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1.
Front Pharmacol ; 11: 635763, 2020.
Article in English | MEDLINE | ID: mdl-33613289

ABSTRACT

Schizophrenia and autism spectrum disorders (ASD) are psychiatric neurodevelopmental disorders that cause high levels of functional disabilities. Also, the currently available therapies for these disorders are limited. Therefore, the search for treatments that could be beneficial for the altered course of the neurodevelopment associated with these disorders is paramount. Preclinical and clinical evidence points to cannabidiol (CBD) as a promising strategy. In this review, we discuss clinical and preclinical studies on schizophrenia and ASD investigating the behavioral, molecular, and functional effects of chronic treatment with CBD (and with cannabidivarin for ASD) during neurodevelopment. In summary, the results point to CBD's beneficial potential for the progression of these disorders supporting further investigations to strengthen its use.

2.
Neuropharmacology ; 155: 44-53, 2019 09 01.
Article in English | MEDLINE | ID: mdl-31103618

ABSTRACT

Studies suggest that the endocannabinoid and endovanilloid systems are implicated in the pathophysiology of schizophrenia. The Spontaneously Hypertensive Rats (SHR) strain displays impaired contextual fear conditioning (CFC) attenuated by antipsychotic drugs and worsened by pro-psychotic manipulations. Therefore, SHR strain is used to study emotional processing/associative learning impairments associated with schizophrenia and effects of potential antipsychotic drugs. Here, we evaluated the expression of CB1 and TRPV1 receptors in some brain regions related to the pathophysiology of schizophrenia. We also assessed the effects of drugs that act on the endocannabinoid/endovanilloid systems on the CFC task in SHRs and control animals (Wistar rats - WRs). The following drugs were used: AM404 (anandamide uptake/metabolism inhibitor), WIN55-212,2 (non-selective CB1 agonist), capsaicin (TRPV1 agonist), and capsazepine (TRPV1 antagonist). SHRs displayed increased CB1 expression in prelimbic cortex and cingulate cortex area 1 and in CA3 region of the dorsal hippocampus. Conversely, SHRs exhibited decreases in TRPV1 expression in prelimbic and CA1 region of dorsal hippocampus and increases in the basolateral amygdala. AM404, WIN 55,212-2 and capsaicin attenuated SHRs CFC deficit, although WIN 55,212-2 worsened SHRs CFC deficit in higher doses. WRs and SHRs CFC were modulated by distinct doses, suggesting that these strains display different responsiveness to cannabinoid and vanilloid drugs. Treatment with capsazepine did not modify CFC in either strains. The effects of AM404 on SHRs CFC deficit was not blocked by pretreatment with rimonabant (CB1 antagonist) or capsazepine. These results reinforce the involvement of the endocannabinoid/endovanilloid systems in the SHRs CFC deficit and point to these systems as targets to treat the emotional processing/cognitive symptoms of schizophrenia.


Subject(s)
Affective Symptoms/metabolism , Cannabinoid Receptor Modulators/metabolism , Cognitive Dysfunction/metabolism , Disease Models, Animal , Endocannabinoids/metabolism , Schizophrenia/metabolism , Affective Symptoms/chemically induced , Animals , Arachidonic Acids/agonists , Arachidonic Acids/antagonists & inhibitors , Arachidonic Acids/metabolism , Arachidonic Acids/pharmacology , Arachidonic Acids/therapeutic use , Cannabinoid Receptor Agonists/pharmacology , Cannabinoid Receptor Agonists/therapeutic use , Cognitive Dysfunction/chemically induced , Endocannabinoids/agonists , Endocannabinoids/antagonists & inhibitors , Male , Polyunsaturated Alkamides/agonists , Polyunsaturated Alkamides/antagonists & inhibitors , Polyunsaturated Alkamides/metabolism , Rats , Rats, Inbred SHR , Rats, Wistar , Schizophrenia/chemically induced , Schizophrenia/prevention & control
3.
Article in English | MEDLINE | ID: mdl-30500412

ABSTRACT

The Spontaneously Hypertensive Rat (SHR) strain has been suggested as an animal model of schizophrenia, considering that adult SHRs display behavioral abnormalities that mimic the cognitive, psychotic and negative symptoms of the disease and are characteristic of its animal models. SHRs display: (I) deficits in fear conditioning and latent inhibition (modeling cognitive impairments), (II) deficit in prepulse inhibition of startle reflex (reflecting a deficit in sensorimotor gating, and associated with psychotic symptoms), (III) diminished social behavior (modeling negative symptoms) and (IV) hyperlocomotion (modeling the hyperactivity of the dopaminergic mesolimbic system/ psychotic symptoms). These behavioral abnormalities are reversed specifically by the administration of antipsychotic drugs. Here, we performed a behavioral characterization of young (27-50 days old) SHRs in order to investigate potential early behavioral abnormalities resembling the prodromal phase of schizophrenia. When compared to Wistar rats, young SHRs did not display hyperlocomotion or PPI deficit, but exhibited diminished social interaction and impaired fear conditioning and latent inhibition. These findings are in accordance with the clinical course of schizophrenia: manifestation of social and cognitive impairments and absence of full-blown psychotic symptoms in the prodromal phase. The present data reinforce the SHR strain as a model of schizophrenia, expanding its validity to the prodromal phase of the disorder.


Subject(s)
Disease Models, Animal , Prodromal Symptoms , Rats, Inbred SHR , Schizophrenia , Animals , Antipsychotic Agents/pharmacology , Behavior, Animal/drug effects , Male , Motor Activity , Prepulse Inhibition/drug effects , Rats, Wistar , Reflex, Startle/drug effects , Schizophrenia/drug therapy , Schizophrenia/physiopathology
4.
Article in English | MEDLINE | ID: mdl-29625156

ABSTRACT

Questionnaires that assess symptoms of schizophrenia patients undergo strict statistical validation, often using confirmatory factor analysis (CFA). CFA allows testing the existence of a trait that both collectively explains the symptoms and gathers the information in a single general index. In rodents, some behaviors are used to model psychiatric symptoms, but no single test or paradigm adequately captures the disorder's phenotype in toto. This work investigated the existence of a behavioral trait in the SHR strain underlying five behavioral tasks used in schizophrenia animal studies and altered in this strain: locomotor activity, rearing behavior, social interaction, prepulse inhibition of startle and contextual fear conditioning. The analysis was conducted on a sample of Wistar (n = 290) and Spontaneously Hypertensive Rats (SHRs, n = 290). CFA showed the existence of a continuous trait in both strains, and higher values among SHRs. This work is the first to demonstrate the existence of a schizophrenia-like trait in an animal model. We suggest that using CFA to evaluate behavioral parameters in animals might facilitate the pre-clinical investigation of psychiatric disorders, diminishing the gap between animal and human studies.


Subject(s)
Disease Models, Animal , Rats, Inbred SHR , Schizophrenic Psychology , Animals , Behavior, Animal , Computer Simulation , Conditioning, Psychological , Factor Analysis, Statistical , Fear , Male , Monte Carlo Method , Motor Activity , Prepulse Inhibition , Rats, Wistar , Reflex, Startle , Social Behavior
5.
Schizophr Res ; 176(2-3): 552-559, 2016 10.
Article in English | MEDLINE | ID: mdl-27338757

ABSTRACT

Schizophrenia is a highly disabling mental disorder, in which genetics and environmental factors interact culminating in the disease. The treatment of negative symptoms and cognitive deficits with antipsychotics is currently inefficient and is an important field of research. Environmental enrichment (EE) has been suggested to improve some cognitive deficits in animal models of various psychiatric disorders. In this study, we aimed to evaluate a possible beneficial effect of early and long-term exposure to EE on an animal model of schizophrenia, the SHR strain. Young male Wistar rats (control strain) and SHRs (21 post-natal days) were housed for 6weeks in two different conditions: in large cages (10 animals per cage) containing objects of different textures, forms, colors and materials that were changed 3 times/week (EE condition) or in standard cages (5 animals per cage - Control condition). Behavioral evaluations - social interaction (SI), locomotion, prepulse inhibition of startle (PPI) and spontaneous alternation (SA) - were performed 6weeks after the end of EE. SHRs presented deficits in PPI (a sensorimotor impairment), SI (mimicking the negative symptoms) and SA (a working memory deficit), and also hyperlocomotion (modeling the positive symptoms). EE was able to reduce locomotion and increase PPI in both strains, and to prevent the working memory deficit in SHRs. EE also increased the number of neurons in the CA1 and CA3 of the hippocampus. In conclusion, EE can be a potential nonpharmacological strategy to prevent some behavioral deficits associated with schizophrenia.


Subject(s)
Environment , Housing, Animal , Schizophrenia/prevention & control , Animals , Cerebrum/pathology , Disease Models, Animal , Male , Motor Activity , Neurons/pathology , Prepulse Inhibition , Random Allocation , Rats, Inbred SHR , Rats, Wistar , Reflex, Startle , Schizophrenia/pathology , Schizophrenia/physiopathology , Social Behavior
6.
Eur Neuropsychopharmacol ; 25(12): 2416-25, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26476704

ABSTRACT

Schizophrenia is a multifactorial neurodevelopmental disorder with high heritability. First-episode psychosis (FEP) is a critical period for determining the disease prognosis and is especially helpful for identifying potential biomarkers associated with the onset and progression of the disorder. We investigated the mRNA expression of 12 schizophrenia-related genes in the blood of antipsychotic-naïve FEP patients (N=73) and healthy controls (N=73). To evaluate the influences of antipsychotic treatment and progression of the disorder, we compared the gene expression within patients before and after two months of treatment with risperidone (N=64). We observed a significantly increased myelin basic protein (MBP) and nuclear distribution protein nudE-like 1 (NDEL1) mRNA levels in FEP patients compared with controls. Comparing FEP before and after risperidone treatment, no significant differences were identified; however; a trend of relatively low NDEL1 expression was observed after risperidone treatment. Animals chronically treated with saline or risperidone exhibited no significant change in Ndel1 expression levels in the blood or the prefrontal cortex (PFC), suggesting that the trend of low NDEL1 expression observed in FEP patients after treatment is likely due to factors other than risperidone treatment (i.e., disease progression). In addition to the recognized association with schizophrenia, MBP and NDEL1 gene products also play an essential role in the functions that are deregulated in schizophrenia, such as neurodevelopment. Our data strengthen the importance of these biological processes in psychotic disorders, indicating that these changes can be detected peripherally and potentially represent putative novel blood biomarkers of susceptibility and disorder progression.


Subject(s)
Carrier Proteins/metabolism , Gene Expression Regulation/physiology , Myelin Basic Protein/metabolism , Psychotic Disorders/blood , Adolescent , Adult , Age Factors , Animals , Antipsychotic Agents/therapeutic use , Female , Gene Expression Regulation/drug effects , Humans , Male , Psychiatric Status Rating Scales , Psychotic Disorders/drug therapy , Rats , Rats, Inbred SHR , Rats, Wistar , Sex Factors , Statistics as Topic , Young Adult
7.
CNS Neurol Disord Drug Targets ; 14(8): 970-8, 2015.
Article in English | MEDLINE | ID: mdl-26350340

ABSTRACT

Since most patients with schizophrenia do not respond properly to treatment, scientific effort has been driven to the development of new compounds acting on pharmacological targets beyond the dopaminergic system. Therefore, the aim is to review basic and clinical research findings from studies evaluating the effects of cannabidiol (CBD), an inhibitor of the reuptake and metabolism of anandamide and several other effects on nervous system, and sodium nitroprusside, a nitric oxide donor, on the prevention and treatment of psychosis. Animal and human research supports that CBD and sodium nitroprusside might be effective in the prevention and treatment of psychosis in general and especially in schizophrenia. The evidence available to date shows that CBD and sodium nitroprusside act in pathways associated with psychotic symptoms and that they may be important agents in the management of prodromal psychotic states and psychosis. This underscores the relevance of further research on the effects of these agents and others that mediate the activity of the cannabinoid system and of nitric oxide, as well as comparative studies of their antipsychotic effects and those of other antipsychotic drugs currently used to treat schizophrenia.


Subject(s)
Antipsychotic Agents/therapeutic use , Cannabidiol/therapeutic use , Nitroprusside/therapeutic use , Psychotic Disorders/drug therapy , Schizophrenia/drug therapy , Animals , Antipsychotic Agents/pharmacology , Brain/drug effects , Brain/physiopathology , Cannabidiol/pharmacology , Humans , Nitroprusside/pharmacology , Psychotic Disorders/physiopathology , Schizophrenia/physiopathology
8.
Psychiatry Res ; 219(3): 674-9, 2014 Nov 30.
Article in English | MEDLINE | ID: mdl-25041985

ABSTRACT

The spontaneously hypertensive rat (SHR) strain was shown to be a useful animal model to study several behavioral, pathophysiological and pharmacological aspects of schizophrenia and attention-deficit/hyperactivity disorder. To further understand the genetic underpinnings of this model, our primary goal in this study was to compare the gene expression profile of neurotransmitter receptors and regulators in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) of SHR and Wistar rats (control group). In addition, we investigated DNA methylation pattern of promoter region of the genes differentially expressed. We performed gene expression analysis using a PCRarray technology, which simultaneously measures the expression of 84 genes related to neurotransmission. Four genes were significantly downregulated in the PFC of SHR compared to Wistar rats (Gad2, Chrnb4, Slc5a7, and Qrfpr) and none in nucleus accumbens. Gad2 and Qrfpr have CpG islands in their promoter region. For both, the promoter region was hypomethylated in SHR group, and probably this mechanism is not related with the downregulation of these genes. In summary, we identified genes that are downregulated in the PFC of SHR, and might be related to the behavioral abnormalities exhibited by this strain.


Subject(s)
Attention Deficit Disorder with Hyperactivity/metabolism , Attention Deficit Disorder with Hyperactivity/psychology , Nucleus Accumbens/metabolism , Prefrontal Cortex/metabolism , Receptors, Neurotransmitter/genetics , Synaptic Transmission , Animals , CpG Islands , Disease Models, Animal , Down-Regulation/genetics , Gene Expression , Glutamate Decarboxylase , Male , Nerve Tissue Proteins , Nucleus Accumbens/physiopathology , Polymerase Chain Reaction , Prefrontal Cortex/physiopathology , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Rats, Wistar , Receptors, G-Protein-Coupled , Receptors, Nicotinic , Symporters
9.
Schizophr Res ; 157(1-3): 163-8, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24893910

ABSTRACT

Antipsychotic drugs (APDs) are the standard treatment for schizophrenia. The therapeutic effect of these drugs is dependent upon the dopaminergic D2 blockade, but they also modulate other neurotransmitter pathways. The exact mechanisms underlying the clinical response to APDs are not fully understood. In this study, we compared three groups of animals for the expression of 84 neurotransmitter genes in the prefrontal cortex (PFC) and nucleus accumbens (NAcc). Each group was treated with a different APD (risperidone, clozapine or haloperidol), and with a non-treated group of spontaneously hypertensive rats (SHRs), which is an animal model for schizophrenia. This study also explored whether or not differential expression was regulated by DNA methylation in the promoter region (PR). In the clozapine group, we found that Chrng was downregulated in the NAcc and six genes were downregulated in the PFC. In the haloperidol group, Brs3 and Glra1 were downregulated, as was Drd2 in the clozapine group and Drd3, Galr3 and Gabrr1 in the clozapine and haloperidol groups. We also encountered four hypermethylated CG sites in the Glra1 PR, as well as three in the risperidone group and another in the haloperidol group, when compared to non-treated rats. Following the APD treatment, the gene expression results revealed the involvement of genes that had not previously been described, in addition to the activity of established genes. The investigation of the involvement of these novel genes can lead to better understanding about the specific mechanisms of action of the individual APDs studied.


Subject(s)
Antipsychotic Agents/pharmacology , Gene Expression/drug effects , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Animals , Clozapine/pharmacology , DNA Methylation/drug effects , Disease Models, Animal , Haloperidol/pharmacology , Male , Neurotransmitter Agents/genetics , Neurotransmitter Agents/metabolism , Promoter Regions, Genetic/drug effects , Rats, Inbred SHR , Risperidone/pharmacology , Schizophrenia
10.
J Psychiatr Res ; 56: 130-6, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24935901

ABSTRACT

A study of the gene expression levels in the blood of individuals with schizophrenia in the beginning of the disease, such as first-episode psychosis (FEP), is useful to detect gene expression changes in this disorder in response to treatment. Although a large number of genetic studies on schizophrenia have been conducted, little is known about the effects of antipsychotic treatment on gene expression. The aim of the present study was to examine differences in the gene expression in the blood of antipsychotic-naïve FEP patients before and after risperidone treatment (N = 44) and also to verify the correlation with treatment response. In addition, we determined the correlations between differentially expressed genes and clinical variables. The expression of 40 neurotransmitter and neurodevelopment-associated genes was assessed using the RT2 Profiler PCR Array. The results indicated that the GABRR2 gene was downregulated after risperidone treatment, but no genes were associated with response to treatment and clinical variables after Bonferroni correction. GABRR2 downregulation after treatment can both suggest an effect of risperidone treatment or processes related to disease progression, either not necessarily associated with the improvement of symptoms. Despite this change was observed in blood, this decrease in GABRR2 mRNA levels might be an effect of changes in GABA concentrations or other systems interplay consequently to D2 blockage induced by risperidone, for example. Thus, it is important to consider that antipsychotics or the progression of psychotic disorders might interfere with gene expression.


Subject(s)
Antipsychotic Agents/therapeutic use , Psychotic Disorders/blood , Psychotic Disorders/drug therapy , Receptors, GABA-A/genetics , Risperidone/therapeutic use , Down-Regulation , Female , Follow-Up Studies , Gene Expression/drug effects , Humans , Male , Psychiatric Status Rating Scales , RNA, Messenger/blood , Receptors, GABA-A/blood , Treatment Outcome , Young Adult
11.
Einstein (Sao Paulo) ; 10(2): 209-15, 2012.
Article in English, Portuguese | MEDLINE | ID: mdl-23052457

ABSTRACT

OBJECTIVE: To describe the Single Photon Emission Microscope (SPEM), a state-of-the-art instrument for small animal SPECT imaging, and characterize its performance presenting typical images of different animal organs. METHODS: SPEM consists of two independent imaging devices based on high resolution scintillators, high sensitivity and resolution Electron-Multiplying CCDs and multi-pinhole collimators. During image acquisition, the mouse is placed in a rotational vertical holder between the imaging devices. Subsequently, an appropriate software tool based on the Maximum Likelihood algorithm iteratively produces the volumetric image. Radiopharmaceuticals for imaging kidneys, heart, thyroid and brain were used. The mice were injected with 74 to 148 MBq/0,3mL and scanned for 40 to 80 minutes, 30 to 60 minutes afterwards. During this procedure, the animals remained under ketamine/xilazine anesthesia. RESULTS: SPEM images of different mouse organs are presented, attesting the imaging capabilities of the instrument. CONCLUSION: SPEM is an innovative technology for small animal SPECT imaging providing high resolution images with appropriate sensitivity for pre-clinical research. Its use with appropriate radiotracers will allow translational investigation of several animal models of human diseases, their pharmacological treatment and the development of potential new therapeutic agents.


Subject(s)
Brain/diagnostic imaging , Heart/diagnostic imaging , Kidney/diagnostic imaging , Thyroid Gland/diagnostic imaging , Tomography, Emission-Computed, Single-Photon/instrumentation , Animals , Equipment Design , Male , Mice
12.
Curr Pharm Des ; 18(32): 4960-5, 2012.
Article in English | MEDLINE | ID: mdl-22716146

ABSTRACT

OBJECTIVES: Clinical and neurobiological findings suggest that cannabinoids and their receptors are implicated in schizophrenia. Cannabidiol (CBD), a non-psychotomimetic compound of the Cannabis sativa plant, has been reported to have central therapeutic actions, such as antipsychotic and anxiolytic effects. We have recently reported that spontaneously hypertensive rats (SHR) present a deficit in contextual fear conditioning (CFC) that is specifically ameliorated by antipsychotics and aggravated by proschizophrenia manipulations. These results led us to suggest that the CFC deficit presented by SHR could be used as a model to study emotional processing impairment in schizophrenia. The aim of this study is to evaluate the effects of CBD and rimonabant (CB1 receptor antagonist) on the contextual fear conditioning in SHR and Wistar rats (WR). METHODS: Rats were submitted to CFC task after treatment with different doses of CBD (experiment 1) and rimonabant (experiment 2). RESULTS: In experiment 1, SHR showed a decreased freezing response when compared to WR that was attenuated by 1 mg/kg CBD. Moreover, all CBD-treated WR presented a decreased freezing response when compared to control rats. In experiment 2, SHR showed a decreased freezing response when compared to WR that was attenuated by 3 mg/kg rimonabant. DISCUSSION: Our results suggest a potential therapeutical effect of CBD and rimonabant to treat the emotional processing impairment presented in schizophrenia. In addition, our results reinforce the anxiolytic profile of CBD.


Subject(s)
Cannabidiol/pharmacology , Cannabinoid Receptor Antagonists/pharmacology , Disease Models, Animal , Emotions , Piperidines/pharmacology , Pyrazoles/pharmacology , Schizophrenia/drug therapy , Schizophrenic Psychology , Animals , Cannabidiol/therapeutic use , Cannabinoid Receptor Antagonists/therapeutic use , Male , Piperidines/therapeutic use , Pyrazoles/therapeutic use , Rats, Wistar , Rimonabant
14.
Behav Brain Res ; 225(1): 15-22, 2011 Nov 20.
Article in English | MEDLINE | ID: mdl-21741413

ABSTRACT

We have recently reported that spontaneously hypertensive rats (SHRs) exhibit a deficit in contextual fear conditioning that is specifically reversed by antipsychotic and potentiated by psychostimulants and other manipulations thought to produce schizophrenia-like states in rodents. Based on these findings, we suggested that this deficit in fear conditioning could be used as an experimental model of emotional processing impairments observed in schizophrenia. This strain has also been suggested as a model by which to study attention deficit/hyperactivity disorder (ADHD). Considering that schizophrenia and ADHD are both characterized by poor social function, this study aimed to investigate possible behavioral deficits of SHRs in a social context. Furthermore, we sought to examine the effects of typical and atypical antipsychotics (used for the treatment of schizophrenia) and a psychostimulant (used to treat ADHD) on these behaviors. Pairs of unfamiliar rats of the same or different (i.e., Wistar) strains were treated with one of the aforementioned drugs and placed in an open-field for 10min. During this time, social behaviors, locomotion and rearing frequencies were scored. Atypical antipsychotics increased social interaction in Wistar rats (WRs) and improved the deficit in social interaction exhibited by SHRs. In addition, the SHR group displayed hyperlocomotion that was attenuated by all antipsychotics (quetiapine and clozapine also decreased locomotion in WRs) and potentiated by amphetamine (which also increased locomotion in WRs). Our results reveal that the behavioral profile of the SHR group demonstrates that this strain can be a useful animal model to study several aspects of schizophrenia.


Subject(s)
Amphetamine/pharmacology , Antipsychotic Agents/pharmacology , Behavior, Animal/drug effects , Central Nervous System Stimulants/pharmacology , Rats, Inbred SHR/physiology , Social Behavior , Analysis of Variance , Animals , Drug Interactions , Exploratory Behavior/drug effects , Male , Motor Activity/drug effects , Motor Activity/genetics , Rats
15.
Prog Neuropsychopharmacol Biol Psychiatry ; 35(7): 1748-52, 2011 Aug 15.
Article in English | MEDLINE | ID: mdl-21693159

ABSTRACT

Deficits in an operational measure of sensorimotor gating - the prepulse inhibition of startle (PPI) - are presented in psychiatric disorders such as schizophrenia, bipolar disorder, and attention deficit/hyperactivity disorder (ADHD). Some previous studies showed that the spontaneously hypertensive rats (SHR) present PPI deficit. Although SHR is suggested as an animal model to study ADHD, we have suggested that the behavioral phenotype of this strain mimics some aspects of schizophrenia. The aim of this study was to characterize the PPI response in SHR. Pharmacological characterization consisted in the evaluation of the effects of the following drugs administered to adult Wistar rats (WR) and SHR previously to the PPI test: amphetamine (used for ADHD and also a psychotomimetic drug), haloperidol and clozapine (antipsychotic drugs), metoclopramide (dopamine antagonist without antipsychotic properties) and carbamazepine (mood stabilizer). Our results showed that SHR presented reduced PPI. This deficit was similar to that induced by amphetamine in WR. Only the atypical antipsychotic clozapine improved the PPI deficit observed in SHR. These findings reinforce the SHR strain as an animal model to study several aspects of schizophrenia, including the abnormalities in sensorimotor gating associated with this disease.


Subject(s)
Antipsychotic Agents/pharmacology , Reflex, Startle/physiology , Schizophrenia/drug therapy , Sensory Gating/physiology , Acoustic Stimulation , Amphetamine/pharmacology , Amphetamine/therapeutic use , Animals , Antimanic Agents/pharmacology , Antimanic Agents/therapeutic use , Antipsychotic Agents/therapeutic use , Carbamazepine/pharmacology , Carbamazepine/therapeutic use , Clozapine/pharmacology , Clozapine/therapeutic use , Disease Models, Animal , Dopamine Antagonists/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Male , Metoclopramide/pharmacology , Metoclopramide/therapeutic use , Rats , Rats, Inbred SHR , Rats, Wistar , Reflex, Startle/drug effects , Schizophrenia/physiopathology , Sensory Gating/drug effects
16.
Prog Neuropsychopharmacol Biol Psychiatry ; 35(7): 1607-11, 2011 Aug 15.
Article in English | MEDLINE | ID: mdl-21708209

ABSTRACT

OBJECTIVES: We have recently reported that spontaneously hypertensive rats (SHR) present a contextual fear conditioning (CFC) deficit. This deficit is improved by antipsychotic drugs, potentiated by proschizophrenia manipulations and not altered by acute administration of carbamazepine, lamotrigine and valproic acid. Nevertheless, the effects of lithium-a classical mood stabilizer-or repeated treatment with these drugs were not evaluated. The main aim of the present study was to extend our previous work by investigating a possible beneficial effect of acute and/or chronic treatments with lithium or lamotrigine on the acquisition deficit of CFC presented by SHR. METHODS: Rats were submitted to CFC task after an acute treatment with lithium and/or a repeated treatment with lithium and lamotrigine. RESULTS: Our data revealed that the CFC deficit presented by SHR is not improved by acute or repeated treatment with lithium. Repeated lamotrigine treatment potentiated the deficit presented by SHR and impaired CFC in control animals (Wistar Rats). CONCLUSIONS: These data reinforce the absence of beneficial effects of mood stabilizers on the emotional context processing impairment modeled by SHR.


Subject(s)
Affect/physiology , Antimanic Agents/pharmacology , Conditioning, Psychological/physiology , Fear/physiology , Lithium Carbonate/pharmacology , Locomotion/drug effects , Mood Disorders/physiopathology , Affect/drug effects , Animals , Antimanic Agents/therapeutic use , Conditioning, Psychological/drug effects , Fear/drug effects , Lithium Carbonate/therapeutic use , Locomotion/physiology , Male , Mood Disorders/drug therapy , Rats , Rats, Inbred SHR , Rats, Wistar
17.
Schizophr Bull ; 35(4): 748-59, 2009 Jul.
Article in English | MEDLINE | ID: mdl-18281713

ABSTRACT

Schizophrenia, bipolar disorder, and attention deficit/hyperactivity disorder (ADHD) present abnormalities in emotion processing. A previous study showed that the spontaneously hypertensive rats (SHR), a putative animal model of ADHD, present reduced contextual fear conditioning (CFC). The aim of the present study was to characterize the deficit in CFC presented by SHR. Adult male normotensive Wistar rats and SHR were submitted to the CFC task. Sensitivity of the animals to the shock and the CFC performance after repeated exposure to the task were investigated. Pharmacological characterization consisted in the evaluation of the effects of the following drugs administered previously to the acquisition of the CFC: pentylenetetrazole (anxiogenic) and chlordiazepoxide (anxiolytic); methylphenidate and amphetamine (used for ADHD); lamotrigine, carbamazepine, and valproic acid (mood stabilizers); haloperidol, ziprasidone, risperidone, amisulpride, and clozapine (neuroleptic drugs); metoclopramide and SCH 23390 (dopamine antagonists without antipsychotic properties); and ketamine (a psychotomimmetic). The effects of paradoxical sleep deprivation (that worsens psychotic symptoms) and the performance in a latent inhibition protocol (an animal model of schizophrenia) were also verified. No differences in the sensitivity to the shock were observed. The repeated exposure to the CFC task did not modify the deficit in CFC presented by SHR. Considering pharmacological treatments, only the neuroleptic drugs reversed this deficit. This deficit was potentiated by proschizophrenia manipulations. Finally, a deficit in latent inhibition was also presented by SHR. These findings suggest that the deficit in CFC presented by SHR could be a useful animal model to study abnormalities in emotional context processing related to schizophrenia.


Subject(s)
Antipsychotic Agents/pharmacology , Disease Models, Animal , Emotions , Memory , Schizophrenia/diagnosis , Schizophrenic Psychology , Amphetamine/pharmacology , Animals , Behavior, Animal/drug effects , Conditioning, Psychological/drug effects , Conditioning, Psychological/physiology , Dopamine Antagonists/pharmacology , Electroshock , Emotions/drug effects , Fear/drug effects , Fear/physiology , Freezing Reaction, Cataleptic/drug effects , Inhibition, Psychological , Male , Memory/drug effects , Pain Threshold/drug effects , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Rats, Wistar , Schizophrenia/drug therapy , Sleep Deprivation , Vocalization, Animal/drug effects
18.
Prog Neuropsychopharmacol Biol Psychiatry ; 32(5): 1277-82, 2008 Jul 01.
Article in English | MEDLINE | ID: mdl-18499322

ABSTRACT

We have recently demonstrated that paradoxical sleep deprivation (PSD) potentiates the induction of amphetamine (AMPH)-induced behavioural sensitization by increasing its conditioned component. In the present study, the effects of sleep rebound (induced by 24 h recovery period from PSD) were studied on AMPH-induced behavioural sensitization. Sleep rebound attenuated the acute locomotor-stimulating effect of AMPH. AMPH-induced behavioural sensitization was context-specific and was also attenuated by sleep rebound. These results strengthen the notion that sleep conditions can influence AMPH-induced behavioural sensitization.


Subject(s)
Amphetamine/pharmacology , Behavior, Animal/drug effects , Central Nervous System Stimulants/pharmacology , Conditioning, Psychological/drug effects , Sleep, REM/drug effects , Analysis of Variance , Animals , Locomotion/drug effects , Locomotion/physiology , Male , Mice , Mice, Inbred C57BL , Motor Activity/drug effects , Sleep, REM/physiology
19.
Physiol Behav ; 92(4): 773-9, 2007 Nov 23.
Article in English | MEDLINE | ID: mdl-17632187

ABSTRACT

BACKGROUND: Environmental enrichment or paradoxical sleep deprivation (PSD) has been shown to modify some responses elicited by drugs of abuse. The aims of the present study were to examine the effects of environmental enrichment and PSD, conducted separately or in association, on open-field behavior elicited by amphetamine (AMP) in mice. METHODS: Male C57BL/6 mice were randomly assigned to live in either an enriched environmental condition (EC) or a standard environmental condition (SC) for 12 months since weaning. Some of the EC and SC mice were sleep deprived for 48 h, while others were maintained in their home-cages. Immediately after PSD or home-cage stay, the animals received an ip injection of saline, 2.5 mg/kg AMP or 5.0 mg/kg AMP. Fifteen minutes later, their open-field behavior was quantified. RESULTS: Whereas PSD enhanced total and peripheral locomotor activity of acutely AMP-treated mice, environmental enrichment presented only a trend toward enhancement. When PSD and environmental enrichment were combined, an increase in the total and peripheral locomotion frequencies of AMP-treated animals, similar to that observed after PSD, was revealed. In addition, PSD, environmental enrichment or their combination did not modify the effects of AMP on the other open-field behavioral parameters that were analyzed. CONCLUSION: The present findings demonstrate that some (but not all) of the behavioral effects caused by AMP acute administration can be similarly and specifically enhanced by both environmental enrichment and PSD in C57BL/6 mice.


Subject(s)
Amphetamine/pharmacology , Central Nervous System Stimulants/pharmacology , Environment , Exploratory Behavior/physiology , Motor Activity/drug effects , Sleep Deprivation/physiopathology , Analysis of Variance , Animals , Euphoria/drug effects , Euphoria/physiology , Exploratory Behavior/drug effects , Male , Mice , Mice, Inbred C57BL , Motor Activity/physiology , Random Allocation , Statistics, Nonparametric
20.
Neuropharmacology ; 48(7): 993-1001, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15857626

ABSTRACT

Oral dyskinesias are implicated in a series of neuropathologies and have been associated to an increase in oxidative stress. Several antioxidants, including vitamin E, decrease reserpine-induced oral dyskinesia (OD) in rodents and we have described a protective role of striatal catalase against the development of OD. The aim of this study was to verify the effects of vitamin C alone or in combination with vitamin E on reserpine-induced OD as well as to determine a possible role of catalase in the antidyskinetic property of these vitamins. Different doses of vitamin C attenuated reserpine-induced increase in OD. A similar treatment with an effective dose of vitamin C concomitant to an effective dose of vitamin E potentiated the antidyskinetic effect of both vitamins when administered alone. The administration of these vitamins alone produced an increase in striatal catalase activity that likewise was potentiated by their combined administration. In addition, the antidyskinetic property of vitamin E and vitamin C was abolished by a concomitant treatment with the catalase inhibitor aminotriazole. These results indicate a beneficial effect of these vitamins and reinforce the critical role of striatal catalase against the development of oral dyskinesias.


Subject(s)
Ascorbic Acid/therapeutic use , Catalase/metabolism , Corpus Striatum/enzymology , Dyskinesia, Drug-Induced/enzymology , Dyskinesia, Drug-Induced/prevention & control , Vitamin E/therapeutic use , Animals , Ascorbic Acid/pharmacology , Corpus Striatum/drug effects , Male , Rats , Rats, Wistar , Reserpine/toxicity , Vitamin E/pharmacology
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