Pharmacological Animal Models Research Articles

Scopolamine animal model of memory impairment

In this study, we reassessed the suitability of a commonly used pharmacological animal model of Alzheimer's disease (AD) - scopolamine-induced memory impairment. The goal of the study was to explore if this animal model induces other behavioral changes associated with AD. One of the key behavioral features of AD, manifesting already during the early stages of the illness, is apathy-like behavior. We also evaluated how behavioral alterations induced by scopolamine compare to those seen in healthy aging animals. To achieve these goals, locomotor activity and short-term memory of young male Wistar rats were tested in the open field, novel object recognition (NOR) and T-maze spontaneous alternation tests before, during and after 21 daily administrations of scopolamine. Three-, ten- and nineteen-month-old male and female rats were used to measure age-related changes in these behaviors. Our data showed that although both scopolamine treatment and aging reduced the number of approaches to the objects and their exploration time during the NOR test, correlation with impaired object recognition memory was only observed in the scopolamine treated animals. Furthermore, treatment with scopolamine significantly increased the locomotor activity, which could be observed even one week after treatment discontinuation. Contrary, locomotor activity in older rats was significantly lower than that of younger rats. These findings demonstrate that the animal model of scopolamine-induced memory impairment fails to incorporate apathy-like symptoms characteristic to the AD and age-related reduction in physical activity of older rats.

Analysis of Differential microRNA Expression in the Hippocampus of Scopolamine-Induced Amnesic Mouse Model.

Amnesia is characterized by memory deficits linked to various neurodegenerative pathologies and can be induced by the administration of scopolamine, a cholinergic antagonist. Scopolamine-induced amnesia is a well-studied pharmacological animal model that simulates memory impairment caused by aging, brain illnesses, neuropathologies, and trauma. However, the molecular mechanism of amnesia, more importantly in terms of microRNA (miRNA) regulation, is not well understood. Therefore, this study aimed to analyze miRNA profiles in the hippocampus of both control mice and those treated with scopolamine (amnesic mice). Initially, a short cDNA library was prepared for each sample and then sequenced on the Illumina platform. Among the total differentially expressed miRNAs, 113 were significantly upregulated and 96 were downregulated in the scopolamine group in comparison to the control group. Ten upregulated and ten downregulated miRNAs were validated to confirm the reliability of the sequencing results using qRT-PCR (quantitative real-time PCR). Furthermore, we performed a target prediction analysis intersecting the results from TargetScan, miRDB (miRNA database), and Miranda to analyze the targets of the dysregulated miRNAs. We also conducted a pathway analysis to investigate the molecular, cellular, and biological functions of these targets. miRNA‒target interactions were found to play roles in various signaling pathways during amnesia. These results provide an initial insight for the contribution of miRNAs to scopolamine-induced amnesia, as well as their possible application as markers of disease pathology.

Pharmacological animal models of schizophrenia for antipsychotic drug discovery and development

Schizophrenia is a chronic psychoneurological condition that encompasses a wide variety of neurochemical, morphological, bioelectrical and behavioural changes. Comprehension of the mechanisms underlying schizophrenia and psychosis cannot be fully acquired in clinical studies with humans. For this reason, a number of experimental animal models of schizophrenia have been developed. Although none of the existing models of schizophrenia fully reproduces the complete spectrum of schizophrenia, critical aspects of pathology processes can be experimentally recapitulated. In this review we summarise the pathological features, advantages and limitations of the major pharmacological animal models of schizophrenia, including maternal immune activation. Commonly used pharmacological models of schizophrenia are useful for the preclinical evaluation of antipsychotic drugs and involve the dysfunction of various neurotransmitter systems, including dopamine, glutamate, serotonin. The review also describes maternal immune activation and neurodevelopmental rat models of schizophrenia. Positive, negative, and cognitive symptoms vary in degree and combination depending on the type of model used. A greater understanding of the strengths and weaknesses of various animal models of schizophrenia and the use of more than one model to evaluate antipsychotic activity would help to improve the efficiency of the drug discovery process and therapy translation from preclinical studies to patients.

Probable role of the hyperpolarization-activated current in the dual effects of CB1R antagonism on behaviors in a Parkinsonism mouse model

Recent evidence from genetic and pharmacological animal models of Parkinson's disease (PD) suggests alteration in activity of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) occurs following dopamine (DA) depletion. Further, based on data from our lab and others, the endocannabinoid system (ECB_S) appears to be involved in PD-related processes. Therefore, we compared the motor and non-motor effects of an intracerebroventricular (i.c.v.) injection of the cannabinoid receptor type 1 (CB1R) agonist WIN 55,212-2 (WIN) and selective antagonist AM251 (AM) on motor and non-motor symptoms (NMS) of PD in a mouse model generated by an i.c.v. injection of 6-hydroxydopamine (6-OHDA). To provide further knowledge about the link between CB1R and the hyperpolarization-activated current (Ih), we conducted ex vivo investigations in the ventral tegmental area (VTA). In the current study, pharmacological antagonism of CB1R ameliorated explorative behaviors, balance, muscle strength, and passive avoidance memory deficits induced by 6-OHDA, however, anxious, and depressive-like behaviors were heightened. AM was also effective in reducing a 6-OHDA-induced TH level deficit. 6-OHDA exposure induced severe alterations in the spontaneous and evoked firing behavior of DA neurons, as evidenced by a significant increase in the mean number of spikes and a decrease in spike half-width, respectively. Interestingly, an increase in the amplitude of the sag voltage and in the amplitude of the steady state Ih current was seen. Consistent with an effect of increasing Ih, WIN exacerbated 6-OHDA-induced actions by further reducing the spike half-width and increasing the firing frequency. In addition, greater amplitudes of sEPSPs were elicited. The effects of 6-OHDA on sag voltage, Ih current amplitude, and firing frequency were reversed by administration of AM. These results suggest that ECBs might be involved in some of the 6-OHDA-induced electrophysiological alterations in VTA DA neurons in this animal model of PD. In addition, the CB1R antagonistic mechanism could be effective in modulating the devastating effects of 6-OHDA.

Pharmacologically induced N-methyl-D-aspartate receptor hypofunction impairs goal-directed food seeking in rats.

AimAcute N‐methyl‐D‐aspartate (NMDA) receptor antagonism is an important pharmacological animal model of schizophrenia. In previous studies, schizophrenia patients show impaired goal‐directed behavior in an outcome‐specific devaluation procedure. In this study, we investigated whether the rat model of the NMDA receptor blockade also showed altered goal‐directed behavior in a satiety‐induced outcome devaluation paradigm.MethodsIn experiments 1 and 2, we aimed to establish the satiety‐induced outcome devaluation test using sucrose and lipid rewards in operant conditioning and free consumption paradigms. In experiment 3, we tested the effect of MK‐801 (0.1 mg/kg, i.p.) on outcome‐specific devaluation.ResultsExperiments 1 and 2 demonstrated that 1‐h ad libitum food consumption is sufficient to induce outcome‐specific devaluation in both lever‐press and free consumption tests in rats. Experiment 3 showed that the administration of MK‐801 impaired satiety‐induced devaluation in the lever‐press test but not in the subsequent free consumption test.ConclusionsOur results suggest that acute pharmacological NMDA receptor antagonism in rats is a useful animal model for impaired goal‐directed behavior in schizophrenia.

Striatal Dopamine D2-Muscarinic Acetylcholine M1 Receptor-Receptor Interaction in a Model of Movement Disorders.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor control deficits, which is associated with the loss of striatal dopaminergic neurons from the substantia nigra. In parallel to dopaminergic denervation, there is an increase of acetylcholine within the striatum, resulting in a striatal dopaminergic–cholinergic neurotransmission imbalance. Currently, available PD pharmacotherapy (e.g., prodopaminergic drugs) does not reinstate the altered dopaminergic–cholinergic balance. In addition, it can eventually elicit cholinergic-related adverse effects. Here, we investigated the interplay between dopaminergic and cholinergic systems by assessing the physical and functional interaction of dopamine D2 and muscarinic acetylcholine M1 receptors (D2R and M1R, respectively), both expressed at striatopallidal medium spiny neurons. First, we provided evidence for the existence of D2R–M1R complexes via biochemical (i.e., co-immunoprecipitation) and biophysical (i.e., BRET1 and NanoBiT®) assays, performed in transiently transfected HEK293T cells. Subsequently, a D2R–M1R co-distribution in the mouse striatum was observed through double-immunofluorescence staining and AlphaLISA® immunoassay. Finally, we evaluated the functional interplay between both receptors via behavioral studies, by implementing the classical acute reserpine pharmacological animal model of experimental parkinsonism. Reserpinized mice were administered with a D2R-selective agonist (sumanirole) and/or an M1R-selective antagonist (VU0255035), and alterations in PD-related behavioral tasks (i.e., locomotor activity) were evaluated. Importantly, VU0255035 (10 mg/kg) potentiated the antiparkinsonian-like effects (i.e., increased locomotor activity and decreased catalepsy) of an ineffective sumanirole dose (3 mg/kg). Altogether, our data suggest the existence of putative striatal D2R/M1R heteromers, which might be a relevant target to manage PD motor impairments with fewer adverse effects.

A Natural Product with High Affinity to Sigma and 5-HT7 Receptors as Novel Therapeutic Drug for Negative and Cognitive Symptoms of Schizophrenia.

Dehydrocorybulbine (DHCB), an alkaloid from Corydalis yanhusuo. W.T, has been identified as a dopamine receptor antagonist. We extended our assessment of its pharmacological profile and found that DHCB exhibits high to moderate binding affinities to sigma 1 and 2 receptors, serotonin 5-HT7 receptor, and histamine H2 receptors. This led us to evaluate DHCB properties in pharmacological (apomorphine and MK-801) animal models of schizophrenia in mice. The pharmacological profile of DHCB was screened through radioligand receptor binding assays. Single dose of DHCB reversed the locomotor hyperactivity, stereotypy, and prepulse inhibition deficits induced by the dopaminergic agonist apomorphine. DHCB also reversed the depressive-like behavior and memory deficit induced by the glutamatergic antagonist MK-801 in the forced swim and the novel object recognition assays, respectively. These results indicate that DHCB effectively improves schizophrenia-like behavioral deficits that are induced by the disruption of dopaminergic and glutamatergic systems. The effectiveness of DHCB in reversing responses that mimic negative and cognitive deficits of schizophrenia might suggest that its anti-schizophrenia effects are mediated through modulating the activities of several receptor particularly sigma 1, sigma 2, 5-HT7 and dopamine receptors. Our study casts DHCB as a promising lead for therapeutic treatment of schizophrenia.

Hypoactivity of the lateral habenula contributes to negative symptoms and cognitive dysfunction of schizophrenia in rats

Dopaminergic (DAergic) hypofunction in the medial prefrontal cortex (mPFC) has been implicated in the negative and cognitive symptoms of schizophrenia and is regulated by serotonergic (5-HTergic) neurons in the dorsal raphe nucleus (DRN). The lateral habenula (LHb) is a key element in controlling DRN 5-HT neurons. We investigated how the LHb impacts the activity of mPFC neurons and whether it mediates the involvement of DRN on development of symptoms in a pharmacological animal model of schizophrenia. We used immunohisochemistry to assess cytochrome-c oxidase (COX) activity of the LHb in MK-801 model rats and extracellular firing recording to compare firing rates in LHb neurons of acute MK-801-treated rats. The sucrose preference, social interaction, and radial arm maze tests were used to access schizophrenia-like behavior in rats with electrolytically lesioned LHb. Finally, we examined levels of the dopamine D1 receptor (D1R) and tyrosine hydroxylase (TH) in the mPFC, and tryptophan hydroxylase 2 (TPH2) in the DRN of rats with LHb lesions to determine the possible mechanism underlying the schizophrenia-like behavior associated with lesioned LHb. We found that COX levels and LHb neuron firing rates decreased significantly in MK-801-treated animals. The LHb lesions induced negative and cognitive, but not positive symptoms of schizophrenia. The D1R and TH levels decreased in the mPFC while TPH2 expression elevated in the DRN and mPFC of LHb-lesioned rats. These results suggest that LHb hypoactivity may contribute to the negative and cognitive symptoms of schizophrenia by downregulating D1R expression in the mPFC, which might be mediated by DRN 5-HT neurons.

Transient Cognitive Impairment in Epilepsy.

Impairments of the dialog between excitation and inhibition (E/I) is commonly associated to neuropsychiatric disorders like autism, bipolar disorders and epilepsy. Moderate levels of hyperexcitability can lead to mild alterations of the EEG and are often associated with cognitive deficits even in the absence of overt seizures. Indeed, various testing paradigms have shown degraded performances in presence of acute or chronic non-ictal epileptiform activity. Evidences from both animal models and the clinics suggest that anomalous activity can cause cognitive deficits by transiently disrupting cortical processing, independently from the underlying etiology of the disease. Here, we will review our understanding of the influence of an abnormal EEG activity on brain computation in the context of the available clinical data and in genetic or pharmacological animal models.

Formulations, Pharmacodynamic and Clinical Studies of Nanoparticles for Lung Cancer Therapy - An Overview.

Nanoparticles play an important role in the area of drug delivery and have been applied in lung cancer treatments for the purpose of controlled release and cancer cell targeting. A review covering various nanoparticle formulations for lung cancer therapy is presented. The pharmacodynamic models for evaluating anti-lung cancer drugs are summarized upon drug administration routes. Moreover, the current clinical applications of nano-drugs for lung cancer treatments are also reviewed, including the administration routes, dose forms and clinical trials. The preparation methods of anti-lung cancer nanoparticles varied from different formulations. Owing to the improvement of their bioavailability, stability and residency at lung, the anti-lung cancer drugs encapsulated by nanoparticles showed better therapeutic effects than the naked drug. Likewise, characterization including pharmacology, physical and chemical properties should be taken into consideration. More importantly, different pharmacological animal models should be correctly selected for the pharmacodynamics assessment. Finally, the investigation of anti-lung cancer nanoparticles in clinical trials provided experience on further related research. Nanoparticle delivery system for lung cancer therapy is still in its early stage and expecting numerous challenges.

Neurotoxin-Induced Animal Models of Parkinson Disease: Pathogenic Mechanism and Assessment.

Parkinson disease (PD) is the second most common neurodegenerative movement disorder. Pharmacological animal models are invaluable tools to study the pathological mechanisms of PD. Currently, invertebrate and vertebrate animal models have been developed by using several main neurotoxins, such as 6-hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, paraquat, and rotenone. These models achieve to some extent to reproduce the key features of PD, including motor defects, progressive loss of dopaminergic neurons in substantia nigra pars compacta, and the formation of Lewy bodies. In this review, we will highlight the pathogenic mechanisms of those neurotoxins and summarize different neurotoxic animal models with the hope to help researchers choose among them accurately and to promote the development of modeling PD.

The inhibition of the kynurenine pathway prevents behavioral disturbances and oxidative stress in the brain of adult rats subjected to an animal model of schizophrenia

Evidence has shown that the kynurenine pathway (KP) plays a role in the onset of oxidative stress and also in the pathophysiology of schizophrenia. The aim of this study was to use a pharmacological animal model of schizophrenia induced by ketamine to investigate if KP inhibitors could protect the brains of Wistar rats against oxidative stress and behavioral changes. Ketamine, injected at the dose of 25mg/kg, increased spontaneous locomotor activity. However, the inhibitors of tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO) and kynurenine-3-monooxygenase (KMO) were able to reverse these changes. In addition, the IDO inhibitor prevented lipid peroxidation, and decreased the levels of protein carbonyl in the prefrontal cortex (PFC), hippocampus and striatum. It also increased the activity of superoxide dismutase (SOD) in the hippocampus, as well as increasing the levels of catalase activity in the PFC and hippocampus. The TDO inhibitor prevented lipid damage in the striatum and reduced the levels of protein carbonyl in the hippocampus and striatum. Also, the TDO inhibitor increased the levels of SOD activity in the striatum and CAT activity in the hippocampus of ketamine-induced pro-oxidant effects. Lipid damage was not reversed by the KMO inhibitor. The KMO inhibitor increased the levels of SOD activity in the hippocampus, and reduced the levels of protein carbonyl while elevating the levels of CAT activity in the striatum of rats that had been injected with ketamine. Our findings revealed that the KP pathway could be a potential mechanism by which a schizophrenia animal model induced by ketamine could cause interference by producing behavioral disturbance and inducing oxidative stress in the brain, suggesting that the inhibition of the KP pathway could be a potential target in treating schizophrenia.

A quantitative review of the postmortem evidence for decreased cortical N-methyl-d-aspartate receptor expression levels in schizophrenia: How can we link molecular abnormalities to mismatch negativity deficits?

Evidence suggests that anomalous mismatch negativity (MMN) in schizophrenia is related to glutamatergic abnormalities, possibly involving N-methyl-D-aspartate (NMDA) receptors. Decreased cortical expressions of NMDA receptor subunits have been observed in schizophrenia, though not consistently. To aid with integration and interpretation of previous work, we performed a meta-analysis of effect sizes of mRNA or protein levels of the obligatory NR1 subunit in prefrontal cortex from people with schizophrenia. In schizophrenia compared to unaffected controls the pooled effect size was -0.64 (95% confidence interval: -1.08 to -0.20) for NR1 mRNA reduction and -0.44 (95% confidence interval: -0.80 to -0.07) for NR1 protein reduction. These results represent the first step to a deeper understanding of the region-specific, cell-specific, and stage-specific NMDA receptor hypofunction in schizophrenia, which could be linked to mismatch negativity deficits via transgenic and pharmacological animal models.

Effects of the selective 5-HT7 receptor antagonist SB-269970 on premature responding in the five-choice serial reaction time test in rats

The antagonists of serotonin 5-HT7 receptors have been demonstrated to ameliorate cognitive impairments in pharmacological animal models of schizophrenia that involve blockade of N-methyl-D-aspartate receptors (NMDARs). The administration of NMDAR antagonists evokes a broad range of cognitive deficits, including a loss of impulse control. The involvement of 5-HT7 receptors in the modulation of impulsivity has been recently suggested but has not been studied in great detail. The aim of the present study was to examine the effect of a selective 5-HT7 receptor antagonist SB-269970 on a measure of impulsive action, i.e., premature responding on the five-choice serial reaction time task (5-CSRTT) in rats. The antagonist of 5-HT2A receptor M100,907 was used as a positive control. The efficacies of both compounds were assessed in conditions of increased impulsivity that were produced by the administration of the NMDAR antagonist MK-801 or/and non-drug stimuli, i.e., using variable inter-trial intervals (vITIs). To examine the general ability of SB-269970 to counteract the MK-801-induced impairments, a discrete paired-trial delayed alternation task in a T-maze was employed. MK-801 significantly increased the number of premature responses in 5-CSRTT, and this effect was abolished by the administration of M100,907 (0.5 mg/kg) and SB-269970 (1 mg/kg). In addition, M100,907, but not SB-269970, reduced premature responding in the prolonged ITI trials. Both M100,907 and SB-269970 attenuated MK-801-induced working memory impairment in a T-maze. The present study demonstrated the efficacy of SB-269970 against MK-801-induced premature responding in the 5-CSRTT. This anti-impulsive action may offer additional benefits to the cognitive-enhancing effects of pharmacological blockade of 5-HT7 receptors.

Antidiabetic action of Anoda cristata aqueous extract and compounds

Different ethnobotanical studies refer that the main use of Anoda cristata (Malvaceae) is as food, however it is also employed to treat stomach inflammation, fever, cough, wounds and diabetes. In this work we describe the antidiabetic action of an infusion of A. cristata and its major compounds [acacetin (1) and diosmetin (2)] using different pharmacological animal models. The free-mucilage aqueous extract (100 and 316 mg/kg) reduced glucose and triglyceride blood levels and increased insulin levels in metabolic syndrome-induced rats. The aqueous extract (31.6, 100 and 316 mg/kg) provoked significant hypoglycemic and antihyperglycemic effect in diabetic NA-STZ (50; 130 mg/kg, i.p.) mice, and compounds 1 and 2 (3, 10 and 31.6 mg/kg) have also significant hypoglycemic effect. This work provides scientific evidence supporting the use of A. cristata as antidiabetic agent in folk medicine.

In between - Proteomics of dog biological fluids.

Dogs are relevant to biomedical research in connection both to veterinary medicine for their role as pets and to basic investigations for their use as animal models in pathology, pharmacology and toxicology studies. Proteomic analysis of biological fluids is less advanced for dogs than for other animal species but a wealth of information has already been gathered, which we summarize in this review. As a remarkable feature, we also assemble here for due reference a number of 2-DE serum/plasma or urine patterns in health and disease; some of them correspond to unpublished data from the University of Veterinary Medicine Vienna.

Schizophrenia‐like behaviors in the offspring after maternal stress and prenatal NMDA receptor hypofunction (1144.9)

Pharmacological animal models have been developed and used to study the neurobiological deficits most commonly associated with schizophrenia. Evidence suggests that NMDA receptor (NMDAR) activity is an integral component in the pathophysiology of the disease, because antagonizing this receptor leads to schizophrenic‐like neurophysiological alterations and behaviors. In this study we sought to determine the influence of maternal NMDAR hypofunction combined with stress in the outcome of schizophrenia‐like behaviors of the offspring. After daily prenatal injections of MK‐801 and induction of stress in female mice, pregnancy was allowed to ensue and the litter was allowed to develop to P21‐P30. Analysis of schizophrenia‐like behaviors was performed on the offspring by measuring cognition as well as anxiety and other related behaviors. Our results suggest that maternal NMDAR dysfunction together with environmental stress impact the neurodevelopmental status of the offspring. These results not only strengthen the view that NMDAR function is involved in normal brain development, but also show that changes induced prenatally can affect the brains of the offspring.

Poster #T233 A DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED WITHDRAWAL STUDY OF LURASIDONE FOR THE MAINTENANCE OF EFFICACY IN PATIENTS WITH SCHIZOPHRENIA

Schizophrenia is a chronic, debilitating disorder with a complex behavioral and cognitive phenotype underlined by a similarly complex etiology involving an interaction between susceptibility genes and environmental factors during early development. Limited progress has been made in developing novel pharmacotherapy, partly due to a lack of valid animal models. The recent recognition of the potentially causal role of central and peripheral energy metabolism in the pathophysiology of schizophrenia raises the need of research on animal models that combine both behavioral and metabolic phenotypic domains, similar to what have been identified in humans. In this review we focus on selected genetic (DBA/2J mice, leptin receptor mutants, and PSD-93 knockout mice), early neurodevelopmental (maternal protein deprivation) and pharmacological (acute phencyclidine) animal models that capture the combined behavioral and metabolic abnormalities shown by schizophrenic patients. In reviewing behavioral phenotypes relevant to schizophrenia we apply the principles established by the Research Domain Criteria (RDoC) for better translation. We demonstrate that etiologically diverse manipulations such as specific breeding, deletion of genes that are primarily involved in metabolic regulation and in synaptic plasticity, as well as early metabolic deprivation and adult pharmacological challenge of the glutamate system can lead to schizophrenia-related behavioral and metabolic phenotypes, which suggest that these pathways might be interlinked. We propose that using animal models that combine different domains of schizophrenia can be used as a translationally valid approach to capture the system-level complex interplay between peripheral and central processes in the development of psychopathology.

Physiological and pathological implications of cholesterol

Cholesterol has evolved to fulfill sophisticated biophysical, cell signaling and endocrine requirements of animal systems. At a cellular level, cholesterol is found in membranes, where it increases both bilayer stiffness and impermeability to water and ions. Furthermore, cholesterol is integrated into specialized lipid-protein membrane microdomains with critical topographical and signaling functions. At an organismal level, cholesterol is the precursor for all steroid hormones, including gluco- and mineralo-corticoids, sex hormones and vitamin D, all of which regulate carbohydrate, sodium, reproductive and bone homeostasis, respectively. This sterol is also the precursor for bile acids, which are important for intestinal absorption of dietary lipids as well as energy and glucose metabolic regulation. Importantly, complex mechanisms maintain cholesterol within physiological ranges and the disregulation of these mechanisms results in embryonic or adult diseases, caused by either excessive or reduced tissue cholesterol levels. The causative role of cholesterol in these diseases has been demonstrated by diverse genetic and pharmacologic animal models that are commented in this review.

New insights into pharmacological profile of LASSBio-579, a multi-target N-phenylpiperazine derivative active on animal models of schizophrenia

Previous behavioral and receptor binding studies on N-phenylpiperazine derivatives by our group indicated that LASSBio-579, LASSBio-580 and LASSBio-581 could be potential antipsychotic lead compounds. The present study identified LASSBio-579 as the most promising among the three compounds, since it was the only one that inhibited apomorphine-induced climbing (5 mg/kg p.o.) and apomorphine-induced hypothermia (15 mg/kg p.o.). Furthermore, LASSBio-579 (0.5 mg/kg p.o.) was effective in the ketamine-induced hyperlocomotion test and prevented the prepulse inhibition deficits induced by apomorphine, DOI and ketamine with different potencies (1 mg/kg, 0.5 mg/kg and 5 mg/kg p.o., respectively). LASSBio-579 also induced a motor impairment, catalepsy and a mild sedative effect but only at doses 3-120 times higher than those with antipsychotic-like effects. In addition, LASSBio-579 (0.5 and 1 mg/kg p.o.) reversed the catalepsy induced by WAY 100,635, corroborating its action on both dopaminergic and serotonergic neurotransmission and pointing to the contribution of 5-HT(1A) receptor activation to its pharmacological profile. Moreover, co-administration of sub-effective doses of LASSBio-579 with sub-effective doses of clozapine or haloperidol prevented the apomorphine-induced climbing without induction of catalepsy. In summary, our results characterize LASSBio-579 as a multi-target ligand active in pharmacological animal models of schizophrenia, confirming that this compound could be included in development programs aiming at a new drug for treating schizophrenia.