Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neonatal ventral hippocampal lesions in the rat result in post-pubertal onset of behavioural abnormalities, modelling some aspects of schizophrenia. We further assessed the behavioural effects of neonatal lesions in rats in a variety of cognitive tasks and in the prepulse inhibition (PPI) of startle response paradigm. Prepubescent, lesioned rats exhibited startle responses and PPI similar to controls whereas, at adulthood, they showed a deficit in PPI. Lesioned rats acquired both passive and active avoidance responses. However, compared to controls, they showed a deficit in passive avoidance retention and in acquisition of active avoidance responses. In a cued Morris water-maze task, lesioned rats demonstrated adequate sensorimotor functions and appropriate motivation to escape from water. However, they were impaired in place learning and in remembering the location of a submerged platform. In conclusion, neonatal ventral hippocampal lesions result in the post-pubertal emergence of long-lasting deficits in sensorimotor gating and in the capacity to acquire and retain information in tests of spatial and avoidance learning. Therefore, this neurodevelopmental model of schizophrenia seems to exhibit an interesting degree of validity in possibly simulating some cognitive impairments and sensorimotor gating deficits frequently observed in psychotic patients.
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PMID:Spatial and associative learning deficits induced by neonatal excitotoxic hippocampal damage in rats: further evaluation of an animal model of schizophrenia. 1110 80

The frontal cortex (FrC) and cingulate cortex (CgC) are critical sites for normal cognitive function, as well as cognitive dysfunction in schizophrenia. Thus, modulation of synaptic transmission within these cortical areas may, in part, account for the therapeutic actions of antipsychotic drugs such as haloperidol and clozapine. FosB and DeltaFosB are immediate-early gene (IEG) products sensitive to changes in response to chronic neuroleptic drug administration. We quantitatively examine whether there are light microscopic regional and/or laminar variations in FosB or DeltaFosB in the FrC or CgC of normal adult rats, or animals receiving 6 months administration of either drinking water clozapine, or depot haloperidol. Only animals receiving chronic haloperidol developed vacuous chewing movements, the equivalent of tardive dyskinesia in humans. In control animals, the deep and superficial layers of the FrC showed a higher area density of FosB, but not DeltaFosB immunoreactive cells than the medial layers of FrC or any of the CgC layers. In animals receiving clozapine, but not haloperidol there was increase in the area density of FosB immunoreactive neurons in all FrC layers, but the major increase occurs in medial layers. These findings suggest that FosB expression identifies those FrC neurons that are most active during normal waking behaviors and are further activated following chronic administration of atypical neuroleptics without motor side effects. The results also indicate that the actions of clozapine are attributed in large part to modulation of the output of frontal cortical pyramidal neurons residing in the medial layers.
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PMID:Enhancement of laminar FosB expression in frontal cortex of rats receiving long chronic clozapine administration. 1125 27

Several lines of evidence suggest that the glutamatergic N-methyl-D-aspartate (NMDA) receptor is involved in schizophrenia pathophysiology. Post-mortem studies have revealed a lower density of glutamatergic receptors in patients with schizophrenia. Other studies of cerebrospinal fluid reported lower levels of glutamate in patients with schizophrenia in healthy comparison subjects. The most compelling evidence is provided by the psychomimetic effects of the NMDA antagonists phencyclidine and ketamine. Recently, much interest has been given to the study related to the role of NMDA receptor in pathophysiology of schizophrenia by administration of sub-anesthetic doses of ketamine. A phencyclidine hydrochloride derivate, ketamine, is a dissociative anesthetic and a non competitive antagonist of the NMDA receptor. In healthy subjects, ketamine produces: 1) positive symptoms of psychosis, such as illusions, thought disorder and delusions; 2) negative symptoms similar to those associated with schizophrenia including blunted emotional responses, emotional detachment, and psychomotor retardation; 3) cognitive impairments, in particular impairments on tests of frontal cortical function including increased distractibility, reduced verbal fluency and poorer performance on the Wisconsin Card Sorting Test. During smooth pursuit eye tracking, ketamine induces nystagmus as well as abnormalities which are among the characteristics of schizophrenia. In patients with schizophrenia, the administration of ketamine produces an activation of their psychotic symptoms, which have striking similarities to symptoms of their usual psychotic episodes. Ketamine effects on memory and other cognitive functions in schizophrenic patients are controversial. The psychomimetic effects of ketamine are transitional, reversible and influenced by time, dose and administration conditions. Susceptibility to the psychotomimetic effects of ketamine is minimal or absent in children and becomes maximal in early adulthood. The similarity between ketamine effects and endogenous psychoses created interest in the capacity of antipsychotic medications to block ketamine effects. Haloperidol failed to block this ketamine-induced psychomimetic effects in healthy subjects and in schizophrenic patients. However, clozapine, the prototype of atypical antipsychotic agents significantly reduced the ketamine-induced increase in positive symptoms in schizophrenic patients. Recently, lamotrigine significantly decreased ketamine-induced positive and negative symptoms in healthy subjects. Brain regions responsible for NMDA-mediated psychosis have not been established. Using positron emission tomography and [18F] fluorodeoxyglucose, the sub-anesthetic ketamine administration produces bilateral increases in metabolic activity in the prefrontal cortex. In a [15O] H2O positron emission tomography study, ketamine selectively increases cerebral blood flow in the anterior cingulate cortex and reduces cerebral blood flow in the hippocampus and primary visual cortex. The mechanism of neuropsychiatric effects of sub-anesthetic ketamine is not clear. A dysfunction in glutamate-dopaminergic interactions has been suggested as a mechanism for these effects of ketamine. Ketamine has been reported to primarily block NMDA receptor complex giving support to a glutamate deficiency hypothesis in schizophrenia. In addition, ketamine caused increases in cortical and striatal synaptic dopamine concentrations. The effects of NMDA receptor antagonist administration are argued to support a neurobiological hypothesis of schizophrenia, which includes pathophysiology within several neurotransmitter systems, manifested in behavioral pathology. Pharmacological modulation of the effects of NMDA receptor antagonists, such as ketamine, may lead to development of novel therapeutic agents for psychiatric illnesses such as schizophrenia.
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PMID:[Glutaminergic hypothesis of schizophrenia: clinical research studies with ketamine]. 1129 39

Regional cerebral blood flow (rCBF) data from two PET-15O water schizophrenia studies were analyzed using individually placed, magnetic resonance (MR)-guided hippocampal volumes of interest (VOI). In one study, normal (N = 10) and schizophrenic (N = 18) volunteers performed an overlearned auditory discrimination task in rest, control, and decision conditions. In the other study, schizophrenic and normal volunteers received the noncompetitive NMDA receptor antagonist ketamine and placebo and had sequential rCBF evaluations. Moreover, the schizophrenic volunteers were off drug in one study and on antipsychotic drug in the second study, allowing an additional comparison of medication status. VOIs were placed on anterior, middle, and posterior hippocampal areas in each PET image from both studies, redirected from an MR scan, and individually adjusted. While no hippocampal activation was apparent in either the normal or schizophrenic group in the task vs. condition comparison, rCBF was higher in the schizophrenic than in the normal hippocampus in both task and control conditions, independently. In addition, at rest rCBF was significantly higher in the unmedicated group of schizophrenics than in the group of medicated patient volunteers and higher than in the normal comparison group. This suggests that schizophrenia is associated with elevated rCBF in the hippocampus, which "normalizes" with antipsychotic drug treatment. Ketamine, the noncompetitive NMDA receptor antagonist, was more potent in reducing rCBF in the schizophrenic group compared to the normal volunteer group. These data are consistent with a previous report from our laboratory of reduced NMDA receptor NR1 subunit expression and possible abnormal NMDA receptor composition in schizophrenia. These data show an abnormality of hippocampal function in schizophrenia and suggest that this abnormality may be associated with the pathophysiology of the illness.
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PMID:Probing the human hippocampus using rCBF: contrasts in schizophrenia. 1173 7

Nicotinic acetylcholine receptors (nAChRs) are membrane-bound, pentameric ligand-gated ion channels associated with a variety of human disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia, and pain. Most known nAChRs contain an unusual eight-membered disulfide-containing cysteinyl-cysteine ring, ox-[Cys-Cys], as does the soluble acetylcholine binding protein (AChBP) found in the snail Lymnaea stagnalis. The cysteinyl-cysteine ring is located in a region implicated in ligand binding, and conformational changes involving this ring may be important for modulation of nAChR function. We have studied the preferred conformations of Ac-ox-[Cys-Cys]-NH2 by NMR in water and computationally by Monte Carlo simulations using the OPLS-AA force field and GB/SA water model. ox-[Cys-Cys] adopts four distinct low-energy conformers at slightly above 0 degrees C in water. Two populations are dependent on the peptide omega2 dihedral angle, with the trans amide favored over the cis amide by a ratio of ca. 60:40. Two ox-[Cys-Cys] conformers with a cis amide bond (C+ and C-) differ from each other primarily by variation of the chi3 dihedral angle, which defines the orientation of the helicity about the S-S bond (+/- 90 degrees ). Two trans amide conformers have the same S-S helicity (chi3 approximately -90 degrees ), but are distinguished by a backbone rotation about phi2 and psi1 (T- and T'-). The ratio of T-/T'-/C+/C- is 47:15:29:9. The orientation of the pendant moieties from the eight-membered ring is more compact for the major trans conformer (T-) than for the extended conformations adopted by T'-, C+, and C-. These conformational preferences are also observed in tetrapeptide and undecapeptide fragments of the human alpha7 subtype of the nAChR that contains the ox-[Cys-Cys] unit. Conformer T- is nearly identical to the conformation seen in the X-ray structure of ox-[Cys(187)-Cys(188)] found in the unliganded AChBP, and is a Type VIII beta-turn.
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PMID:Conformational analysis of the eight-membered ring of the oxidized cysteinyl-cysteine unit implicated in nicotinic acetylcholine receptor ligand recognition. 1174 32

Selective muscarinic agonists could be useful in the treatment of neurological disorders such as Alzheimer's disease, schizophrenia, and chronic pain. Many muscarinic agonists have been developed, yet most exhibit at best limited functional selectivity for a given receptor subtype perhaps because of the high degree of sequence homology within the putative binding site, which appears to be buried within the transmembrane domains. Bivalent compounds containing essentially two agonist pharmacophores within the same molecule were synthesized and tested for receptor binding affinity and muscarinic agonist activity. A series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine linked by an alkyloxy moiety exhibited very high affinity (K(i) < 1 nM) and strong agonist activity. The degree of activity depended on the length of the linking alkyl group, which could be replaced by a poly(ethylene glycol) moiety, resulting in improved water solubility, binding affinity, and agonist potency.
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PMID:Design, synthesis, and biological characterization of bivalent 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as selective muscarinic agonists. 1174 75

The dopamine hypothesis of schizophrenia postulates hyperactivity of dopaminergic neurotransmission in the mesolimbic system. However, the possible underlying causes for this dopaminergic overfunction are not well understood. Therefore, the main aim of this study was to examine the effect of central cholinergic denervation on dopamine-mediated functions. We also examined the effect of neonatal cholinergic denervation upon adult brain function. The immunotoxin 192 IgG-saporin causes severe lesions of the basal forebrain cholinergic system when infused into the lateral ventricles by targeting neurons expressing the p75 neurotrophin receptor. The toxin may also damage p75-expressing Purkinje neurons in the cerebellum. We have compared the behavioral effects of intracerebroventricular injections of 192 IgG-saporin to adult rats with that of injections to neonate rats. As expected, adult treated rats displayed an almost complete cholinergic denervation of forebrain corticohippocampal areas concomitant with a marked impairment in the Morris water maze. When tested as adults, neonatally treated animals had a less complete cholinergic denervation and showed lesser impairments in water maze behaviors. Interestingly, adult treated rats showed increased spontaneous horizontal activity and a remarkable increase in locomotor response to d-amphetamine as evidenced by increased horizontal and vertical activity. There were no marked changes of spontaneous or drug-induced locomotor activity in adult rats treated with 192 IgG-saporin as neonates. These results suggest that cholinergic denervation of the forebrain causes a marked enhancement of behavioral responses related to dopaminergic activity, probably mainly mediated presynaptically. However, it cannot be fully excluded that damage to noncholinergic systems, e.g., Purkinje cells, might contribute to the effects. The striking overreaction to dopaminergic stimuli, presumably caused by the cholinergic deficit, is discussed in relation to the suggested role of cholinergic malfunctioning in schizophrenia.
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PMID:Facilitation of dopamine-mediated locomotor activity in adult rats following cholinergic denervation. 1186 38

Positron emission tomography ([(15)O] water PET) was used to examine the relationship between age and regional cerebral blood flow (rCBF) in schizophrenia. Forty-nine unmedicated male patients, ages 20-51, underwent imaging during an eyes-closed resting condition. Negative correlations were observed between age and rCBF in the anterior cingulate, as well as in frontal (Brodmann area 8) and parietal cortex (area 40) bilaterally. The observation of reduced rCBF in the anterior cingulate with increased age is consistent with previous findings in healthy subjects. In contrast, the reduced flow observed in the frontal and parietal regions may be unique to schizophrenia.
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PMID:Age and regional cerebral blood flow in schizophrenia: age effects in anterior cingulate, frontal, and parietal cortex. 1188 50

Antipsychotic drugs (APD) are used in the treatment of schizophrenia and other psychotic disorders and exert their effects, in part, through dopamine receptor blockade. APD treatment causes many changes in the brains of humans and experimental animals including therapeutic, pathologic, or changes associated with motor side effects. Typical APD given chronically to animals induce behavioral sequelae that mimic tardive dyskinesia in several ways. Our previous work has shown that chronic treatment with haloperidol decreases striatal synaptic density but that symmetric synapses are lost only in rats that develop oral dyskinesias. The goals of this study were to determine if the density of dopaminergic terminals was affected by chronic haloperidol treatment and/or correlated with dyskinesias. Rats were given haloperidol (1.5 mg/kg/rat) or water, as a control. After 6 months of treatment, rats were divided into nondyskinetic or dyskinetic groups according to the behavior scores determined in the last month. Striatal volume was similar between controls and drug-treated rats. Synaptic density, calculated using stereological methods, was obtained from the matrix of the ventrolateral striatum. The density of symmetric synapses (mean +/- SD, per 100/microm(3)) formed by tyrosine hydroxylase (TH) containing terminals in haloperidol treated rats (3.58 +/- 1.64) was not significantly different from that of controls (3.06 +/- 1.00). The density of TH-labeled terminals forming symmetric synapses in the nondyskinetic group (3.65 +/- 1.67) vs. the dyskinetic group (3.54 +/- 1.73) was similar and neither was different from that of the controls. These data indicate that terminals other than dopaminergic ones form fewer symmetric synapses in dyskinetic rats. Moreover, these data have implications for interpreting results obtained in humans treated with typical antipsychotic drugs.
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PMID:Dopaminergic synapses in the matrix of the ventrolateral striatum after chronic haloperidol treatment. 1211

NMDA receptor hypofunction has been implicated in the pathophysiology of schizophrenia, and pharmacological and genetic approaches have been used to model such dysfunction. We previously have described two mouse lines carrying point mutations in the NMDA receptor glycine binding site, Grin1(D481N) and Grin1(K483Q), which exhibit 5- and 86-fold reductions in receptor glycine affinity, respectively. Grin1(D481N) animals exhibit a relatively mild phenotype compatible with a moderate reduction in NMDA receptor function, whereas Grin1(K483Q) animals die shortly after birth. In this study we have characterized compound heterozygote Grin1(D481N/K483Q) mice, which are viable and exhibited biphasic NMDA receptor glycine affinities compatible with the presence of each of the two mutated alleles. Grin1(D481N/K483Q) mice exhibited a marked NMDA receptor hypofunction revealed by deficits in hippocampal long-term potentiation, which were rescued by the glycine site agonist d-serine, which also facilitated NMDA synaptic currents in mutant, but not in wild-type, mice. Analysis of striatal monoamine levels revealed an apparent dopaminergic and serotonergic hyperfunction. Behaviorally, Grin1(D481N/K483Q) mice were insensitive to acute dizocilpine pretreatment and exhibited increased startle response but normal prepulse inhibition. Most strikingly, mutant mice exhibited a sustained, nonhabituating hyperactivity and increased stereotyped behavior that were resistant to suppression by antipsychotics and the benzodiazepine site agonist Zolpidem. They also displayed a disruption of nest building behavior and were unable to perform a cued learning paradigm in the Morris water maze. We speculate that the severity of NMDA receptor hypofunction in these mice may account for their profound behavioral phenotype and insensitivity to antipsychotics.
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PMID:Severe impairment of NMDA receptor function in mice carrying targeted point mutations in the glycine binding site results in drug-resistant nonhabituating hyperactivity. 1215 50


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