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)

Recent studies have indicated that impaired neural circuitry in the prefrontal cortex is a prominent feature of the neuropathology of schizophrenia. Clozapine is one of the most effective antipsychotic drugs used for this debilitating disease. Despite its effectiveness, the mechanism by which clozapine acts on prefrontal cortical circuitry remains poorly understood. In this study, in vitro multiple whole cell recordings were performed in slices of the ferret prefrontal cortex. Clozapine, which effectively inhibited the spontaneous synchronized network activities in the prefrontal neurons, achieved the suppressive effect by decreasing the recurrent excitation among pyramidal neurons and by enhancing the inhibitory inputs onto pyramidal cells through a likely network mechanism. Indeed, under the condition of disinhibition, the depressing effects were reversed and clozapine enhanced the recurrent excitation. These results suggest that the therapeutic actions of clozapine in alleviating the positive symptoms of schizophrenia are achieved, at least partially, through the readjustment of synaptic balance between the excitation and inhibition in the prefrontal cortical circuitry.
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PMID:Acute clozapine suppresses synchronized pyramidal synaptic network activity by increasing inhibition in the ferret prefrontal cortex. 1718 15

A comparison of the clinical and pathophysiological features of postictal psychosis and brief interictal or alternating psychosis was undertaken to examine if the underlying mechanisms are distinct in these 2 conditions. A selective review of the published literature in English on epilepsy and brief psychosis was carried out. The literature indicates that even though brief postictal and alternating psychoses are considered to be separate syndromes, they have a number of similarities. It can be argued that the underlying pathomechanisms are common, with the brain's inhibitory processes in response to seizures playing a key role in the development of the psychosis. These homeostatic mechanisms manifest as electrophysiological, cerebral blood flow, and neurotransmitter and receptor changes. Both syndromes are likely to be associated with prolonged inhibition in limbic circuits, with further seizures modifying the psychosis depending upon whether it is associated with disinhibition or hypersynchrony involving enhanced inhibition. The neurotransmitter with a key role is GABA, although ionic currents, catecholamines, opiates, adenosine, glutamate, and nitric oxide play a role. Brief postictal and alternating psychoses provide an opportunity to understand the complex relationships between epilepsy and schizophrenia-like brief psychotic episodes, and this understanding can assist in their management.
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PMID:Alternating and postictal psychoses: review and a unifying hypothesis. 1733 47

The prefrontal cortex (PFC) is involved in the pathophysiology of schizophrenia. PFC neuronal activity is modulated by monoaminergic receptors for which antipsychotic drugs display moderate-high affinity, such as 5-HT(2A) and alpha(1)-adrenoceptors. Conversely, PFC pyramidal neurons project to and modulate the activity of raphe serotonergic neurons and serotonin (5-HT) release. Under the working hypothesis that atypical antipsychotic drugs may partly exert their action in PFC, we assessed their action on the in vivo 5-HT release evoked by increasing glutamatergic transmission in rat medial PFC (mPFC). This was achieved by applying S-AMPA in mPFC (reverse dialysis) or by disinhibiting thalamic excitatory afferents to mPFC with bicuculline. The application of haloperidol, chlorpromazine, clozapine and olanzapine in mPFC by reverse dialysis (but not reboxetine or diazepam) reversed the S-AMPA-evoked local 5-HT release. Likewise, the local (in mPFC) or systemic administration of these antipsychotic drugs reversed the increased prefrontal 5-HT release produced by thalamic disinhibition. These effects were shared by the 5-HT(2A) receptor antagonist M100907 and the alpha(1)-adrenoceptor antagonist prazosin. However, raclopride (DA D2 antagonist) had very modest effects. These results suggest that, besides their action in limbic striatum, antipsychotic drugs may attenuate glutamatergic transmission in PFC, possibly by interacting with 5-HT(2A) and/or alpha(1)-adrenoceptors.
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PMID:Antipsychotic drugs reverse the AMPA receptor-stimulated release of 5-HT in the medial prefrontal cortex. 1739 45

NMDA receptors mediate excitatory postsynaptic potentials throughout the brain but, paradoxically, NMDA receptor antagonists produce cortical excitation in humans and behaving rodents. To elucidate a mechanism for these diverging effects, we examined the effect of use-dependent inhibition of NMDA receptors on the spontaneous activity of putative GABA interneurons and pyramidal neurons in the prefrontal cortex of awake rats. We find that inhibition of NMDA receptors predominately decreases the activity of putative GABA interneurons but, at a delayed rate, increases the firing rate of the majority of pyramidal neurons. Thus, NMDA receptors preferentially drive the activity of cortical inhibitory interneurons suggesting that NMDA receptor inhibition causes cortical excitation by disinhibition of pyramidal neurons. These findings support the hypothesis that NMDA receptor hypofunction, which has been implicated in the pathophysiology of schizophrenia, diminishes the inhibitory control of PFC output neurons. Reducing this effect may be critical for treatment of schizophrenia.
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PMID:NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. 1795 92

Transmission of reward signals is a function of dopamine, a neurotransmitter known to be involved in the mechanism of psychosis. Using functional magnetic resonance imaging (fMRI), we investigated how expectation and receipt of monetary rewards modulate brain activation in patients with bipolar mania and schizophrenia. We studied 12 acutely manic patients with a history of bipolar disorder, 12 patients with a current episode of schizoaffective disorder or schizophrenia and 12 healthy subjects. All patients were treated with dopamine antagonists at the time of the study. Subjects performed a delayed incentive paradigm with monetary reward in the scanner that allowed for investigating effects of expectation, receipt, and omission of rewards. Patients with schizophrenia and healthy control subjects showed the expected activation of dopaminergic brain areas, that is, ventral tegmentum activation upon expectation of monetary rewards and nucleus accumbens activation during receipt vs omission of rewards. In manic patients, however, we did not find a similar pattern of brain activation and the differential signal in the nucleus accumbens upon receipt vs omission of rewards was significantly lower compared to the healthy control subjects. Our findings provide evidence for abnormal function of the dopamine system during receipt or omission of expected rewards in bipolar disorder. These deficits in prediction error processing in acute mania may help to explain symptoms of disinhibition and abnormal goal pursuit regulation.
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PMID:Abnormal reward system activation in mania. 1798 58

One of the core deficits that characterizes schizophrenia is an increase in distractibility and disinhibition at all levels of information processing. Patients with schizophrenia seem unable to focus attention on the relevant events while ignoring the irrelevant stimuli. This pattern of behavior is also observed in unmedicated schizotypal individuals who may carry liability for schizophrenia. In this review, we focus on studies of attentional inhibition, as assessed by the negative priming paradigm, to elucidate the relationships among deficits in inhibition, clinical symptoms and medication effects. We then consider models of the etiology of deficits in negative priming in schizophrenia and schizotypal personality. Finally, we discuss the potential power of utilizing hypothesis-driven cognitive paradigms in psychiatric research.
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PMID:Attentional window in schizophrenia and schizotypal personality: Insight from negative priming studies. 1819 80

A patient with schizophrenia may generate an action (whether manual or verbal), but not attribute the generation of that action to himself. We distinguish self-monitoring and attribution of agency, relating only the former to forward models and the mirror system. We suggest that alien hand experiences occur when an action progresses through hand control pathways with no record of disinhibition having been kept and is then seen but dismissed as external. Analogously, auditory pathways are active during verbal hallucinations and produce a subvocal verbal process, but since no record is kept of the words being created, they are treated as external. The subject then proceeds to confabulate, to provide an account for the agency.
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PMID:Other faces in the mirror: a perspective on schizophrenia. 1823 56

Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia.
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PMID:Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. 1839 5

Postmortem studies have shown that schizophrenia produces a reduction in the 67-kilodalton isoform of glutamic acid decarboxylase (GAD67), a key enzyme for gamma-aminobutyric acid (GABA) synthesis. N-methyl-d-aspartate receptor (NMDAR) antagonists have been extensively used to study schizophrenia because they can induce many aspects of the disease, including the decrease in GAD67. It is generally thought that this reduction in GAD implies a reduction in functional inhibition, but direct evidence had been lacking. We have therefore performed physiological studies in slices of prefrontal cortex taken from rats treated with the NMDAR antagonist ketamine. Both frequency and amplitude of miniature inhibitory postsynaptic currents were reduced. Consistent with a reduction of inhibition, we observed an increase in postsynaptic excitability. The increased excitability is likely to result from disinhibition because miniature excitatory postsynaptic current properties and intrinsic excitability were not changed. Ketamine did not affect inhibition or GAD levels in young rats, indicating a developmental regulation that may be related to the developmental increase in ketamine sensitivity that occurs in humans. Our results show that NMDAR antagonist produces biochemical changes in the GABA system that lead to a functional disinhibition. Such disinhibition would be expected to decrease gamma oscillations, which are reduced in schizophrenia.
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PMID:Prolonged exposure to NMDAR antagonist suppresses inhibitory synaptic transmission in prefrontal cortex. 1852 22

FREQUENCY: The prevalence of cigarette smoking is significantly higher among patients with schizophrenia (60-90%) than in the general population (23-30%). While tobacco smoking decreases in the general population (from 45% in the 1960's to 23-30% in the 2000's), smoking in patients with schizophrenia remains high. Patients with schizophrenia smoke more cigarettes than control subjects. Patients smoke more deeply, thereby increasing their exposure to the harmful elements in tobacco smoke. IMPACT OF SMOKING IN SCHIZOPHRENIC PATIENTS: As in the general population, smoking contributes to the reduced life expectancy in patients with schizophrenia. Patients with schizophrenia are at increased risk for cardiovascular disease due to high rates of cigarette smoking. In the Department of Mental Health of the commonwealth of Massachusetts, cardiovascular disease was the factor the most strongly associated with excess mortality. Cardiac deaths were elevated more than six-fold. Weight gain, insulin resistance, metabolic syndrome and diabetes mellitus are frequent in patients with schizophrenia, and may worsen the risk of cardiovascular diseases. It has been reported that the risk for lung cancer in patients with schizophrenia is lower than that of the general population, despite increased smoking. However, in a study conducted in Finland, a slightly increased cancer risk was found in patients with schizophrenia. Half of the excess cases were attributable to lung cancer. IMPROVEMENT OF COGNITIVE DEFICITS: Patients with schizophrenia may use nicotine to reduce cognitive deficits and negative symptoms or neuroleptic side effects. Smoking may transiently alleviate negative symptoms in schizophrenic patients by increasing dopaminergic and glutamatergic neurotransmission in the prefrontal cortex. In patients with schizophrenia, nicotine improves some cognitive deficits: (1) sensory gating deficits and abnormalities in smooth pursuit eye movements associated with schizophrenia are transiently normalized with the administration of nicotine ; (2) high-dose nicotine transiently normalizes the abnormality in P50 inhibition in patients with schizophrenia and in their relatives; (3) in tasks that tax working memory and selective attention, nicotine may improve performance in schizophrenia patients by enhancing activation of and functional connectivity between brain regions that mediate task performance (Jacobsen et al. 2004; Paktar et al.2002); (4) cigarette smoking may selectively enhance visuospatial working memory and attentional deficits in smokers with schizophrenia. However, Harris et al., found that nicotine affects only the attention without effects of nicotine on learning, memory or visuospatial/constructional abilities. In addition, smoking could facilitate disinhibition in schizophrenic patients.
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PMID:[Smoking and schizophrenia: epidemiological and clinical features]. 1855 53


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