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)

The release of dopamine in the ventral tegmental area (VTA) plays an important role in the autoinhibition of the dopamine neurons of the mesocorticolimbic system through the activation of somatodendritic dopamine D2 autoreceptors. Accordingly, the intra-VTA application of dopamine D2 receptor agonists reduces the firing rate and release of dopamine in the VTA, and this control appears to possess a tonic nature because the corresponding antagonists enhance the somatodendritic release of the transmitter. In addition, the release of dopamine in the VTA is increased by potassium or veratridine depolarization and abolished by tetrodotoxin and calcium omission. Overall, it appears that the somatodendritic release of dopamine is consistently lower than that in nerve endings. Apart from intrinsic dopaminergic mechanisms, other transmitter systems such as serotonin, noradrenaline, acetylcholine, GABA and glutamate play a role in the control of the activity of dopaminergic neurons of the VTA, although the final action depends on the particular receptor involved as well as the neuronal type where it is localized. Given the involvement of the mesocorticolimbic dopaminergic systems in the pathogenesis of severe neuropsychiatric disorders such as schizophrenia, the knowledge of the factors that regulate the release of dopamine in the VTA could provide new insight into the ethiogenesis of the disease as well as its implication on the mechanisms of action of therapeutic drugs.
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PMID:The somatodendritic release of dopamine in the ventral tegmental area and its regulation by afferent transmitter systems. 1528 6

Repetitive or acute treatment of methamphetamine (MAP) or amphetamine (AMP) induces sensitization to both subsequent challenge treatment of the drugs, and exposure to emotional and physiological stress. In addition, chronic treatment of AMP enhanced DA utilization/release in striatum. Similarly, repetitive exposure to footshock or tail shock stress induces sensitization of noradrenaline or 3-methoxy-4-hydroxyphenylglycol (MHPG) to subsequent mild stress and to small amounts of AMP or MAP injection. Striatum, nucleus accumbens and prefrontal dopaminergic systems have an important role in the development of this sensitization. Immediate early gene (IEG) expression in the hypothalamus, nucleus accumbens and striatum may be involved in this process. Neurobiological vulnerability to schizophrenia may be induced by the interaction of multiple gene disposition and environmental insult, and schizophrenia onset and/or relapse in response to mild, non-specific stress. Stress-sensitive systems therefore are postulated in the pathophysiology of schizophrenia. In this regard, mesolimbic DA systems may be involved in the pathophysiology of schizophrenia. In contrast to MAP- or AMP- and stress-induced sensitization, haloperidol and clozapine induce IEG expression in the caudate-putamen and amygdala. Collectively, MAP- or AMP-induced sensitization may, in part, share an early functional process of neurobiological mechanisms.
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PMID:[Stress sensitization induced by stressor and methamphetamine]. 1529 Dec 45

Several lines of evidence suggest that dysfunctions of neurotransmitters are associated with schizophrenia. DOPA decarboxylase (DDC) is an enzyme involved directly in the synthesis of dopamine and serotonin, and indirectly in the synthesis of noradrenaline. Therefore, the DDC gene can be considered a candidate gene for schizophrenia. We performed an association study between three single nucleotide polymorphisms in the DDC gene and paranoid schizophrenia. However, in our study no significant differences were found in the genotype distributions and allele frequencies between 80 paranoid schizophrenics and 108 controls for any of the polymorphisms. Neither did the haplotypes of the single nucleotide polymorphisms show any association with paranoid schizophrenia. Therefore, we conclude that the polymorphisms studied do not play a major role in paranoid schizophrenia pathogenesis in the population investigated.
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PMID:No association between polymorphisms in the DDC gene and paranoid schizophrenia in a northern Chinese population. 1531 31

The dominant research subject on schizophrenia, mood disorders, autism and other central nervous system diseases has been related to neurotransmitter system abnormalities. For example, the dopamine hypothesis states that schizophrenia is the result of dopaminergic hyperactivity. The therapeutic approach has also been directed towards finding agents which will modulate or regulate these neurotransmitter systems at any step. There is substantial and mounting evidence that subtle abnormalities of reactive oxygen species (ROS) and nitric oxide (NO) may underlie a wide range of neuropsychiatric disorders. NO has chemical properties that make it uniquely suitable as an intracellular and intercellular messenger. It is produced by the activity of nitric oxide synthases which are present in peripheral tissues and in neurons. On the other hand, NO is known to be an oxygen radical in the central and peripheral nervous systems. NO has been implicated in a number of physiological functions such as noradrenaline and dopamine releases, memory and learning and certain pathologies such as schizophrenia, bipolar disorder and major depression. Evidence has been considered here for the proposal that an abnormality of NO metabolism may be a contributory factor in some neuropsychiatric disorders. The direct evidence for NO abnormalities in schizophrenia and other psychiatric disorders remains relatively limited to date, although there are some clinical and experimental studies. The suggestion that NO and other ROS may play a role in some neuropsychiatric disorders clearly has important implications for new treatment possibilities. The primary objective of the present review was to summarize and critically evaluate the current knowledge regarding a potential contribution of NO to the neuropathophysiology of schizophrenia as well as other neuropsychiatric disorders.
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PMID:Nitric oxide as a physiopathological factor in neuropsychiatric disorders. 1534 Nov 94

In this article, we have reevaluated the role of noradrenergic dysfunction in the pathogenesis of schizophrenia in the light of today's neuroscience and clinical data. Neurophysiological, psychophysiological, psychopharmacological, and biochemical findings that have accumulated in last decades indicate that certain noradrenergic dysfunctions play important roles in the pathogenesis of the disorder. Moreover, these findings provide us with consistent evidence for the existence of two syndromes generated by either overactivity or underactivity of the central noradrenaline (NA) system. The former appears to correspond to the type I syndrome (positive symptoms) and the latter to the type II syndrome (negative symptoms). We conclude that the involvement of brain NA in cerebral metabolism and blood flow as well as the amine's role in brain development and neuronal differentiation may provide the mechanisms underlying the disease process in schizophrenia. Development of chemical agents acting specifically on the brain noradrenergic mechanisms may be a promising approach to novel treatments of the disorder.
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PMID:Proposal for a noradrenaline hypothesis of schizophrenia. 1590 14

Quetiapine is a novel atypical antipsychotic drug with multi-receptorial affinity. Using in vivo microdialysis, we investigated if quetiapine modulates extracellular noradrenaline and dopamine in brain areas generally believed to be involved in the pathophysiology of schizophrenia and in the action of antipsychotic drugs. Quetiapine (5, 10 and 20 mg/kg, i.p.) increased levels of noradrenaline in both the prefrontal cortex and the caudate nucleus, while it increased dopamine levels mainly in the prefrontal cortex. It is argued that the marked increase of dopaminergic transmission in the prefrontal cortex induced by quetiapine might be relevant to its therapeutical action.
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PMID:The atypical antipsychotic quetiapine increases both noradrenaline and dopamine release in the rat prefrontal cortex. 1550 22

Dopamine-glutamate interactions in the prefrontal cortex (PFC) are associated with higher order cognitive functions, and are involved in the pathophysiology of schizophrenia and addiction. Recordings with intracellular sharp microelectrodes and patch-clamp pipettes were used to investigate these interactions in layer V pyramidal cells of brain slices obtained from the rat PFC. Dopamine (100 microM) potentiated N-methyl-d-aspartate (NMDA; 10mM)-evoked depolarizations, but did not change those elicited by alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid (AMPA; 1mM). Dopamine (100 microM) increased the amplitude of the NMDA (30 microM)-induced currents as well, and 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF 38393; 1, 10 microM), a D(1) receptor agonist, concentration-dependently reproduced this effect. Furthermore, 7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzapine hydrochloride (SCH 23390; 10 microM), a D(1) receptor antagonist, reversed both the dopamine- and the SKF 38393-evoked potentiation. The D(2) receptor agonists lisuride and quinpirole (10 microM both), as well as noradrenaline (100 microM) failed to mimic the stimulatory effect of dopamine. Isoproterenol (1, 10 microM) concentration-dependently facilitated NMDA responses. However, neither this effect at 10 microM nor that of dopamine at 100 microM could be antagonized by propranolol (10 microM), a non-selective beta adrenoceptor blocker. The isoproterenol-induced facilitation of NMDA currents was abolished by SCH 23390 (10 microM). The results indicate that dopamine potentiates NMDA responses in layer V pyramidal cells of the PFC solely by activating D(1) receptors. D(2) receptors and alpha or beta adrenoceptors are not involved in the dopamine-NMDA interaction.
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PMID:D1 but not D2 dopamine receptors or adrenoceptors mediate dopamine-induced potentiation of N-methyl-d-aspartate currents in the rat prefrontal cortex. 1553 Oct 94

N-methyl-D-aspartate (NMDA)/glutamate receptor antagonists, such as phencyclidine (PCP), induce behavioral abnormalities (locomotor hyperactivity, sensorimotor gating deficits, impairments of cognition) in animals that are thought to model aspects of schizophrenia. The administration of PCP increases noradrenaline transmission in the rat prefrontal cortex, a brain structure required for normal cognitive processes. Noradrenaline, in turn, works through a set of receptors that have themselves been implicated directly in NMDA antagonist-induced deficits; we recently reported that the alpha-2 agonist, clonidine, is effective at preventing PCP-induced deficits of working memory and visual attention in rats. Here, we further investigated the role for alpha-2 adrenoreceptors in the effects of PCP on spatial working memory performance. The alpha-2 agonist clonidine (0.001-0.01 mg/kg, subcutaneously (s.c.)) produced a significant amelioration of PCP-induced working memory deficits; the effects of PCP (1.0 mg/kg, s.c.), but not clonidine, were reduced in noradrenaline-depleted rats. In addition, the alpha-2A-preferring agonist guanfacine (0.05-1.0 mg/kg, s.c.) dose-dependently prevented the deficits of spatial working memory performance produced by PCP. Although the highly selective alpha-2 receptor antagonist, atipamezole (ATI), failed to affect spatial working memory on its own, at the doses studied (0.1-0.5 mg/kg, s.c.), it dramatically enhanced the working memory deficit produced by PCP. These data indicate that alpha-2 adrenoreceptors tonically inhibit PCP-induced deficits of spatial working memory, suggesting an important role for these receptors in cognitive deficits associated with NMDA receptor hypofunction.
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PMID:Alpha-2 adrenoceptor activation inhibits phencyclidine-induced deficits of spatial working memory in rats. 1571 23

The major brain noradrenergic nucleus locus coeruleus (LC) has long been thought to be involved in states of alertness and cognitive processes. These functional characteristics make this nucleus interesting with regard to the signs of schizophrenia, especially the negative symptoms of the disease. In the present in-vivo electrophysiological study we analyse a putative interaction between endogenous kynurenic acid (KYNA) and the antipsychotic drugs clozapine and haloperidol on noradrenergic LC neurons. Previous studies have shown that systemically administered antipsychotic drugs increase the neuronal activity of LC noradrenaline (NA) neurons. In line with these findings, our results show that clozapine (1.25-10 mg/kg i.v.) and haloperidol (0.05-0.08 mg/kg i.v.) increased the firing rate of LC NA neurons in anaesthetized rats. Pretreatment with PNU 156561A (40 mg/kg i.v., 3 h), a potent inhibitor of kynurenine 3-hydroxylase, produced a 2-fold increase in rat brain KYNA levels. This treatment prevented the increase in firing rate of LC NA neurons induced by haloperidol (0.05-0.08 mg/kg i.v.) and clozapine in high doses (2.5-10 mg/kg i.v.). However, the excitatory action of the lowest dose of clozapine (1.25 mg/kg i.v.) was not abolished by elevated levels of brain KYNA. Furthermore, pretreatment with L-701,324 (4 mg/kg i.v.) a selective antagonist at the glycine site of the NMDA receptor prevented the excitatory effects of both clozapine and haloperidol. The present results suggest that the excitation of LC NA neurons by haloperidol and clozapine involves a glutamatergic component.
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PMID:Activation of noradrenergic locus coeruleus neurons by clozapine and haloperidol: involvement of glutamatergic mechanisms. 1573 50

Depression is a frequent symptom in psychiatry, either isolated (major depression) or entangled with other psychiatric symptoms (psychotic depression, depression of bipolar disorders). Many antidepressant drugs are available with different pharmacological profiles from different classes: tricyclic antidepressants, monoamine oxydase inhibitors, selective serotonin reuptake inhibitors (SSRI). However, there are some limitations with these drugs because there is a long delay before relief for symptoms, some patients with major depression are resistant to treatment, there is a risk to induce manic symptoms in patients with bipolar disorders and these drugs have no effect on the psychotic symptoms frequently associated to major depression. The leading hypothesis for the search of more efficient new antidepressants has been the amine deficit hypothesis: noradrenaline and/or serotonin deficit and more recently dopamine deficit. Moreover, a dopamine deficit has been also hypothesized as the central mechanism explaining the negative symptoms of schizophrenia. These symptoms are the consequence of a deficit of normal behaviours and include affective flattening, alogia, apathy, avolition and social withdrawal. There is thus a great overlap between symptoms of depression and negative symptoms of schizophrenia. Atypical antipsychotics, in contrast with conventional neuroleptics, have been shown to decrease negative symptoms, most probably through the release of dopamine in prefrontal cortex, thus improving psychomotor activity, motivation, pleasure, appetite, etc. The dopamine deficit in cortical prefrontal areas was thus an unifying hypothesis to explain both some symptoms of depression and negative symptoms of schizophrenia. Studies in animal confirm this view and show that the association of an atypical antipsychotic drug and an SSRI (olanzapine plus fluoxetine) increases synergistically the release of dopamine in prefrontal areas. Moreover, most of the atypical antipsychotics have a large action spectrum, beyond the only dopamine receptors: their effects on the serotonin receptors--particularly the 5-HT2A and 5-HT2C receptors--suggest that their association to SSRI could be a promising treatment for depression. Indeed, SSRI act mainly by increasing the serotonin level in the synapse, thus leading to a non specific activation of all pre- and post-synaptic serotonin receptors. Among them, 5-HT2A/2C receptors have been involved in some of the unwanted effects of SSRI: agitation, anxiety, insomnia, sexual disorders, etc. The inhibition of these receptors could be thus beneficial for patients treated with SSRI. Amisulpride is an unique atypical antipsychotic that selectively blocks dopamine receptors presynaptically in the frontal cortex, possibly enhancing dopaminergic transmission. The antidepressant effect of amisulpride was shown in dysthymia in many clinical studies versus placebo, tricyclic antidepressants, SSRI or others. However, a shorter delay for symptom relief was not demonstrated for amisulpride as compared to comparative antidepressants. Other atypical antipsychotics (clozapine, olanzapine), which act on a large variety of receptors, have shown antidepressant effects--mainly in association with SSRI--in different psychiatric diseases: treatment-resistant major depression, major depression with psychotic symptoms and depression of bipolar disorders, with no increase of manic symptoms in this latter case. Moreover, the delay for symptom relief was greatly shortened. More comparative double-blind studies are required to confirm and to precise the antidepressant effects of atypical antipsychotics. Nevertheless, these studies suggest that atypical anti-psychotics could be of great value in depressive conditions reputed for their resistance to treatment with usual antidepressants. Particularly, new strategies emerge that combine atypical antipsychotics and antidepressants for greater efficacy and more rapid relief of depression symptoms.
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PMID:[Efficacy of atypical antipsychotics in depressive syndromes]. 1573 62


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