulty quitting smoking. While smokers with PTSD report that smoking provides significant relief of negative affect and PTSD symptoms, the effects of smoking or nicotine deprivation on startle reactivity among smokers with PTSD are unknown.     

Corticosteroid dependent and independent effects of a cannabinoid agonist on core temperature,motor activity,and prepulse inhibition of the acoustic startle reflex in Wistar rats

Rationale  

There are inconsistent reports on the effects of cannabinoid agonists on prepulse inhibition of the startle reflex (PPI) with increases, decreases, and no effects. It has been hypothesized that the conflicting observations may be as a result of modulation of the effects of cannabinoid agonists by the regulation of corticosteroid release.     

Electrophysiological and behavioral responses to ketamine in mice with reduced Akt1 expression

Rationale

A number of studies have associated reduced Akt1 expression with vulnerability for schizophrenia. Although mice with deletion of a single copy of the Akt1 gene (Akt1^+/?) show reduced Akt1 expression relative to wild-type (WT) animals, the extent to which these mice show schizophrenia-like phenotypic changes and/or increased susceptibility to epigenetic or non-genetic factors related to schizophrenia is unknown.

Objectives

Mutant mice were assessed on electroencephalographic/event-related potential (EEG/ERP) and behavioral (acoustic startle and pre-pulse inhibition) measures relevant to schizophrenia. Mice were also assessed following exposure to the NMDA receptor antagonist ketamine, a potent psychotomimetic drug, in order to assess the role of reduced Akt1 expression as a vulnerability factor for schizophrenia. Methods Akt1^+/?, Akt1^?/?, and WT mice received a series of paired-click, white noise stimuli, following ketamine (50 mg/kg) and saline injections. EEG was analyzed for ERPs and event-related power. Akt1^+/? and WT mice were also assessed on PPI following ketamine (50 mg/kg) or saline injection.

Results

Akt1^+/? and Akt1^?/? mice displayed reduced amplitude of the P20 component of the ERP to the first click of a paired-click stimulus, as well as reduced S1–S2 difference for P20 and N40 components, following ketamine. Mutant mice also showed increased reduction in gamma synchrony and theta suppression following ketamine. Akt1^+/? mice displayed reduced pre-pulse inhibition.

Conclusions

Reduced genetic expression of Akt1 facilitated ketamine-induced changes of EEG and behavior in mice, suggesting that reduced Akt1 expression can serve as a vulnerability factor for schizophrenia.     

Motivation to quit smoking and startle modulation in female smokers: context specificity of smoking cue reactivity

Rationale  

Cue reactivity and startle reflex modulation paradigms have been used in addiction research to determine the affective motivational state of craving induced by viewing drug-related cues. However, recent studies suggest that cue reactivity and startle reflex modulation in people with addictions can be suppressed, or even reversed, depending on context.     

Dexamphetamine effects on prepulse inhibition (PPI) and startle in healthy volunteers

Rationale

Amphetamine challenge in rodent prepulse inhibition (PPI) studies has been used to model potential dopamine involvement in effects that may be relevant to schizophrenia, though similar studies in healthy humans have failed to report replicable or robust effects.

Objectives

The present study investigated dexamphetamine effects on PPI in healthy humans with an increased dose and a range of startling stimulus intensities to determine participants' sensitivity and range of responses to the stimuli.

Methods

A randomised, placebo-controlled dexamphetamine (0.45 mg/kg, per os.), double-blind, counterbalanced, within-subject design was used. PPI was measured in 64 participants across a range of startling stimulus intensities, during two attention set conditions (ATTEND and IGNORE). Startle magnitudes for pulse-alone and prepulse-pulse magnitudes were modelled using the startle reflex magnitude (sigmoid) function. Parameters were extracted from these fits, including the upper limit of the asymptote (maximum startle reflex capacity, R _MAX), intensity threshold, stimulus intensity that elicits a half-maximal response (ES₅₀) and the maximum rate of change of startle response magnitude to an increase in stimulus intensity.

Results

Dexamphetamine increased the threshold and ES₅₀ of the response to pulse-alone trials in both sexes and reduced R _MAX exclusively in females. Dexamphetamine modestly increased PPI of the R _MAX across both attention conditions. PPI of R _MAX was reduced during the ATTEND condition compared to the IGNORE condition.

Conclusions

Results indicate that sex differences exist in motor, but not sensory, components of the startle reflex. Findings also reveal that administration of 0.45 mg/kg dexamphetamine to healthy humans does not mimic PPI effects observed in schizophrenia.     

GluN2C/GluN2D subunit-selective NMDA receptor potentiator CIQ reverses MK-801-induced impairment in prepulse inhibition and working memory in Y-maze test in mice

Background and Purpose

Despite ample evidence supporting the N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia, progress in the development of effective therapeutics based on this hypothesis has been limited. Facilitation of NMDA receptor function by co-agonists (d-serine or glycine) only partially alleviates the symptoms in schizophrenia; other means to facilitate NMDA receptors are required. NMDA receptor sub-types differ in their subunit composition, with varied GluN2 subunits (GluN2A-GluN2D) imparting different physiological, biochemical and pharmacological properties. CIQ is a positive allosteric modulator that is selective for GluN2C/GluN2D-containing NMDA receptors (Mullasseril et al.).

Experimental Approach

The effect of systemic administration of CIQ was tested on impairment in prepulse inhibition (PPI), hyperlocomotion and stereotypy induced by i.p. administration of MK-801 and methamphetamine. The effect of CIQ was also tested on MK-801-induced impairment in working memory in Y-maze spontaneous alternation test.

Key Results

We found that systemic administration of CIQ (20 mg·kg⁻¹, i.p.) in mice reversed MK-801 (0.15 mg·kg⁻¹, i.p.)-induced, but not methamphetamine (3 mg·kg⁻¹, i.p.)-induced, deficit in PPI. MK-801 increased the startle amplitude to pulse alone, which was not reversed by CIQ. In contrast, methamphetamine reduced the startle amplitude to pulse alone, which was reversed by CIQ. CIQ also partially attenuated MK-801- and methamphetamine-induced hyperlocomotion and stereotyped behaviours. Additionally, CIQ reversed the MK-801-induced working memory deficit in spontaneous alternation in a Y-maze.

Conclusion and Implications

Together, these results suggest that facilitation of GluN2C/GluN2D-containing receptors may serve as an important therapeutic strategy for treating positive and cognitive symptoms in schizophrenia.     

The effects of PRX-07034, a novel 5-HT<Subscript>6</Subscript> antagonist,on cognitive flexibility and working memory in rats

Rationale  

Accumulating evidence indicates that schizophrenia and autism spectrum disorder patients are marked by cognitive deficits in working memory and strategy switching. There is accumulating evidence that 5-hydroxytryptamine (5-HT)₆ receptors may serve as a useful target to improve cognitive functioning.     

Increased cortical inhibition deficits in first-episode schizophrenia with comorbid cannabis abuse

Rationale/objectives  

There is a high prevalence of substance use disorder (SUD) in first-episode schizophrenia (SZ), but its contribution to the underlying SZ pathophysiology remains unclear. Several studies using transcranial magnetic stimulation (TMS) have observed abnormalities in human motor cortex (M1) excitability in SZ. Studies on cortical excitability comparing SZ patients with and without comorbid substance abuse are lacking.     

Potentiated startle as a measure of the negative affective consequences of repeated exposure to nicotine in rats

Rationale  

Elevated acoustic startle amplitude has been used to measure anxiety-like effects of drug withdrawal in humans and animals. Withdrawal from a single opiate administration has been shown to produce robust elevations in startle amplitude (“withdrawal-potentiated startle”) that escalate in severity with repeated exposure. Although anxiety is a clinical symptom of nicotine dependence, it is currently unknown whether anxiety-like behavior is elicited during the early stages of nicotine dependence in rodents.