Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγ 35 S binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca 2+ mobilization assay. SAR218645 potentiated mGluR2 agonist-induced contralateral turning. When SAR218645 was tested in models of the positive symptoms of schizophrenia, it reduced head twitch behavior induced by DOI, but it failed to inhibit conditioned avoidance and hyperactivity using pharmacological and transgenic models. Results from experiments in models of the cognitive symptoms associated with schizophrenia showed that SAR218645 improved MK-801-induced episodic memory deficits in rats and attenuated working memory impairment in NMDA Nr1 neo−/− mice. The drug reversed disrupted latent inhibition and auditory-evoked potential in mice and rats, respectively, two endophenotypes of schizophrenia. This profile positions SAR218645 as a promising candidate for the treatment of cognitive symptoms of patients with schizophrenia, in particular those with abnormal attention and sensory gating abilities.

COMPOUND A is a positive allosteric modulator of mGluR2 and has a procognitive profile.The present study investigated the effects of COMPOUND A in two clinically relevant cognition models, Latent Inhibition (LI) and Auditory Evoked Potentials (AEPs). LI and AEP are cross-species phenomena that are deficient in schizophrenia and that can be recorded in both rodents and human. Deficits in LI are believed to reflect aberrant switching/distractibility akin to schizophrenia. Deficiencies in AEPs have been regarded as manifestations of impaired sensory and attentional processing, leading to disturbed perception in patients with schizophrenia. In the LI model, amphetamine disrupted the learning behavior. COMPOUND A reversed this amphetamine deficit at doses of 1 and 10 mg/kg (po). A reversal of amphetamine disrupted LI was also seen with haloperidol (0.3 mg/kg ip). In the AEP model, amphetamine caused a disruption of paired auditory stimuli gating in a manner similar to that seen in schizophrenia. Whereas COMPOUND A did not affect baseline (vehicle control) gating (at 3 mg/kg po), COMPOUND A did reverse the amphetamine disrupted gating at doses of 0.3 and 3 mg/kg po.Reversal of amphetamine disrupted LI is thought to be an indicator of improved selective attention, and/or positive symptom efficacy. As our companion poster (Black et al ) has indicated minimal effects of COMPOUND A in positive symptom models and robust improvements in cognition, we propose the effects of COMPOUND A here represent pro-cognitive activity. In agreement with this effect is the reversal of amphetamine-disrupted gating by COMPOUND A that could be indicative of sustained attention. As both techniques (LI and AEP) can be performed in a similar manner in humans, this opens up the ability to perform dose ranging studies for COMPOUND A in clinical trials; either by disrupting these phenomena with amphetamine in Phase I or Phase II studies in patients with natural deficits.

SAR110894 is a novel histamine H3-R ligand, displaying high and selective affinity for human, rat or mouse H3-Rs. SAR110894 is a potent H3-R antagonist at native receptors, reversing R-α-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPγS binding at human H3-Rs demonstrating inverse agonist properties. In behavioral models addressing certain aspects of cognitive impairment associated with schizophrenia (CIAS) and attention deficit/hyperactivity disorder (ADHD), SAR110894 improved memory performances in several variants of the object recognition task in mice (0.3–3mg/kg, p.o.) or rats (0.3–1mg/kg, p.o.). Moreover, SAR110894 (1mg/kg, p.o.) reversed a deficit in working memory in the Y-maze test, following an acute low dose of phencyclidine (PCP) (0.5mg/kg, i.p.) in mice sensitized by repeated treatment with a high dose of PCP (10mg/kg, i.p.). In the latent inhibition (LI) model, SAR110894 potentiated LI in saline-treated rats (1 and 3mg/kg, i.p.) and reversed abnormally persistent LI induced by neonatal nitric oxide synthase (NOS) inhibition in rodents (0.3–3mg/kg, i.p.). In a social novelty discrimination task in rats, SAR110894 attenuated selective attention deficit induced by neonatal PCP treatment (3 and 10mg/kg, p.o.) or a parametric modification of the procedure (3 and 10mg/kg, p.o.). SAR110894 showed efficacy in several animal models related to the cognitive deficits in Alzheimer's disease (AD). It prevented the occurrence of episodic memory deficit induced by scopolamine in rats (0.01–10mg/kg, p.o.) or by the central infusion of the toxic amyloid fragment β25–35 in the object recognition test in mice (1 and 3mg/kg, p.o.). Altogether, these findings suggest that SAR110894 may be of therapeutic interest for the treatment of the cognitive symptoms of AD, schizophrenia and certain aspects of ADHD.

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.

This is the first study to examine the effect of subchronic olanzapine (OLZ) on energy homeostasis in rats, covering all aspects of energy balance, including energy intake as metabolizable energy, storage, and expenditure. We further analyzed whether, and by which mechanism, the CB1‐antagonist AVE1625 might attenuate OLZ‐induced body weight gain. For this purpose, we selected juvenile female Hanover Wistar rats that robustly and reproducibly demonstrated weight gain on OLZ treatment, accepting limitations to model the aberrations on lipid and carbohydrate metabolism. Rats received 2 mg/kg OLZ orally twice daily for 12 days. Body weight and body composition were analyzed. Moreover daily food intake, energy expenditure, and substrate oxidation were determined in parallel to motility and body core temperature. OLZ treatment resulted in substantial body weight gain, in which lean and fat mass increased significantly. OLZ‐treated rats showed hyperphagia that manifested in increased carbohydrate oxidation and lowered fat oxidation (FO). Energy expenditure was increased, motility decreased, but there was no indication for hypothermia in OLZ‐treated rats. Coadministration of OLZ and AVE1625 (10 mg/kg orally once daily) attenuated body weight gain, diminishing the enhanced food intake while maintaining increased energy expenditure and decreased motility. Our data reveal that energy expenditure was enhanced in OLZ‐treated rats, an effect not critically influenced by motility. Energy uptake, however, exceeded energy expenditure and led to a positive energy balance, confirming hyperphagia as the major driving factor for OLZ‐induced weight gain. Combination of OLZ treatment with the CB1‐antagonist AVE1625 attenuated body weight gain in rats.

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.

Schizophrenia symptoms can be segregated into positive, negative and cognitive, which exhibit differential sensitivity to drug treatments. Accumulating evidence points to efficacy of α 7 nicotinic receptor (nAChR) agonists for cognitive deficits in schizophrenia but their activity against positive symptoms is thought to be minimal. The present study examined potential pro-cognitive and antipsychotic activity of the novel selective α 7 nAChR partial agonist SSR180711 using the latent inhibition (LI) model. LI is the reduced efficacy of a previously non-reinforced stimulus to gain behavioral control when paired with reinforcement, compared with a novel stimulus. Here, no-drug controls displayed LI if non-reinforced pre-exposure to a tone was followed by weak but not strong conditioning (2 vs 5 tone-shock pairings). MK801 (0.05 mg/kg, i.p.) -treated rats as well as rats neonatally treated with nitric oxide synthase inhibitor L -NoArg (10 mg/kg, s.c.) on postnatal days 4–5, persisted in displaying LI with strong conditioning, whereas amphetamine (1 mg/kg) -treated rats failed to show LI with weak conditioning. SSR180711 (0.3, 1, 3 mg/kg, i.p.) was able to alleviate abnormally persistent LI produced by acute MK801 and neonatal L -NoArg; these models are believed to model cognitive aspects of schizophrenia and activity here was consistent with previous findings with α 7-nAChR agonists. In addition, unexpectedly, SSR180711 (1, 3 mg/kg, i.p.) potentiated LI with strong conditioning in no-drug controls and reversed amphetamine-induced LI disruption, two effects considered predictive of activity against positive symptoms of schizophrenia. These findings suggest that SSR180711 may be beneficial not only for the treatment of cognitive symptoms in schizophrenia, as reported multiple times previously, but also positive symptoms.

La presente invention concerne une methode pour traiter des deficits cognitifs chez un patient souffrant de schizophrenie en administrant audit patient une quantite therapeutiquement efficace d'un antagoniste du recepteur CB1 comme decrit dans la presente. Sous un autre aspect, la presente invention concerne egalement une combinaison d'un ou plusieurs antagonistes du recepteur CB1 avec un ou plusieurs agents antipsychotiques utiles dans le traitement de troubles psychiatriques. La combinaison selon l'invention fournit des resultats synergiques dans la mesure ou elle ameliore les symptomes positifs et negatifs de la schizophrenie, le gain de poids et la catalepsie.

BACKGROUND:Positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) modulators enhance glutamate transmission via the AMPA receptor by altering the rate of desensitization; alone they have no intrinsic activity. They are the only class of compounds known that may pharmacologically separate AMPA subtypes.OBJECTIVE:This manuscript will review preclinical work on positive AMPA modulators, with clinical examples where relevant.RESULTS:The activity of these compounds appears to be determined by the AMPA receptor subunit composition. Studies have shown that splice variant and/or subunit combinations change the desensitization rate of this receptor. Also, these subunits are heterogeneously expressed across the central nervous system. Therefore, the functional outcome of different positive AMPA modulators could indeed be different. The origins of this pharmacological class come from hippocampal long-term potentiation studies, so quite naturally they were first studied in models of short- and long-term memory (e.g., delayed match to sample, maze performance). In general, these agents were procognitive. However, more recent work with different chemical classes has suggested additional therapeutic effects in models of schizophrenia (e.g., amphetamine locomotor activity), depression (e.g., forced swim test), neuroprotection (e.g., NMDA agonist lesions) and Parkinson's disease (e.g., 6-hydroxydopamine lesion).CONCLUSIONS:In conclusion, positive modulation of AMPA may offer numerous therapeutic avenues for central nervous system drug discovery.

The startle reflex is an unconditioned, quantifiable behavior used to study sensory modalities. We examined whether the acoustic startle reflex (ASR) was sensitive to lesions induced by focal cerebral ischemia. Sprague-Dawley rats were pre-screened for startle reflex responses 3–6 days prior to surgery and there were no differences in mean startle amplitude across groups. Animals were subjected to permanent middle cerebral artery occlusion (pMCAo) or a sham surgical procedure. Twenty-four hours later rats were evaluated for ASR prior to sacrifice. Infarct volumes were subsequently determined by quantitative image analysis of 2,3,5-triphenyltetrazolium chloride-stained brain sections. Infarct volumes of rats undergoing pMCAO ranged from 0 to 48%. Data were divided into three groups based upon percent infarction: mild (0–20%), moderate (21–35%), and severe (>35%). A within-subject analysis revealed a significant decrease in mean startle amplitude of only severely infarcted rats relative to their pre-surgery startle responses. Furthermore, the lesioned brain areas observed in these animals provide an anatomical basis for these results. Our findings demonstrate that ASR is affected in a model of stroke. Further work is needed to characterize this behavioral test and to determine whether it may have application as a surrogate endpoint for clinical stroke studies.

In an effort to compare and contrast the mechanisms of action of typical and atypical antipsychotic drugs, [3H] 2-deoxyglucose metabolic mapping was employed following acute and chronic administration of haloperidol (1 mg/kg i.p. acute and 0.5 mg/kg i.p. chronic) and clozapine (20 mg/kg i.p., both acute and chronic). Optical density ratios (ODR) were measured in 62 brain structures. An overall decrease in ODR was observed in many of the regions analyzed. Acute haloperidol elicited significant decreases, particularly in the thalamus and hippocampus. Acute clozapine decreased glucose uptake in the caudate putamen, hippocampus, central gray, locus coreleus, and the thalamus. In both chronically treated haloperidol and clozapine animals, significant decreases in ODR were seen in the thalamus and hippocampal areas most dramatically, with other changes in the superior colliculus, retrospenial cortex, and the cerebellum. Clozapine caused significant effects in 32 nuclei acutely and only 19 nuclei chronically. Haloperidol caused significant effects in 23 nuclei acutely and 15 nuclei chronically. The pattern of change induced by haloperidol and clozapine were remarkably similar when considering their pharmacology is somewhat different. Both antipsychotics elicited fewer significant changes upon chronic administration.

Attention has focused on drugs that modulate AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid) receptors because of their potential for enhancing memory and treating certain pathologies that involve glutamatergic neurotransmission. The aim of this study was to compare and contrast the functionality of positive allosteric modulators of AMPA receptors in the hippocampus and medial prefrontal cortex. Electrically stimulated EPSPs (excitatory postsynaptic potential) in the hippocampus were augmented by CX516 [(1-quinoxaline-6-ylcarbonyl)piperidine], aniracetam and 1-BCP [(1-(1,3-benzodioxol-5-ylcarbonyl)piperidine] and not by cyclothiazide. Using grease gap electrophysiology, it was found that the mode of application dramatically altered the effect of the modulators of AMPA-induced depolarization. When added simultaneously with AMPA, aniracetam, 1-BCP and CX516 augmented the response in the frontal cortex. However, in the hippocampus, only aniracetam and cyclothiazide augmented the response when simultaneously added to AMPA. Therefore, in addition to regional variations, there appears to be differences in modulator response dependent upon whether a response is generated endogenously or exogenously by AMPA.

NADPH-d (nicotinamide-adenine dinucleotide phosphate-diaphorase) neurons are thought to migrate improperly during development in the brains of schizophrenic patients. This enzyme is a nitric oxide synthase (NOS). Nitric oxide (NO) is known to affect neurodevelopmental processes in the CNS. Therefore, we hypothesized that interference of NO generation during development may produce some aspects of schizophrenia symptomatology in a rat model. In these experiments, neonatal rats were challenged with a NOS inhibitor (L-nitroarginine 1-100 mg/kg s.c.) daily on post-natal days 3-5. L-Nitroarginine (L-NoArg) treated male rats developed a hypersensitivity to amphetamine in adulthood versus vehicle treated controls, whereas female rats did not. However, L-NoArg treated female rats developed a hypersensitivity to phencyclidine (PCP) at juvenile and adult ages versus vehicle treated controls, whereas male animals did not. L-NoArg treated male rats also had deficits in pre-pulse inhibition of startle whereas adult female rats did not. The results are discussed in terms of a new neurodevelopmental model of schizophrenia and male/female differences inherent in this disease.

The effects of several glycine antagonists at the strychnine-insensitive site on N-methyl-D-aspartate (NMDA) receptors in an acute in vitro electrophysiological model of ischemia in the rat hippocampus were studied. Hippocampal slices were subjected to 9 min of hypoxia and hypoglycemia (ischemia). The noncompetitive NMDA antagonist MK-801 produced significant protection of the slices, whereas the competitive NMDA antagonist D-CPP did not. Administration of the strychnine-insensitive glycine-modulatory site antagonists (ACEA 1021, GV150,526A, and L701,324) up to 10 mu M did not result in significant recovery of function. Other animal models have suggested that glycine antagonists are beneficial 6-48 hours after ischemic insult; this model assayed functional recovery for only 1 hour after the insult. Therefore, we conclude that this acute in vitro electrophysiologic model may not be useful in detecting the potential neuroprotective properties of glycine antagonists. (C) 1999 Wiley-Liss, Inc.

A neurodevelopmental model of schizophrenia in rats has recently been proposed employing neonatal hippocampal lesions. The present study further characterizes this model by investigating the long-term effects of neonatal hippocampal lesions up to 100 days after birth, in male rats as well as female rats. Lesions were performed on postnatal day seven (PD 7).Our results showed that neonatal hippocampal lesions produced enhanced hyperlocomotory behavior during spontaneous locomotion and after amphetamine administration. In general, these hyperlocomotory effects were more apparent and appeared earlier in male lesioned animals than in female lesioned animals. Lesioned males exhibited a significant increase in spontaneous locomotion on PD 56 and PD 100, whereas lesioned females showed a significant increase in spontaneous locomotion on PD 100 only. On all test days, amphetamine injection produced a significant enhancement of hyperlocomotion in lesioned males and females vs. control; this effect was more pronounced in males. No changes in receptor binding characteristics (D-2, 5HT(2A) and neurotensin) were found between lesioned and sham-operated animals of either sex. These data lend support to the validity of the neonatal hippocampal lesion model of schizophrenia. (C) 1998 Wiley-Liss, Inc.