Sex-Dependent Antipsychotic Capacity of 17��-Estradiol in the Latent Inhibition Model: A Typical Antipsychotic Drug in Both Sexes, Atypical Antipsychotic Drug in Males

The estrogen hypothesis of schizophrenia suggests that estrogen is a natural neuroprotector in women and that exogenous estrogen may have antipsychotic potential, but results of clinical studies have been inconsistent. We have recently shown using the latent inhibition (LI) model of schizophrenia that 17β-estradiol exerts antipsychotic activity in ovariectomized (OVX) rats. The present study sought to extend the characterization of the antipsychotic action of 17β-estradiol (10, 50 and 150 μg/kg) by testing its capacity to reverse amphetamine- and MK-801-induced LI aberrations in gonadally intact female and male rats. No-drug controls of both sexes showed LI, ie, reduced efficacy of a previously non-reinforced stimulus to gain behavioral control when paired with reinforcement, if conditioned with two but not five tone-shock pairings. In both sexes, amphetamine (1 mg/kg) and MK-801 (50 μg/kg) produced disruption (under weak conditioning) and persistence (under strong conditioning) of LI, modeling positive and negative/cognitive symptoms, respectively. 17β-estradiol at 50 and 150 μg/kg potentiated LI under strong conditioning and reversed amphetamine-induced LI disruption in both males and females, mimicking the action of typical and atypical antipsychotic drugs (APDs) in the LI model. 17β-estradiol also reversed MK-induced persistent LI, an effect mimicking atypical APDs and NMDA receptor enhancers, but this effect was observed in males and OVX females but not in intact females. These findings indicate that in the LI model, 17β-estradiol exerts a clear-cut antipsychotic activity in both sexes and, remarkably, is more efficacious in males and OVX females where it also exerts activity considered predictive of anti-negative/cognitive symptoms.     

AVE1625, a cannabinoid CB1 receptor antagonist, as a co-treatment with antipsychotics for schizophrenia: improvement in cognitive function and reduction of antipsychotic-side effects in rodents

Rationale

The psychotomimetic effects of cannabis are believed to be mediated via cannabinoid CB1 receptors. Furthermore, studies have implicated CB1 receptors in the pathophysiology of schizophrenia.

Objective

These studies investigated the effects of the CB1 receptor antagonist, AVE1625, in acute pharmacological and neurodevelopmental models of schizophrenia. AVE1625 was administered to rodents alone or as a co-treatment with clinically used antipsychotic drugs (APDs).

Methods

The antipsychotic potential of AVE1625 was tested using psychotomimetic-induced hyperactivity and latent inhibition (LI) deficit models. The procognitive profile was assessed using hole board, novel object recognition, auditory evoked potential, and LI techniques. In addition, the side-effect profile was established by measuring catalepsy, antipsychotic-induced weight gain, plasma levels of prolactin, and anxiogenic potential.

Results

AVE1625 (1, 3, and 10?mg/kg ip), reversed abnormally persistent LI induced by MK-801 or neonatal nitric oxide synthase inhibition in rodents, and improved both working and episodic memory. AVE1625 was not active in positive symptom models but importantly, it did not diminish the efficacy of APDs. It also decreased catalepsy and weight gain induced by APDs, suggesting that it may decrease APD-induced extrapyramidal side effects (EPS) and compliance. Unlike other CB1 antagonists, AVE1625 did not produce anxiogenic-like effects.

Conclusions

These preclinical data suggest that AVE1625 may be useful to treat the cognitive deficits in schizophrenia and as a co-treatment with currently available antipsychotics. In addition, an improved side-effect profile was seen, with potential to ameliorate the EPS and weight gain issues with currently available treatments.     

The alpha-7 nicotinic receptor partial agonist/5-HT3 antagonist RG3487 enhances cortical and hippocampal dopamine and acetylcholine release

Rationale

Alpha-7 nicotinic acetylcholine receptor (nAChR) agonists may ameliorate cognitive deficits in schizophrenia, in part, because of their ability to enhance dopaminergic and cholinergic neurotransmission.

Objectives

In the current study, the effects of partial nAChR agonist and 5-HT₃ receptor antagonist RG3487 (previously R3487/MEM3454) on dopamine (DA) and acetylcholine (ACh) effluxes in rat prefrontal cortex (mPFC) and hippocampus (HIP) were investigated in awake, freely moving rats.

Results

R3487/MEM3454, at doses of 0.1–10 mg/kg, s.c., enhanced DA and ACh effluxes in rat mPFC and (HIP), with a peak effect at 0.3- to 0.6-mg/kg doses, producing a bell-shaped dose–response curve. Pretreatment with the selective nAChR antagonist, methyllycaconitine (1.0 mg/kg), completely blocked RG3487-induced (0.45 mg/kg) DA but not ACh efflux, while the selective 5-HT₃ receptor agonist 1-(m-chlorophenyl)-biguanide (1.0 mg/kg) partially inhibited cortical ACh but not DA efflux. RG3487 (0.45 mg/kg) combined with atypical antipsychotic drug (APD) risperidone (0.1 mg/kg), but not typical APD haloperidol (0.1 mg/kg), induced a significantly greater increase in HIP ACh efflux. Their combined effect on DA efflux was additive. RG3487, combined with other atypical APDs, namely aripiprazole (0.3 mg/kg), olanzapine (1.0 mg/kg), and quetiapine (30 mg/kg), also produced additive effects on DA efflux.

Conclusions

These results suggest that RG3487 enhances DA efflux by nAChR stimulation, whereas ACh efflux is primarily mediated via 5-HT₃ receptor antagonism, and that RG3487 alone or as augmentation may improve cognitive impairment in schizophrenia.     

Procognitive and antipsychotic efficacy of glycine transport 1 inhibitors (GlyT1) in acute and neurodevelopmental models of schizophrenia: latent inhibition studies in the rat

Rationale

SSR103800 and SSR504734 are novel glycine transport 1 (GlyT1) inhibitors with therapeutic potential for the treatment of schizophrenia.

Objective

The present studies investigated the effects of GlyT1 inhibitors in acute pharmacological and neurodevelopmental models of schizophrenia using latent inhibition in the rat; these latent inhibition (LI) models are believed to be predictive for treatments of positive, negative, and cognitive aspects of schizophrenia.

Materials and methods

LI, the poorer conditioning to a previously irrelevant stimulus, was measured in a conditioned emotional response procedure in male rats. The effects of SSR103800 or SSR504734 (both at 1, 3, and 10 mg/kg, i.p.) were determined on amphetamine-induced disrupted LI, MK-801-induced abnormally persistent LI, and neurodevelopmentally induced abnormally persistent LI in adult animals that had been neonatally treated with a nitric oxide synthase inhibitor.

Results

SSR103800 (1 and 3 mg/kg) and SSR504734 (1 and 10 mg/kg) potentiated LI under conditions where LI was not present in nontreated controls and SSR103800 (1 mg/kg) reversed amphetamine-induced disrupted LI while not affecting LI on its own. Additionally, SSR103800 (1 and 3 mg/kg) and SSR504734 (3 and 10 mg/kg) reversed abnormally persistent LI induced by MK-801. In the neurodevelopmental model, SSR504734 (3 and 10 mg/kg) reverted the LI back to control (normal) levels.

Conclusions

These preclinical data, from acute and neurodevelopmental models, suggest that GlyT1 inhibition may exhibit activity in the positive, negative, and cognitive symptom domains of schizophrenia.     

Differential effects of estrogen and testosterone on auditory sensory gating in rats

Rationale

Estrogen has been shown to have beneficial effects in patients with schizophrenia. However, the mechanisms involved in this protective effect are unclear. Schizophrenia is associated with deficits in sensory gating, a filtering mechanism which normally prevents sensory overload. In rodent models, acute treatment with drugs such as the dopamine D1/D2 receptor agonist, apomorphine; the dopamine releaser, amphetamine; and the glutamate NMDA receptor antagonists, phencyclidine or MK-801, can induce a phenotype similar to that seen in schizophrenia.

Objectives

Given the putative protective action of estrogen in schizophrenia, here we investigated the effect of ovariectomy (OVX) and estrogen replacement in female rats on drug-induced auditory gating deficits. For comparison, we also assessed the effects of castration (CAST) and dihydrotestosterone (DHT) replacement in male rats.

Methods

Rats were instrumented with cortical surface electrodes. Test sessions comprised of 150 presentations of paired clicks, 500 ms apart (S1 and S2).

Results

Administration of all drugs increased the ratio of responses to S2/S1 in sham-operated female and male rats. OVX reduced event-related potential amplitudes but did not alter S2/S1 ratio or drug effects. In OVX rats with 17β-estradiol implants, the effect of apomorphine was abolished, but there was no change in that of amphetamine and phencyclidine. There were no effects of CAST or DHT replacement in male rats.

Conclusions

Chronic estrogen replacement in OVX rats protected against sensory gating deficits caused by direct dopamine D1/D2 receptor stimulation. These data could indicate a possible mechanism by which estrogen exerts a protective action in schizophrenia.     

Opposite effects of typical and atypical anti-psychotic drugs on sensitized dopamine receptors: Sub-chronic low dose Olanzapine exposure reverses sensitization but a similar regimen of low dose haloperidol potentiates sensitization effects

Rationale

Both typical and atypical antipsychotic drugs are D2 receptor antagonists but yet appear to have markedly different effects upon the induction of dopamine sensitization.

Objective

This study aims to compare the effects of subchronic regimens of low-dose olanzapine and haloperidol administered to rats previously sensitized to apomorphine.

Methods

Initially, rats received apomorphine (2.0 mg/kg) or vehicle treatments for five consecutive days followed by a conditioning test and an apomorphine challenge test. Next, there was an antipsychotic exposure phase in which three vehicle groups and three apomorphine groups received 10 daily injections of either vehicle, haloperidol (0.03 mg/kg) or olanzapine (0.01 mg/kg). In the final phase, all groups were given a second conditioning test and apomorphine challenge test.

Results

Apomorphine induced sensitization and conditioning effects. Following haloperidol exposure, apomorphine conditioned and sensitization effects were potentiated but, in contrast, olanzapine exposure eliminated apomorphine sensitization effects. In addition, the sensitization induced by apomorphine transformed the low-dose haloperidol treatment into a potent locomotor stimulant treatment. In the vehicle groups, haloperidol and olanzapine exposure effects were equivalent and not different from vehicle treatment.

Conclusions

The profound differences observed between typical and atypical antipsychotic exposure in animals with an upregulated dopamine system are consistent with clinical evidence for lower risk of psychomotor disturbances with chronic treatment with atypical antipsychotic. Importantly, the finding that a very low dose of olanzapine reversed sensitization effects suggests that low-dose olanzapine may have clinical utility in a variety of disorders linked to sensitization of the dopamine system.     

Inhibition of phosphodiesterase 10A has differential effects on dopamine D1 and D2 receptor modulation of sensorimotor gating

Rationale

Inhibitors of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the mammalian striatum, enhance activity in direct (dopamine D1 receptor-expressing) and indirect (D2 receptor-expressing striatal output) pathways. The ability of such agents to act to potentiate D1 receptor signaling while inhibiting D2 receptor signaling suggest that PDE10A inhibitors may have a unique antipsychotic-like behavioral profile differentiated from the D2 receptor antagonist-specific antipsychotics currently used in the treatment of schizophrenia.

Objectives

To evaluate the functional consequences of PDE10A inhibitor modulation of D1 and D2 receptor pathway signaling, we compared the effects of a PDE10A inhibitor (TP-10) on D1 and D2 receptor agonist-induced disruptions in prepulse inhibition (PPI), a measure of sensorimotor gating disrupted in patients with schizophrenia.

Results

Our results indicate that, in rats: (1) PDE10A inhibition (TP-10, 0.32–10.0 mg/kg) has no effect on PPI disruption resulting from the mixed D1/D2 receptor agonist apomorphine (0.5 mg/kg), confirming previous report; (2) Yet, TP-10 blocked the PPI disruption induced by the D2 receptor agonist quinpirole (0.5 mg/kg); and attenuated apomorphine-induced disruptions in PPI in the presence of the D1 receptor antagonist SCH23390 (0.005 mg/kg).

Conclusions

These findings indicate that TP-10 cannot block dopamine agonist-induced deficits in PPI in the presence of D1 activation and suggest that the effect of PDE10A inhibition on D1 signaling may be counterproductive in some models of antipsychotic activity. These findings, and the contribution of TP-10 effects in the direct pathway on sensorimotor gating in particular, may have implications for the potential antipsychotic efficacy of PDE10A inhibitors.     

Dissociating scopolamine-induced disrupted and persistent latent inhibition: stage-dependent effects of glycine and physostigmine

Rationale  

Latent inhibition (LI) is the poorer conditioning to a stimulus seen when conditioning is preceded by repeated non-reinforced pre-exposure to the stimulus. LI indexes the ability to ignore irrelevant stimuli and is used extensively to model attentional impairments in schizophrenia. We showed that the pro-psychotic muscarinic antagonist scopolamine can produce LI disruption or LI persistence depending on dose and stage of administration: low doses disrupt LI acting in the pre-exposure stage of the LI procedure, whereas higher dose produces abnormally persistent LI via action in the conditioning stage. The two LI abnormalities show distinct response to antipsychotic drugs (APDs), with LI disruption, but not LI persistence, reversed by APDs.     

Scopolamine induces disruption of latent inhibition which is prevented by antipsychotic drugs and an acetylcholinesterase inhibitor.

The fact that muscarinic antagonists may evoke a psychotic state ('antimuscarinic psychosis'), along with findings of cholinergic alterations in schizophrenia, have kindled an interest in the involvement of the cholinergic system in this disorder. Latent inhibition (LI) is a cross-species phenomenon manifested as a poorer conditioning of a stimulus seen when the stage of conditioning is preceded by a stage of repeated nonreinforced pre-exposure to that stimulus, and is considered to index the capacity to ignore irrelevant stimuli. Amphetamine-induced LI disruption and its reversal by antipsychotic drugs (APDs) is a well-established model of positive symptoms of schizophrenia. Here, we tested whether the muscarinic antagonist scopolamine would disrupt LI and whether such disruption would be reversed by APDs and by the acetylcholinesterase inhibitor physostigmine. The results showed that scopolamine at doses of 0.15 and 0.5 mg/kg disrupted LI, and that this effect was due to the action of the drug in the pre-exposure stage, suggesting a role of muscarinic transmission in attentional processes underlying LI. Both the typical and the atypical APDs, haloperidol and clozapine, reversed scopolamine-induced LI disruption when given in conditioning or in both stages, but not in pre-exposure, indicating that the mechanism of antipsychotic action in this model is independent of the mechanism of action of the propsychotic drug. Scopolamine-induced LI disruption was reversed by physostigmine (0.05 and 0.15 mg/kg), which was ineffective in reversing amphetamine-induced LI disruption, pointing to distinct mechanisms underlying LI disruption by these two propsychotic drugs. The latter was further supported by the finding that unlike amphetamine, the LI-disrupting doses of scopolamine did not affect activity levels. We propose scopolamine-induced LI disruption as a model of cholinergic-related positive symptoms in schizophrenia.     

Asenapine effects in animal models of psychosis and cognitive function

Rationale

Asenapine, a novel psychopharmacologic agent in the development for schizophrenia and bipolar disorder, has high affinity for serotonergic, α-adrenergic, and dopaminergic receptors, suggesting potential for antipsychotic and cognitive-enhancing properties.

Objectives

The effects of asenapine in rat models of antipsychotic efficacy and cognition were examined and compared with those of olanzapine and risperidone.

Materials and methods

Amphetamine-stimulated locomotor activity (Amp-LMA; 1.0 or 3.0 mg/kg s.c.) and apomorphine-disrupted prepulse inhibition (Apo-PPI; 0.5 mg/kg s.c.) were used as tests for antipsychotic activity. Delayed non-match to place (DNMTP) and five-choice serial reaction (5-CSR) tasks were used to assess short-term spatial memory and attention, respectively. Asenapine doses varied across tasks: Amp-LMA (0.01–0.3 mg/kg s.c.), Apo-PPI (0.001–0.3 mg/kg s.c.), DNMTP (0.01–0.1 mg/kg s.c.), and 5-CSR (0.003–0.3 mg/kg s.c.).

Results

Asenapine was highly potent (active at 0.03 mg/kg) in the Amp-LMA and Apo-PPI assays. DNMTP or 5-CSR performance was not improved by asenapine, olanzapine, or risperidone. All agents (P?<?0.01) reduced DNMTP accuracy at short delays; post hoc analyses revealed that only 0.1 mg/kg asenapine and 0.3 mg/kg risperidone differed from vehicle. All active agents (asenapine, 0.3 mg/kg; olanzapine, 0.03–0.3 mg/kg; and risperidone, 0.01–0.1 mg/kg) significantly impaired 5-CSR accuracy (P?<?0.05).

Conclusions

Asenapine has potent antidopaminergic properties that are predictive of antipsychotic efficacy. Asenapine, like risperidone and olanzapine, did not improve cognition in normal rats. Rather, at doses greater than those required for antipsychotic activity, asenapine impaired cognitive performance due to disturbance of motor function, an effect also observed with olanzapine and risperidone.     

A comparison of drug effects in latent inhibition and the forced swim test differentiates between the typical antipsychotic haloperidol,the atypical antipsychotics clozapine and olanzapine,and the antidepressants imipramine and paroxetine

Current animal models of antipsychotic activity that have the capacity to dissociate between typical and atypical antipsychotic drugs (APDs) have two drawbacks: they require previous administration of a psychotomimetic drug, and they achieve the dissociation by demonstrating effectiveness of atypical but not typical APDs, thus losing specificity and selectivity for APDs. The present experiments were designed to solve these problems by using two non-pharmacological tests: latent inhibition (LI), in which potentiation of the deleterious effects of non-reinforced stimulus pre-exposure on its subsequent conditioning served as a behavioral index for a common action of typical and atypical APDs (antipsychotic), and the forced swim test (FST), in which reduction of immobility served as a behavioral index for a dissimilar action of these drugs (antidepressant). The typical APD haloperidol (0.1 mg/kg), the atypical APDs clozapine (2.5 mg/kg) and olanzapine (0.6 mg/kg), and the antidepressants imipramine (10 mg/kg) and paroxetine (7.0 mg/kg), produced distinct patterns of action in the two tests: haloperidol potentiated LI and increased immobility in the FST, clozapine and olanzapine potentiated LI and decreased immobility in the FST, and imipramine and paroxetine decreased immobility in the FST and did not potentiate LI. Thus, the comparison of drug effects in LI and FST enabled a discrimination between typical and atypical APDs without losing selectivity for APDs.     

Treatment of methamphetamine-induced psychosis: a double-blind randomized controlled trial comparing haloperidol and quetiapine

Rationale

To our knowledge, only a few double-blind randomized controlled trials with antipsychotic drugs have been conducted to examine the treatment of methamphetamine-induced psychosis (MAP).

Objectives

The aims of this study are to compare the antipsychotic and adverse events of quetiapine, an atypical antipsychotic drug, to haloperidol, a standard treatment for primary psychotic disorder, in individuals with MAP.

Methods

Eighty individuals with MAP were randomly assigned into two groups, i.e. treatment with quetiapine (n?=?36) and haloperidol (n?=?44). Sixty-eight patients (85 %) completed the study protocol, i.e. treatment with quetiapine at least 100 mg per day or haloperidol at least 2 mg per day orally once a day for 4 weeks. The doses were increased every 5 days until no psychotic symptom was observed from the Positive and Negative Syndrome Scale (PANSS). Data were analysed by survival analysis with Cox’s proportional regression analysis, general estimating equations and log-rank tests.

Results

Thirty-two (89 %) subjects from the quetiapine group and 37 subjects (84 %) from the haloperidol group met the remission criteria at the end of the study. Baseline PANSS total scores of quetiapine and haloperidol groups were 82.4?±?16.6 and 90.0?±?18.4, respectively (mean?±?SD; p?=?0.06). The change-from-baseline scores were ?47.8 for the quetiapine group and ?53.2 for the haloperidol group. There were no significant differences between the antipsychotic effects (coefficient value?=??2.6, p?=?0.32, 95%CI?=??7.6, 2.5) and the adverse effects of quetiapine and haloperidol.

Conclusions

Quetiapine may be used as an antipsychotic treatment for MAP with comparable therapeutic effects and adverse events to treatment with classical antipsychotic drugs.     

Time-dependent effects of haloperidol on glutamine and GABA homeostasis and astrocyte activity in the rat brain

Rationale

Schizophrenia is a severe, persistent, and fairly common mental illness. Haloperidol is widely used and is effective against the symptoms of psychosis seen in schizophrenia. Chronic oral haloperidol administration decreased the number of astrocytes in the parietal cortex of macaque monkeys (Konopaske et al., Biol Psych 63:759–765, 2008). Since astrocytes play a key role in glutamate metabolism, chronic haloperidol administration was hypothesized to modulate astrocyte metabolic function and glutamate homeostasis.

Objectives

This study investigated the effects of chronic haloperidol administration on astrocyte metabolic activity and glutamate, glutamine, and GABA homeostasis.

Methods

We used ex vivo ¹³C magnetic resonance spectroscopy along with high-performance liquid chromatography after [1-¹³C]glucose and [1,2-¹³C]acetate administration to analyze forebrain tissue from rats administered oral haloperidol for 1 or 6 months.

Results

Administration of haloperidol for 1 month produced no changes in ¹³C labeling of glutamate, glutamine, or GABA, or in their total levels. However, a 6-month haloperidol administration increased ¹³C labeling of glutamine by [1,2-¹³C]acetate. Moreover, total GABA levels were also increased. Haloperidol administration also increased the acetate/glucose utilization ratio for glutamine in the 6-month cohort.

Conclusions

Chronic haloperidol administration in rats appears to increase forebrain GABA production along with astrocyte metabolic activity. Studies exploring these processes in subjects with schizophrenia should take into account the potential confounding effects of antipsychotic medication treatment.     

Chronic nicotine improves cognitive performance in a test of attention but does not attenuate cognitive disruption induced by repeated phencyclidine administration

Rationale

Nicotine-induced cognitive enhancement may be a factor maintaining tobacco smoking, particularly in psychiatric populations suffering from cognitive deficits. Schizophrenia patients exhibit higher smoking rates compared with the general population, suggesting that attempts to self-medicate cognitive schizophrenia deficits may underlie these high smoking levels.

Objectives

The present study explored pro-cognitive effects of nicotine in a model of schizophrenia-like cognitive dysfunction to test this self-medication hypothesis.

Materials and methods

We investigated whether chronic nicotine (3.16 mg/kg/day, base) would attenuate the performance disruption in the five-choice serial reaction time task (5-CSRTT, a task assessing various cognitive modalities, including attention) induced by repeated administration of phencyclidine (PCP), an N-methyl-d-aspartate receptor antagonist that induces cognitive deficits relevant to schizophrenia.

Results

Chronic nicotine administration shortened 5-CSRTT response latencies under baseline conditions. Nicotine-treated rats also made more correct responses and fewer omissions than vehicle-treated rats. Replicating previous studies, repeated PCP administration (2 mg/kg, 30 min before behavioral testing for two consecutive days followed 2 weeks later by five consecutive days of PCP administration) decreased accuracy and increased response latencies, premature responding, and timeout responding. Chronic nicotine did not attenuate these PCP-induced disruptions.

Conclusions

Chronic nicotine had pro-cognitive effects by itself, supporting the hypothesis that cognitive enhancement may contribute to tobacco smoking. At the doses of nicotine and PCP used, however, no support was found for the hypothesis that the beneficial effects of nicotine on cognitive deficits induced by repeated PCP administration, assessed in the 5-CSRTT, are larger than nicotine effects in the absence of PCP.     

The antidepressant-like effects of topiramate alone or combined with 17β-estradiol in ovariectomized Wistar rats submitted to the forced swimming test

Rationale

There is a significant delay in the clinical response of antidepressant drugs, and antidepressant treatments produce side effects.

Objective

We examined the relationship between 17β-estradiol and topiramate in ovariectomized Wistar rats submitted to the forced swimming test (FST).

Methods

Topiramate was administered alone or combined with 17β-estradiol to ovariectomized rats submitted to the FST.

Results

Topiramate (20 mg/kg, P?P?P?P?P?Conclusions Topiramate alone or combined with 17β-estradiol produced antidepressant-like actions; and 17β-estradiol shortened the onset of the antidepressant-like effects of topiramate.     

Aminotransferase levels as a prospective predictor for the development of metabolic syndrome in patients with schizophrenia

Rationale

Increased levels of alanine aminotransferase (ALT) are a biomarker for metabolic syndrome (MetS), but this relationship remains unproven in patients with schizophrenia.

Objective

We assessed the relationship between aminotransferase levels and MetS in patients with schizophrenia.

Method

This pooled analysis from two open-label prospective studies included 342 patients with schizophrenia who did not meet criteria for MetS at baseline. The development of MetS was assessed at weeks 12 and 24.

Results

MetS developed in 19.1 % of patients during the 24-week follow-up period. ALT levels were significantly associated with incident MetS: for each sex-specific standard deviation increase in log ALT, the odds ratio (OR) of MetS was 1.357 (p?=?.006) after adjusting for age, sex, duration of illness, smoking, and previous use of antipsychotics. This result remained significant after adjusting for interim weight changes. Compared with patients in the lowest quartile, the OR of MetS in those in the highest quartile within the normal range of ALT levels was 4.276 (p?=?.024). However, this association was significant only in male patients. Using a cutoff value of 23.0 U/L, sensitivity and specificity were 70.6 and 68.3 %, respectively, in male patients whose ALT levels were in the normal range.

Conclusions

A prospective association between ALT levels and MetS highlights the value of ALT levels, even mild ALT elevations within the normal range, as a predictor of the MetS risk in male patients. Baseline liver function tests and monitoring should be obtained during antipsychotic treatment to identify the risk for MetS.     

Reversal of cognitive deficits by an ampakine (CX516) and sertindole in two animal models of schizophrenia—sub-chronic and early postnatal PCP treatment in attentional set-shifting

Rationale

Therapies treating cognitive impairments in schizophrenia especially deficits in executive functioning are not available at present.

Objective

The current study evaluated the effect of ampakine CX516 in reversing deficits in executive functioning as represented in two animal models of schizophrenia and assessed by a rodent analog of the intradimensional–extradimensional (ID–ED) attentional set-shifting task. The second generation antipsychotic, sertindole, provided further validation of the schizophrenia-like disease models.

Methods

Animals were subjected to (a) sub-chronic or (b) early postnatal phencyclidine (PCP) treatment regimes: (a) Administration of either saline or PCP (5 mg/kg, intraperitonally b.i.d. for 7 days) followed by a 7-day washout period and testing on day 8. (b) On postnatal days (PNDs) 7, 9, and 11, rats were subjected to administration of either saline or PCP (20 mg/kg, subcutaneously (s.c.)) and tested on PNDs 56–95, after reaching adulthood. The single test session required rats to dig for food rewards in a series of discriminations following acute administration of either vehicle, or CX516 (5–40 mg/kg, s.c.), or sertindole (1.25 mg/kg, perorally).

Results

The specific extradimensional deficits produced by sub-chronic or early postnatal PCP treatment were significantly attenuated by sertindole and dose-dependently by CX516.

Conclusion

Findings here further establish PCP treatment as model of executive functioning deficits related to schizophrenia and provide evidence that direct glutamatergic interventions could improve these, when assessed in the ID–ED attentional set-shifting task.     

The atypical antipsychotic risperidone reverses the recognition memory deficits induced by post-weaning social isolation in rats

Rationale

Rearing rats in isolation from weaning is an established preclinical neurodevelopmental model which induces behavioural deficits with apparent translational relevance to some core symptoms of schizophrenia.

Objective

This study evaluated the ability of the atypical antipsychotic risperidone to reverse behavioural deficits induced by post-weaning social isolation of rat pups and to further characterise the predictive validity of this model.

Method

Forty-five male Lister hooded rats were housed in groups of 3–4 (n?=?16) or singly (n?=?29) for 4 weeks immediately after weaning on postnatal day (PND) 22–24. On PND 51, novel cage-induced locomotor activity (LMA) was assessed to subdivide rats into groups balanced for behavioural response. On PNDs 58, 59, 65 and 72, rats received either vehicle (1 ml/kg; i.p.) or risperidone (0.2 or 0.5 mg/kg; i.p.) 30 min prior to testing in LMA, novel object discrimination (NOD), prepulse inhibition (PPI) of acoustic startle and conditioned emotional response (CER) learning paradigms, respectively.

Results

Isolation rearing had no effect on PPI, but produced LMA hyperactivity and impaired NOD and CER compared to group-housed controls. Risperidone caused a dose-dependent reduction in LMA, irrespective of rearing condition, but selectively reversed the NOD deficit in isolation-reared rats. Risperidone did not reverse the isolation rearing-induced CER deficit.

Conclusions

Similar to its clinical profile, risperidone only partially reverses the schizophrenic symptomology; since it reversed some, but not all, of the learning and memory deficits induced by post-weaning isolation, the isolation rearing model may be useful to predict antipsychotic activity of novel therapeutic agents.     

Disruption and potentiation of latent inhibition by risperidone: the latent inhibition model of atypical antipsychotic action.

Latent inhibition (LI), that is, retarded conditioning to a stimulus following its nonreinforced pre-exposure, is impaired in some subsets of schizophrenia patients and in amphetamine-treated rats. Potentiation of LI by antipsychotic drugs (APDs) given in conditioning, under conditions that do not lead to LI in controls, is a well-established index of antipsychotic activity. Recently, we have shown that the atypical APD, clozapine, in addition disrupts LI if administered in pre-exposure, under conditions that lead to LI in controls. This study demonstrates the same behavioral profile for the atypical APD risperidone. LI was measured in a thirst-motivated conditioned emotional response procedure by comparing suppression of drinking in response to a tone previously paired with a foot shock in rats that received nonreinforced exposure to the tone prior to conditioning (pre-exposed (PE)) and rats for whom the tone was novel (non-pre-exposed (NPE)). We show that under conditions that did not yield LI in vehicle controls (40 pre-exposures and five conditioning trials), risperidone (0.25, 0.5, and 1.2 mg/kg) led to LI when administered in conditioning. Under conditions that led to LI in vehicle controls (40 pre-exposures and two conditioning trials), risperidone (0.25, 0.5, and 2.5 mg/kg) abolished LI when administered in pre-exposure; the latter effect was not evident with haloperidol. In addition, the effects of risperidone administered in both the pre-exposure and conditioning stages were dose-dependent so that the pre-exposure-based action was manifested at lower but not at higher doses. It is concluded that atypical APDs exert in the LI model a dual pattern of effects, which enables detection of their 'typical' action (conditioning-based LI potentiation) as well as a dissociation from typical APDs by their 'atypical' action (pre-exposure-based LI disruption). It is suggested that the former and latter effects are subserved by D2 and 5HT2A antagonism, respectively.     

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.