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)

Spontaneous blink rates are controlled by a definable neural system originating in PPRF with facilitatory modulation from SN and superior colliculus and inhibitory modulation provided by cerebellum and occipital cortex. The thalamus may also be involved but the result of its influence is not clear. Reflex blinking is often reduced when spontaneous blink rate is increased and the reverse applies as well. The anatomic control of reflex is primarily in structures in the caudal half of pontine tegmentum and rostral midbrain. However, SN and cerebellum and other structures that regulate blink rate also modulate reflex blinking. Neurochemical control as determined by neuropharmacological experiments is exerted by dopaminergic, cholinergic and GABAergic systems of brain stem. Dopamine activity correlates directly with blink rate whereas agonism of the other two relevant neurotransmitter systems may inhibit blink rate. Clinical implications in central nervous system disease are currently restricted to Parkinson's disease, schizophrenia and autism. In the former illness, reduced blink rate signifies a worsening of the illness and a significant increase in blink rate in patients treated with dopamine agonist may be a harbinger of agonist-induced dyskinesia. In schizophrenia, increased blink rate, even in medication-naive subjects, may signify involvement of the structures that regulate blinking. This is important because these structures are rarely invoked as sites of potential pathophysiological import in schizophrenia. Similar considerations apply to autism except that increased blinking more clearly differentiates this disorder from other forms of retardation.
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PMID:Blinking. 248 18

The effect of systemic administration of ritanserin (R 55667), a 5-hydroxytryptamine (5-HT2) receptor antagonist, on midbrain dopamine (DA) neurons was studied with single cell recording techniques in the chloral hydrate anesthetized male rat. Dopamine cells of the zona compacta, substantia nigra (ZC-SN) and the ventral tegmental area (VTA) were identified by established criteria. Ritanserin (0.5-2.0 mg/kg, IV) dose-dependently increased both the burst firing and firing rate of the midbrain DA neurons. These effects were prevented by endogenous 5-HT depletion through pretreatment with the 5-HT synthesis inhibitor para-chlorophenylalanine (PCPA, 300 mg/kg, IP, x3), which did not significantly alter the firing characteristics of the midbrain DA cells when given alone. These results suggest that 5-HT exerts an inhibitory control of midbrain DA cell activity mediated by 5-HT2 receptors. The stimulatory effect of ritanserin on midbrain DA systems might contribute to some of its clinical effects, such as improvement of mood, drive and motivation as well as its therapeutic actions in parkinsonism and type II schizophrenia.
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PMID:Ritanserin, a 5-HT2 receptor antagonist, activates midbrain dopamine neurons by blocking serotonergic inhibition. 252 59

Dopamine receptors are classified into D1 and D2 subtypes on the basis of their pharmacological properties and the intracellular responses they mediate. The cerebral D2 dopamine receptor is the target of drugs used to alleviate the main symptoms of schizophrenia. Although it is considered to be a single molecular entity, there is evidence that multiple D2-receptor subtypes exist. A complementary DNA encoding a D2 receptor has recently been cloned and the deduced 415-amino-acid sequence indicates that it belongs to the large superfamily of receptors coupled to G proteins, and that its topology consists of seven transmembrane domains. In this family, the genes are frequently without introns and each is believed to encode a unique polypeptide product. Here we show that the gene for the D2 receptor produces two receptor isoforms by alternative messenger RNA splicing, providing a route to receptor diversity in this family. One isoform corresponds to the D2(415) receptor, but the second contains an additional sequence encoding a 29-amino-acid fragment, defining a novel D2(444) receptor isoform. Expression of the two isoforms is tissue-specific, and both are regulated by guanyl nucleotides. As the extra sequence is located within a putative cytoplasmic loop that binds to G proteins, the two isoforms might interact with different G proteins and thereby initiate distinct intracellular signals.
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PMID:Alternative splicing directs the expression of two D2 dopamine receptor isoforms. 253 47

Dopamine agonists may be useful in the treatment of neuroleptic-induced hyperprolactinemia and movement disorders; it is a treatment approach that has been avoided for fear of inducing or exacerbating psychotic symptoms. The risks of giving dopamine agonists to psychiatric patients have been well documented in the literature. To further evaluate the psychotogenic effects of bromocriptine, a dopamine receptor agonist, we conducted a double-blind study in which 16 psychiatrically stable patients were treated for tardive dyskinesia with neuroleptics plus high doses of bromocriptine (N = 11) or placebo (N = 5) for 10 weeks. The diagnoses included schizophrenia, schizoaffective disorder, and major depression with psychotic features. Patients were evaluated weekly with the Brief Psychiatric Rating Scale and the Clinical Global Impression Scale during the 10-week treatment phase and for 8 weeks after medication was withdrawn. There were no statistically significant differences between active and placebo groups in behavioral ratings at baseline, week 10, and week 18. These results are compared with the findings of previous studies in which bromocriptine was given to psychiatric patients. Although the literature suggests that bromocriptine can induce or exacerbate psychosis in psychiatric patients, this occurs primarily in those with a psychotic diathesis and who are not currently receiving neuroleptic medication. Other important factors include the dose of bromocriptine, duration of treatment, and the clinical state of the patient at the time bromocriptine treatment is initiated. These results suggest that bromocriptine can be safely used in patients at risk for psychotic illnesses as long as patients are clinically stable and maintained on neuroleptics.
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PMID:The behavioral toxicity of bromocriptine in patients with psychiatric illness. 257 94

Dopamine receptor types D1 and D2 can oppose or enhance each other's actions for electrical, biochemical, and psychomotor effects. We report a D1-D2 interaction in homogenized tissue as revealed by ligand binding. D2 agonists lowered the binding of [3H]raclopride to D2 receptors in striatal and anterior pituitary tissues. Pretreating the tissue with the D1-selective antagonist SCH 23390 prevented the agonist-induced decrease in [3H]raclopride binding to D2 sites in the striatum but not in the anterior pituitary, which has no D1 receptors. Conversely, a dopamine-induced reduction in the binding of [3H]SCH 23390 to D1 receptors could be prevented by the D2-selective antagonist eticlopride. Receptor photolabeling experiments confirmed both these D1-D2 interactions. The blocking effect by SCH 23390 was similar to that produced by a nonhydrolyzable guanine nucleotide analogue, and SCH 23390 reduced the number of agonist-labeled D2 receptors in the high-affinity state. Thus, the D1-D2 link may be mediated by guanine nucleotide-binding protein components. The link may underlie D1-D2 interactions influencing behavior, since the link was missing in over half the postmortem striata from patients with schizophrenia and Huntington disease (both diseases that show some hyperdopamine signs) but was present in human control, Alzheimer, and Parkinson striata.
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PMID:Link between D1 and D2 dopamine receptors is reduced in schizophrenia and Huntington diseased brain. 257 62

Dopamine has been accepted as a possible etiological factor in schizophrenia and most studies have demonstrated that the ingestion of methionine by schizophrenics exacerbated their psychosis. Unfortunately, the methylation theory has failed to support the dopamine theory in schizophrenia. This paper will attempt to demonstrate why abnormal histamine metabolism in schizophrenia can explain the effect of methionine in worsening schizophrenia in certain patients.
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PMID:Histamine methylation in schizophrenia. 268 45

The conference on Fetal Neural Development and Schizophrenia which was held in Washington, DC, May 31-June 1, 1988, focused on factors of possible etiological significance in fetal development. Schizophrenia researchers joined experts in brain imaging, neuropathological, and neurochemical changes in brain development and investigators of potential genetic and neurobehavioral causes of psychosis. The combined evidence suggested dysfunction in frontal and parieto-occipital neocortex, basal ganglia, hippocampus, and amygdala. Dopamine transmission was implicated both in basal ganglia deficits and in widespread neocortical disturbances. Viral infection, or excessive stress, during the second trimester of pregnancy, as well as obstetrical complications, minor physical anomalies, and brain defects, correlated positively with incidence of adult schizophrenia. Autonomic nonresponding, birth complications, and ventricular enlargement were found to be closely related to negative symptom schizophrenia in high-risk populations. A dual factor model of schizophrenia was suggested, where genetic and environmental influences combine to produce psychosis.
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PMID:Fetal neural development and schizophrenia. 271 87

Dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured in cerebrospinal fluid (CSF) of 14 schizophrenic inpatients before and 2 weeks after withdrawal of long-term neuroleptic medication. Total neuroleptic-like activity (NLA) in serum was determined at the same times. DA and its metabolites (DOPAC and HVA) were significantly reduced after neuroleptic discontinuation. NLA was substantially diminished. The decrease in DA and DOPAC was positively correlated with positive symptoms of postwithdrawal deterioration, and low prewithdrawal DOPAC level predicted severe relapse. These results are compatible with the hypothesis linking an overregulated central DA system to the positive symptoms of schizophrenia.
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PMID:CSF dopamine turnover and positive schizophrenic symptoms after withdrawal of long-term neuroleptic treatment. 286 74

Dopamine receptors in the brain play an important role in the treatment of schizophrenia and in the development of tardive dyskinesia. In Parkinson's disease the loss of dopamine innervation and the use of chronic administration of L-DOPA or therapy with dopamine agonists also affects the function of dopamine receptors in brain. Subacute administration of neuroleptic drugs to rodents for a few weeks followed by the withdrawal of the drug induces supersensitivity of dopamine receptors in the striatum. However, the long-term administration of neuroleptic drugs to rodents shows that typical neuroleptic drugs can induce functional supersensitivity of dopamine receptors despite continued administration of drug. In contrast, atypical neuroleptics such as sulpiride, do not appear to induce the same changes in the activity of dopamine receptors. The functional supersensitivity of dopamine receptors produced by repeated administration of neuroleptic is reflected in changes in cholinergic, gamma-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT) and peptide neuronal systems. Chronic treatment of parkinsonian patients with drugs may obscure the changes in the function of dopamine receptors caused by the disease process. However, chronic administration of L-DOPA to normal rats and to rats with a unilateral lesions of the nigrostriatal pathway induced with 6-hydroxydopamine does not produce a down-regulation of the number of dopamine receptors. Rather, these experiments indicate the development of a functional supersensitivity of dopamine receptors in the absence of any obvious change in the nature of dopamine receptor populations in brain. In conclusion, while pharmacological manipulation, using neuroleptic drugs, produces the expected development of receptor supersensitivity, studies involving chronic treatment with agonists suggests that dopamine receptors do not always respond as would be predicted. It appears that there are aspects of the regulation of dopamine receptors in brain following pharmacological manipulation which remain to be resolved.
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PMID:Chronic pharmacological manipulation of dopamine receptors in brain. 288 59

Dopamine (DA) acts as a neurotransmitter in the central nervous system. The main part of the DA cell bodies are localized in the ventral mesencephalon and their axons run together in the medial forebrain bundle before diverging to different terminal areas in the forebrain, like the nucleus caudatus-putamen, nucleus accumbens, septum, amygdala, and several cortical areas like the cingulate, pyriform, entorhinal and prefrontal cortices. The functions of the dopamine systems are discussed in terms of how dopamine can modulate the functions of the area it innervates. Changes in dopaminergic transmission may be found after animals have been exposed to stress. This has implications for the discussion of whether a changed dopaminergic transmission in schizophrenia is a cause to, or a consequence of the disease. Both theories proposing a single localized anatomical site of action for the antipsychotic effect of neuroleptic drugs as well as those implicating a general effect on a number of different regions have been put forward. It is now widely accepted that there exists two classes of DA receptors, the D-1 and D-2 receptors, which have different physiological, and therefore proposed to have different clinical, characteristics. Other research implies however that a subpopulation of D-2 receptors is most important for the antipsychotic effect.
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PMID:The dopamine systems in the brain, functional classification of different dopamine receptors. 289 58


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