Neural basis for a heritable phenotype: differences in the effects of apomorphine on startle gating and ventral pallidal GABA efflux in male Sprague–Dawley and Long–Evans rats

Rationale

Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is heritable and deficient in certain psychiatric disorders, including schizophrenia. Sprague–Dawley (SD) rats are more sensitive to PPI disruptive effects of dopamine (DA) agonists at long interstimulus intervals (60–120 ms) and less sensitive to their PPI-enhancing effects at short (10–30 ms), compared with Long–Evans (LE) rats. These heritable strain differences in sensitivity to the PPI disruptive effects of DA agonists must ultimately reflect neural changes "downstream" from forebrain DA receptors.

Objective

The current study evaluated the effects of the DA agonist, apomorphine (APO), on ventral pallidal (VP) gamma-aminobutyric acid (GABA) and glutamate efflux and PPI in SD and LE rats.

Methods

PPI was tested in SD and LE rats after vehicle or APO (0.5 mg/kg, subcutaneously (s.c.)) in a within-subject design. In different SD and LE rats, VP dialysate was collected every 10 min for 120 min after vehicle or APO (0.5 mg/kg, s.c.) and analyzed for GABA and glutamate content by capillary electrophoresis (CE) coupled with laser-induced fluorescence (LIF).

Results

As predicted, SD rats exhibited greater APO-induced PPI deficits at long intervals and less APO-induced PPI enhancement at short intervals compared to LE rats. APO significantly reduced VP GABA efflux in SD but not in LE rats; glutamate efflux was unaffected in both strains.

Conclusion

Heritable strain differences in PPI APO sensitivity in SD vs LE rats parallel, and may be mediated by, strain differences in the VP GABA efflux.     

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.     

Blockade of nucleus accumbens 5-HT2A and 5-HT2C receptors prevents the expression of cocaine-induced behavioral and neurochemical sensitization in rats

Rationale

The serotonin 5-HT_2A and 5-HT_2C receptors regulate the capacity of acute cocaine to augment behavior and monoamine levels within the nucleus accumbens (NAC), a brain region involved in cocaine??s addictive and psychotogenic properties.

Objectives

In the present study, we tested the hypothesis that NAC 5-HT_2A and 5-HT_2C receptor activation is involved in the expression of cocaine-induced neuroplasticity following protracted withdrawal from a sensitizing repeated cocaine regimen (days?1 and 7, 15?mg/kg; days?2?C6, 30?mg/kg, i.p.).

Methods

The effects of intra-NAC infusions of the 5-HT_2A antagonist R-(+)-??-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methanol (MDL 100907; 0, 50, 100, 500?nM) or the 5-HT_2C antagonist [6-chloro-5-methyl-1-(6-(2-methylpiridin-3-yloxy)pyridine-3-yl carbamoyl] inodoline dihydrochloride (SB 242084; 0, 50, 100, 500?nM) were first assessed upon the expression of locomotor activity elicited by a 15-mg/kg cocaine challenge injection administered at 3-week withdrawal. A follow-up in vivo microdialysis experiment then compared the effects of the local perfusion of 0, 50, or 100?nM of each antagonist upon cocaine-induced dopamine and glutamate sensitization in the NAC.

Results

Although neither MDL 100907 nor SB 242084 altered acute cocaine-induced locomotion, SB 242084 reduced acute cocaine-elevated NAC dopamine and glutamate levels. Intra-NAC perfusion with either compound blocked the expression of cocaine-induced locomotor and glutamate sensitization, but only MDL 100907 pretreatment prevented the expression of cocaine-induced dopamine sensitization.

Conclusions

These data provide the first evidence that NAC 5-HT_2A and 5-HT_2C receptors are critical for the expression of cocaine-induced neuroplasticity following protracted withdrawal, which has relevance for their therapeutic utility in the treatment of addiction.     

Remediation of attentional dysfunction in rats with lesions of the medial prefrontal cortex by intra-accumbens administration of the dopamine D2/3 receptor antagonist sulpiride

Rationale

Anti-psychotic drugs are widely recognised to produce beneficial effects on impaired cognition in schizophrenia but their mechanism of action is poorly understood. The prefrontal cortex (PFC) and nucleus accumbens (NAC) are key brain loci considered to mediate many of the cognitive deficits associated with schizophrenia and related disorders.

Objectives

To investigate (1) the effects of selective damage to the PFC on visuo-spatial attention and cognition in the rat and (2) the ability of the anti-psychotic drug sulpiride after its intra-NAC administration to ameliorate cognitive and behavioural deficits produced by lesions of the PFC.

Methods

Selective lesions of the medial PFC were made using quinolinic acid in rats previously trained on a five-choice serial reaction time task of sustained visual attention (n = 7). Sham rats received phosphate-buffered saline infusions (n = 7). Following a period of recovery, low doses of sulpiride (0.5ng or 1ng) were infused into the core sub-region of the NAC of sham and lesioned rats immediately prior to testing on the five-choice task.

Results

Lesions of the medial PFC produced a range of impairments on the five-choice task, including decreased attentional accuracy, slower latencies to respond correctly and increased omissions and premature responses, the latter an operational measure of impulsivity. Intra-NAC sulpiride dose-dependently ameliorated the increased impulsivity and attentional impairment present in PFC-lesioned rats.

Conclusions

These findings suggest that attentional and cognitive impairment in schizophrenia may be determined in part by a dysregulation of the subcortical dopamine systems occurring as a consequence of damage to the PFC.     

The effect of nicotine on sensorimotor gating is modulated by a CHRNA3 polymorphism

Rationale

Prepulse inhibition (PPI) of the acoustic startle response, a measure of sensorimotor gating, can be enhanced by nicotine. Moreover, the TT genotype of the nicotinic acetylcholine receptor (nAChR) α3-subunit (CHRNA3) rs1051730 polymorphism has previously been associated with diminished PPI and nicotine dependence.

Objectives

We tested whether this CHRNA3 polymorphism also modulates the nicotine-induced enhancement of PPI.

Methods

We assessed the effect of nicotine on PPI, startle reactivity, and habituation in 52 healthy nonsmoking volunteers genotyped for CHRNA3 rs1051730 in a double-blind, placebo-controlled, counterbalanced, within-subjects design. Additionally, cotinine plasma levels were measured.

Results

Nicotine significantly enhanced PPI in TT homozygotes only and tended to worsen PPI in TC and CC carriers. Additionally, nicotine significantly reduced startle habituation.

Conclusions

The present findings imply that the effect of nicotine on sensorimotor gating is modulated by nAChR α3-subunits. Thus, genetic variation in nicotinic receptor genes might be an important connecting link between early attentional processes and smoking behavior.     

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.     

Long-term effects of neonatal MK-801 treatment on prepulse inhibition in young adult rats

Rationale

Blockade of N-methyl-d-asparate (NMDA) receptors has been shown to produce some of the abnormal behaviors related to symptoms of schizophrenia in rodents and human. Neonatal treatment of rats with non-competitive NMDA antagonists has been shown to induce behavioral abnormality in a later period.

Objectives

The aim of this study was to determine whether brief disruption of NMDA receptor function during a critical stage of development is sufficient to produce sensorimotor-gating deficits in the late adolescence or early adulthood in the rat.

Methods

Male pups received the NMDA receptor blocker MK-801 (0.13 or 0.20 mg/kg), or an equal volume of saline on postnatal day (PD) 7 through 10. The animals were tested twice for prepulse inhibition (PPI) and locomotor activity in pre- (PD 35-38) and post- (PD 56-59) puberty.

Results

Neonatal exposure to both doses MK-801 disrupted PPI in the adolescence and early adulthood. Low-dose MK-801 elicited long-term effects on startle amplitudes, whereas high-dose MK-801 did not. Neither dose of MK-801 showed a significant effect on spontaneous locomotor activity, whereas the high dose attenuated rearing.

Conclusions

The results of this study suggest neonatal exposure to MK-801 disrupted sensorimotor gating in the adolescence and early adulthood stages. These findings indicate that rats transiently exposed to NMDA blockers in neonatal periods are useful for the study of the pathophysiology and treatment of schizophrenia.     

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.     

Sildenafil adjunctive therapy to risperidone in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled trial

Rational

It has been suggested that phosphodiesterase 5 inhibitors such as sildenafil may be effective in the treatment of negative symptoms of schizophrenia.

Objective

This study was designed to investigate the effect of sildenafil added to risperidone as augmentation therapy in patients with chronic schizophrenia and prominent negative symptoms in a double-blind and randomized clinical trial.

Methods

Eligible participants in the study were 40 patients with chronic schizophrenia with ages ranging from 18 to 45?years. All patients were inpatients and were in the active phase of the illness and met DSM-IV-TR criteria for schizophrenia. Patients were allocated in a random fashion: 20 to risperidone (6?mg/day) plus sildenafil (75?mg/day) and 20 to risperidone (6?mg/day) plus placebo. The principal measure of outcome was Positive and Negative Syndrome Scale (PANSS).

Results

Although both protocols significantly decreased the score of the positive, negative, and general psychopathological symptoms over the trial period, the combination of risperidone and sildenafil showed a significant superiority over risperidone alone in decreasing negative symptoms and PANSS total scores over the 8-week trial (between-subjects factor; F?=?4.77, df?=?1; P?=?0.03; F?=?5.91, df?=?1, P?=?0.02 respectively).

Conclusion

Therapy with 75?mg/day of sildenafil was well tolerated, and no clinically important side effects were observed. The present study indicates sildenafil as a potential adjunctive treatment strategy for treatment of negative symptoms of schizophrenia. This trial is registered with the Iranian Clinical Trials Registry (IRCT1138901151556N11).     

Critical role of nitric oxide in the modulation of prepulse inhibition in Swiss mice

Rationale

Nitric oxide (NO) modulates the dopamine uptake and release processes and appears to be implicated in dopamine-related pathologies, such as schizophrenia. However, it is unclear whether there is excess or deficient NO synthesis in schizophrenia pathophysiology. Analyses of the intracellular pathways downstream of NO system activation have identified the cyclic nucleotide cyclic guanosine monophosphate (cGMP) as a possible target for drug development. Defects in the sensorimotor gating of the neural mechanism underlying the integration and processing of sensory information have been detected across species through prepulse inhibition (PPI).

Objectives

The aim of this study was to investigate the effects of NO/cGMP increase on sensorimotor gating modulation during dopamine hyperfunction.

Methods

Mice were treated with NO donors and subjected to the PPI test. Treatment with the NO donor sodium nitroprusside was preceded by pretreatment with a soluble guanylate cyclase (sGC) inhibitor. Additionally, the mice were treated with NO donors and phosphodiesterases inhibitors prior to amphetamine treatment.

Results

Pretreatment with the NO donors enhanced the PPI response and attenuated the amphetamine-disruptive effects on the PPI. The sGC inhibitor did not modify the sodium nitroprusside effects. Additionally, the cGMP increase induced by a specific phosphodiesterase inhibitor did not modify the amphetamine-disruptive effect.

Conclusions

This study provides the first demonstration that an increase in NO can improve the PPI response and block the amphetamine-disruptive effects on the PPI response. Our data are consistent with recent clinical results. However, these effects do not appear to be related to an increase in cGMP levels, and further investigation is thus required.     

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.     

CRF1 receptor antagonists do not reverse pharmacological disruption of prepulse inhibition in rodents

Rationale

As enhanced corticotropin-releasing factor (CRF) transmission is associated with induction of sensorimotor gating deficits, CRF₁ receptor antagonists may reverse disrupted prepulse inhibition (PPI), an operational measure of sensorimotor gating.

Objectives

To determine the effects of CRF₁ receptor antagonists in pharmacological models of disrupted PPI and to determine if long-term elevated central CRF levels alter sensitivity towards PPI disrupting drugs.

Methods

CP154,526 (10–40 mg/kg), SSR125543 (3–30 mg/kg) and DMP695 (40 mg/kg) were tested on PPI disruption provoked by d-amphetamine (2.5, 3 mg/kg), ketamine (5, 30 mg/kg) and MK801 (0.2, 0.5 mg/kg) in Wistar rats, C57Bl/6J and CD1 mice, and on spontaneously low PPI in Iffa Credo rats and DBA/2J mice. PPI-disrupting effects of d-amphetamine (2.5–5 mg/kg) and MK801 (0.3–1 mg/kg) were examined in CRF-overexpressing (CRFtg) mice, which display PPI deficits. Finally, we determined the influence of CP154,526 on d-amphetamine-induced dopamine outflow in nucleus accumbens and prefrontal cortex of CRFtg mice using in vivo microdialysis.

Results

No CRF_1?antagonists improved PPI deficits in any test. CRFtg mice showed blunted PPI disruption in response to MK801, but not d-amphetamine. Further, d-amphetamine-induced dopamine release was less pronounced in CRFtg versus wild-type mice, a response normalized by pretreatment with CP154,526.

Conclusion

The inability of CRF₁ receptor antagonists to block pharmacological disruption of sensorimotor gating suggests that the involvement of CRF1 receptors in the modulation of dopaminergic and glutamatergic neurotransmission relevant for sensory gating is limited. Furthermore, the alterations observed in CRFtg mice support the notion that long-term elevated central CRF levels induce changes in these neurotransmitter systems.     

Role of cannabis and endocannabinoids in the genesis of schizophrenia

Rationale

Cannabis abuse and endocannabinoids are associated to schizophrenia.

Objectives

It is important to discern the association between schizophrenia and exogenous Cannabis sativa, on one hand, and the endogenous cannabinoid system, on the other hand.

Results

On one hand, there is substantial evidence that cannabis abuse is a risk factor for psychosis in genetically predisposed people, may lead to a worse outcome of the disease, or it can affect normal brain development during adolescence, increasing the risk for schizophrenia in adulthood. Regarding genetic predisposition, alterations affecting the cannabinoid CNR1 gene could be related to schizophrenia. On the other hand, the endogenous cannabinoid system is altered in schizophrenia (i.e., increased density of cannabinoid CB1 receptor binding in corticolimbic regions, enhanced cerebrospinal fluid anandamide levels), and dysregulation of this system can interact with neurotransmitter systems in such a way that a “cannabinoid hypothesis” can be integrated in the neurobiological hypotheses of schizophrenia. Finally, there is also evidence that some genetic alterations of the CNR1 gene can act as a protectant factor against schizophrenia or can induce a better pharmacological response to atypical antipsychotics.

Conclusions

Cannabis abuse is a risk factor for psychosis in predisposed people, it can affect neurodevelopment during adolescence leading to schizophrenia, and a dysregulation of the endocannabinoid system can participate in schizophrenia. It is also worth noting that some specific cannabinoid alterations can act as neuroprotectant for schizophrenia or can be a psychopharmacogenetic rather than a vulnerability factor.     

SSR504734 enhances basal expression of prepulse inhibition but exacerbates the disruption of prepulse inhibition by apomorphine

Rationale

Inhibition of glycine transporter 1 (GlyT1) elevates extracellular glycine and can thus increase N-methyl-d-aspartate receptor (NMDAR) excitability in the brain. The potent GlyT1 inhibitor, SSR504734, has also been shown to potentiate the behavioral effects of direct and indirect dopamine agonists. Thus, an acute systemic dose of SSR504734 was sufficient to exacerbate the motor-stimulant effect of the dopamine releaser amphetamine in C57BL/6 mice, even though SSR504734 alone exerted no significant effect on motor activity.

Objectives

Here, we explore if SSR504734 might modulate dopamine-dependent sensory gating in the paradigm of prepulse inhibition (PPI) of the acoustic startle reflex.

Methods

Experiment 1 characterized the effect of SSR504734 (10 and 30 mg/kg i.p.) on PPI expression when administered alone. Experiments 2 and 3 investigated the impact of SSR504734 when administered in conjunction with the dopamine receptor agonist, apomorphine (1 and 2 mg/kg s.c.), which is known to reliably disrupt PPI.

Results

When administered alone, acute SSR504734 enhanced PPI only at 30 mg/kg—a dose that has been shown to improve cognitive functions including working memory, which has been linked to enhanced NMDAR function resulting from the elevation of extracellular glycine. However, this effect did not allow SSR504734 to antagonize the PPI-disruptive effect of apomorphine. At the lower dose of 10 mg/kg—that was insufficient to enhance PPI when administered alone—SSR504734 even exacerbated the deleterious effect of apomorphine on PPI.

Conclusions

The therapeutic potential of GlyT1 inhibition against distinct behavioral/cognitive deficiency might require different magnitudes of GlyT1 inhibition.     

Glutamate,N-acetyl aspartate and psychotic symptoms in chronic ketamine users

Rationale

Ketamine, a non-competitive NMDA receptor antagonist, induces acute effects resembling the positive, negative and cognitive symptoms of schizophrenia. Chronic use has been suggested to lead to persistent schizophrenia-like neurobiological changes.

Objectives

This study aims to test the hypothesis that chronic ketamine users have changes in brain neurochemistry and increased subthreshold psychotic symptoms compared to matched poly-drug users.

Methods

Fifteen ketamine users and 13 poly-drug users were included in the study. Psychopathology was assessed using the Comprehensive Assessment of At-Risk Mental State. Creatine-scaled glutamate (Glu/Cr), glutamate?+?glutamine (Glu?+?Gln/Cr) and N-acetyl aspartate (NAA/Cr) were measured in three brain regions—anterior cingulate, left thalamus and left medial temporal cortex using proton magnetic resonance spectroscopy.

Results

Chronic ketamine users had higher levels of subthreshold psychotic symptoms (p?<?0.005, Cohen’s d?=?1.48) and lower thalamic NAA/Cr (p?<?0.01, d?=?1.17) compared to non-users. There were no differences in medial temporal cortex or anterior cingulate NAA/Cr or in Glu/Cr or Glu?+?Gln/Cr in any brain region between the two groups. In chronic ketamine users, CAARMS severity of abnormal perceptions was directly correlated with anterior cingulate Glu/Cr (p?<?0.05, r?=?0.61—uncorrected), but NAA/Cr was not related to any measures of psychopathology.

Conclusions

The finding of lower thalamic NAA/Cr in chronic ketamine users may be secondary to the effects of ketamine use compared to other drugs of abuse and resembles previous reports in individuals at genetic or clinical risk of schizophrenia.     

CB2 receptor agonism reverses MK-801-induced disruptions of prepulse inhibition in mice

Rationale

Whilst cannabinoid CB₂ receptors were thought to exist predominantly in immune cells in the periphery, the recent discovery of CB₂ receptors in the brain has led to an increased interest in the role of these central CB₂ receptors. Several studies have reported an association with CB₂ receptors and schizophrenia. Sensorimotor gating deficits occur in schizophrenia patients and can be induced in animals using psychotomimetic drugs such as N-methyl-D-aspartate (NMDA) receptor antagonists.

Objectives

The aim of this study was to investigate the effect of CB₂ ligands on sensorimotor gating, either alone, or on sensorimotor gating deficits induced by the NMDA receptor antagonist MK-801 in mice.

Method

The effects of CB₂ receptor ligands on prepulse inhibition (PPI), an operational measure of sensorimotor gating, alone or when administrated in combination with MK-801, in Balb-C mice were evaluated.

Results

The CB₂ receptor agonist JWH015 had no significant effect on PPI alone but reversed disruptions in PPI induced by MK-801. This effect was blocked by co-administration of the CB₂ receptor antagonist AM630, but not by co-administration of the CB₁ receptor antagonist AM251, indicating a CB₂-mediated effect. The mixed CB₁/CB₂ receptor agonist JWH203 was partially able to reverse MK-801-induced PPI disruptions. Neither the CB₂ receptor antagonist AM630 nor the CB₁ receptor antagonist AM251 had any significant effect alone or on MK-801-induced disruptions in PPI.

Conclusions

CB₂ receptor agonism reversed MK-801 disruptions in sensorimotor gating deficits in mice, indicating that CB₂ agonism may have a protective effect against aspects of drug-induced psychosis.     

Brain RGS4 and RGS10 protein expression in schizophrenia and depression. Effect of drug treatment

Rationale

Regulator of G-protein signaling (RGS) proteins, RGS4 and RGS10, may be involved in the pathophysiology of schizophrenia. RGS4 has attracted special interest since the reports of genetic association between SNPs in RGS4 and schizophrenia. However, there is no information about the subcellular distribution of RGS4 and RGS10 proteins in psychiatric disorders.

Objectives

Plasma membrane RGS4 and cytosolic RGS10 protein immunoreactivity in prefrontal cortex from schizophrenic subjects (n?=?25), non-diagnosed suicides (n?=?13), and control subjects (n?=?35), matched by age, gender, and postmortem delay, was analyzed by western blot. A second group of depressed subjects (n?=?25) and control subjects (n?=?25) was evaluated. The effect of the antipsychotic or antidepressant treatments was also assessed.

Results

No significant differences in plasma membrane RGS4 and cytosolic RGS10 protein expression were observed between schizophrenic subjects, non-diagnosed suicides, and control subjects. However, RGS4 immunoreactivity was significantly higher (Δ?=?33?±?10 %, p?<?0.05) in the antipsychotic-treated subgroup (n?=?12) than in the antipsychotic-free subgroup (n?=?13). Immunodensities of plasma membrane RGS4 and cytosolic RGS10 proteins did not differ between depressed and matched control subjects.

Conclusions

Expression of RGS4 and RGS10 proteins at their predominant subcellular location was studied in the postmortem brain of subjects with psychiatric disorders. The results suggest unaltered membrane RGS4 and cytosolic RGS10 proteins levels in schizophrenia and major depression. Antipsychotic treatment seems to increase membrane RGS4 immunoreactivity. Further studies are needed to elucidate RGS4 and RGS10 functional status.     

A double-blind, placebo controlled, randomized trial of riluzole as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia

Rationale

Several recent studies have focused on glutamate modulating agents for symptoms relief in schizophrenia, especially negative symptoms which are resistant to conventional therapies.

Objectives

We aimed to assess the efficacy and tolerability of riluzole, an anti-glutamate agent with neuroprotective properties, as an adjunct to risperidone in improving negative symptoms of schizophrenia.

Methods

In this randomized double-blind placebo-controlled parallel-group study, 50 patients with chronic schizophrenia and a score of ≥20 on the negative subscale of positive and negative syndrome scale (PANSS) were enrolled in the active phase of their illness. Participants were equally randomized to receive riluzole (100 mg/day) or placebo in addition to risperidone (up to 6 mg/day) for 8 weeks. Participants were rated by PANSS every 2 weeks. The primary outcome of this study was the difference in the decrease of PANSS negative subscale score from baseline to the study endpoint between the two groups.

Results

By the study endpoint, riluzole-treated patients showed significantly greater improvement in the negative symptoms (P?<?0.001) as well as the PANSS total and general psychopathology subscale scores (P?=?0.001 and P?<?0.001; respectively) compared to the placebo group. Treatment group was the only significant predictor of changes in negative symptom in this trial (β?=??0.56, P?<?0.001). No significant difference was observed between two groups in the frequency of side effects.

Conclusion

These preliminary findings suggest that riluzole may be a safe and effective medication for the treatment of negative symptoms in patients with chronic schizophrenia. Further research and replication of study findings is warranted.

Clinical trial registry name and registration number

Iranian registry of clinical trials www.irct.ir, IRCT201107281556N26