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The amphetamine challenge, in which positron emission tomography (PET) or single photon emission computed tomography radioligand binding following administration of amphetamine is compared to baseline values, has been successfully used in a number of brain imaging studies as an indicator of dopaminergic function, particularly in the striatum. [18F] fallypride is the first PET radioligand that allows...
Our laboratory has recently demonstrated altered expression of phosphodiesterase (PDE) 4A and 4B in subjects with autism, bipolar disorder, and schizophrenia, suggesting disrupted cAMP signaling in these diagnostic groups. In the current study, we measured expression of PDEs in rat frontal cortex (FC) following chronic treatment with clozapine, fluoxetine, haloperidol, lithium, olanzapine, valproic...
Asenapine is a novel psychopharmacologic agent being developed for schizophrenia and bipolar disorder. Like clozapine, asenapine facilitates cortical dopaminergic and N‐methyl‐D‐aspartate (NMDA) receptor‐mediated transmission in rats. The facilitation of NMDA‐induced currents in cortical pyramidal cells by clozapine is dependent on dopamine and D1 receptor activation. Moreover, previous results show...
Haloperidol is a potent dopamine receptor antagonist and used to treat psychotic disorders, such as schizophrenia. Recent clinical and preclinical studies demonstrated the overactivity of the nitric oxide (NO) system in schizophrenia. Neonatal ventral hippocampal (nVH) lesions in rats have been widely used as a neurodevelopmental model that mimics schizophrenia‐like behaviors. Here, we investigate...
Recent research in the etiology of schizophrenia revealed that there may be some neurodevelopmental failures such as neuronal network incompetence in the brain of this disease, and neurotransmitters cannot function accurately or adequately. But, it is unknown precisely what kinds of deficit in neurotransmission may be existed histopathologically. We investigated the expression of vesicle monoamine...
This project was done in order to determine why the annual incidence of metoclopramide‐associated tardive dyskinesia is much higher than that for the commonly used antipsychotics. To test the hypothesis that metoclopramide tardive dyskinesia may be associated with high concentrations of metoclopramide in the substantia nigra under clinical conditions, the nonspecific binding of tritiated antipsychotics...
Recent studies have identified disrupted‐in‐schizophrenia‐1 (DISC1) as a strong genetic risk factor associated with schizophrenia. Previously, we have reported that a mutation in the second exon of the DISC1 gene [leucine to proline at amino acid position 100, L100P] leads to the development of schizophrenia‐related behaviors in mice. Glycogen synthase kinase‐3 (GSK‐3) is a serine/threonine protein...
Most antipsychotic (AP) drugs are dopamine (DA) D2 receptor (DRD2) antagonists and remain the main pharmacological treatment of schizophrenia. Long‐term AP use can give rise to tardive dyskinesia. It has been reported that chronic treatment with APs induces DRD2 upregulation and oxidative stress, which have been associated with tardive dyskinesia. We showed previously that H2O2‐induced oxidative stress...
Schizophrenia is a highly familial, neurodevelopmental disorder that is associated with several neuropsychiatric, psychological, and neuropathological features. Although pharmacological animal models of dopaminergic and glutamatergic dysfunction have helped advance our understanding of the disease biology, there is a clear need for translational models that capture the neuropathological and functional...
Rationale:l‐Stepholidine (l‐SPD), a tetrahydroprotoberberine alkaloid, possesses a pharmacological profile of a D1/5‐HT1A agonist and a D2 antagonist. This unique pharmacological profile makes it a promising novel antipsychotic candidate. Preliminary clinical trials and animal experiments suggest that l‐SPD improves both positive and negative symptoms of schizophrenia without producing significant...
This in vitro study investigates and compares the effects of NK3 receptor ligands on the firing rate of rat and guinea pig midbrain dopamine neurons. The findings are discussed in the light of choosing suitable animal models for investigating pharmacological properties of NK3 receptor antagonists, which have been proposed to possess therapeutic activity in neuropsychiatric diseases like e.g. schizophrenia...
Apamin is a neurotoxin extracted from honey bee venom and is a selective blocker of small‐conductance Ca2+‐activated K+ channels (SK). Several behavioral and electrophysiological studies indicate that SK‐blockade by apamin may enhance neuron excitability, synaptic plasticity, and long‐term potentiation in the CA1 hippocampal region, and, for that reason, apamin has been proposed as a therapeutic agent...
The alpha‐7 nicotinic acetylcholine receptor (α7nAChR) and the dopamine D2 receptor (D2R) are both implicated in attentional processes and cognition, mediated in part through the prefrontal cortex (PFC). We examined the dual electron microscopic immunolabeling of α7nAChR and either D2R or the vesicular acetylcholine transporter (VAChT) in rodent PFC to assess convergent functional activation sites...
The features of schizophrenia are consistent with increased sensitivity to endogenous dopamine. Animal models of schizophrenia reveal an increase in the in vitro proportion of striatal dopamine D2 receptors in the high‐affinity state for dopamine (i.e., D2High), as measured by dopamine/[3H]domperidone competition. However, in vivo studies did not reveal the dopamine agonist [11C](+)PHNO to be elevated...
The long‐term use of many antipsychotic medications carries a risk of tardive dyskinesia in a small proportion of patients. Although metoclopramide is an antipsychotic at high doses, this drug is more commonly used at low daily doses to accelerate stomach movement of food. Because prolonged use of metoclopramide has also been associated with tardive dyskinesia, this drug is convenient to study to...
Neonatal basolateral amygdala (nBLA) lesions in rats have been widely used as a neurodevelopmental model that mimics schizophrenia‐like behaviors. Recently, we reported that nBLA lesions result in significant decreases in the dendritic spine number of layer 3 prefrontal cortex (PFC) pyramidal cells and medium spiny neurons of the nucleus accumbens (NAcc), which all changes after puberty. At present,...
Decreased activity of the medial prefrontal cortex (mPFC) has been considered a basis for core symptoms of schizophrenia, an illness associated with a neurodevelopmental origin. Evidence from preclinical and clinical studies indicates that serotonin (5‐HT)1A receptors play a crucial role in the energy metabolism of the mPFC. This study was undertaken to determine (1) if transient blockade of N‐methyl‐D‐aspartate...
A neonatal ventral hippocampal lesion (NVHL) in rats has been commonly used as a neurodevelopmental model to mimic schizophrenia‐like behaviors. Recently, we reported that NVHL resulted in dendritic retraction and spine loss in pyramidal neurons of the prefrontal cortex (PFC). In addition, the hippocampus and PFC are important structures in the regulation of the electroencephalographic (EEG) activity...
Altered brain serotonin activity is implicated in schizophrenia. We have previously shown differential involvement of serotonergic projections from the dorsal or median raphe nucleus in phencyclidine‐induced hyperlocomotion in rats, a behavioral model of aspects of schizophrenia. Here we further investigated the effects of serotonergic lesions of the raphe nuclei on phencyclidine‐induced hyperlocomotion...
Objective: The aim of this study was to investigate the association between the exonic single nucleotide polymorphisms (SNPs) of synapsin I (SYN1) (rs1142636, Asn170Asn, Xp11.23) and SYN2 (rs2289708, 3′‐untranslated region, 3p25) in schizopherenia. Methods: Two hundred eighty six schizophrenia patients and 304 control subjects were recruited. SNPs with a know heterozygosity and minor allele frequency...
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