Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The dopamine (DA)-sensitive adenylate cyclase in the substantia nigra was assayed in rats which had been subjected to 3 different kinds of brain lesion: (1) unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle; (2) unilateral lesions of the descending strio-nigral and pallido-nigral projections; (3) total lesions of the serotoninergic raphe-nigral pathway. Lesions of the medial forebrain bundle causing 97% depletion of striatal DA, 72% depletion of nigral tyrosine hydroxylase, and no change in nigral glutamate decarboxylase (GAD), resulted in no change in basal or DA-stimulated cyclic AMP production ipsilateral to the injection. Lesions of the globus pallidus, causing 70% and 79% reductions in GAD and substance P respectively in the ipsilateral nigra, produced a reduction in basal cyclic AMP production and abolished the normal increase in cyclic AMP produced by DA on the side of the lesion. Lesions to the dorsal and median raphe nuclei did not affect the normal DA-sensitive adenylate cyclase response in the nigra. The results suggest that one of the neurotransmitter functions of DA in this brain region may be to modulate the release of psi-aminobutyric acid (GABA) or substance P from synaptic terminals afferent to the nigra.
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PMID:Evidence concerning the anatomical location of the dopamine stimulated adenylate cyclase in the substantia nigra. 2 89

Although the intimate mechanism by which psychotropic agents exert their therapeutic effects is still not completely clear, a large bulk of evidence supports the existence of a close correlation between their clinical antipsychotic acitivity and the ability to affect by different mechanisms brain monoamines and/or other real or putative neurotransmitters. Neuroleptic drugs of the phenothiazine type and related classes possess a blocking effect on dopaminergic transmission in nigro-striatal, mesolimbic and mesocortical areas; experiments supporting both a pre-and post-synaptic site of action have been described, together with the interference at the molecular level with DA-sensitive adenylate cyclase activity. In addition, anticholinergic activity and increase in GABA turnover in the striatum have been given as evidence to explain for some neuroleptics (e.g sulpiride, clozapine) lack of extrapyramidal side-effects. Anxiolytics seem to produce their therapeutic effect through a decrease in catecholaminegic and serotoninergic turnover although new avenues have been opened by some recent reports indicating a facilitation of GABAergic and glycinergic transmission in CNS.
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PMID:Psychotropic drugs: mechanism of action at the neurotransmitter level. 2 1

Studies on the biochemical effects of clinically used psychotropic drugs in brain have shown that they all exert their action by a direct or indirect interference with synaptic transmission. Thus, animal studies in vivo and in vitro have shown that the clinical efficacy of antipsychotic drugs correlates with their inhibitory action on dopamine receptors. In vivo these compounds enhance dopamine turnover in the brain and in vitro they inhibit the dopamine sensitive adenylate cyclase and the binding of dopamine to its receptor at neuronal membranes. Tricyclic antidepressants are drugs which have effects on many transmitter systems. No specific biochemical action has been found which is closely correlated with their clinical potency. However, it appears that a stimulation of the function of the noradrenergic system might have some clinical relevance. Benzodiazepines exert their pharmacological activity in the CNS by interacting with a brain specific receptor. This receptor appears to be part of a larger complex including a GABA receptor and the chloride conductance mechanism associated with the GABA receptor. By binding to their receptor, benzodiazepines appear to enhance the sensitivity of the GABA receptor, thus indirectly potentiating GABA-ergic neurotransmission in the brain.
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PMID:[Biochemical effects of psychotropic drugs in central nervous system (author's transl)]. 3 60

In review is concerned with research done on an animal model for the hereditary neuropsychiatric disorder, Huntington's disease (HD). The neuropathology of HD involves primarily a selective degeneration of neurons with cell bodies in the striatum. Injection of kainic acid, a potent neuroexcitant structurally related to glutamic acid, into the rat striatum causes a selective neuronal degeneration resembling that of HD. Striatal cholinergic and GABAergic neurons, including their terminal projections in the substantia nigra, are affected by kainate; dopaminergic axons innervating the striatum as well as corticofugal fibers passing through the region are spared. The striatal kainate lesion has aided in the characterization of the neuronal circuitry in the nigrostriatal axis including the neuronal localization of dopamine-sensitive adenylate cyclase, neuroleptic binding sites, and GABA receptors. Studies in vivo and in vitro with kainate and its analogues suggest that the potent neurotoxicity of kainate involves a cooperative interaction between synaptically released glutamate and injected kainate on vulnerable neurons; prior destruction of cortico-striatal glutamatergic afferents attenuates kainate's neurotoxicity. The kainate model has been used to test drugs that may be of therapeutic benefit for HD. A better understanding of the mechanism of neurotoxicity of kainate may shed light on the cause of neuronal degeneration in HD.
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PMID:An animal model for Huntington's disease. 3 64

Bilateral occlusion of common carotid arteries in Mongolian gerbils was produced for the periods (up to 15 min) which were shown to be totally reversible. There was an initial increase of cyclic AMP and GABA levels and enhanced activities of adenylate cyclase and glutamate decarboxylase, as well as the reduction of norepinephrine level and decreased activities of monoamine oxidase, GABA-transaminase and Na+-K+-ATPase. Following these changes, decreased concentration of dopamine, serotinin and glutamate were found. The activities of total protein kinase and acetylcholinesterase were found to be reduced after longer periods of short-term ischemia. The data are consistent with the concept of increased non-controled release of putative neurotransmitters in ischemia.
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PMID:Alterations of putative neurotransmitters and enzymes during ischemia in gerbil cerebral cortex. 3 75

Electrolytic lesions of the medial forebrain bundle induce a fall in histidine decarboxylase activity (the specific synthetic enzyme of brain histamine) in the ipsilateral cerebral cortex and hippocampus of the guinea pig brain; these results suggest the presence of an ascending histaminergic pathway in the guinea pig brain similar to that described in the rat. Possible alterations in the sensitivity of histaminergic receptors present in the target areas were studied following this type of lesion by combining electrophysiological and biochemical approaches. Microiontophoretic applications of histamine or noradrenaline reveal a hypersensitivity (lower ejecting currents for threshold and maximal responses) in cortical neurons ipsilateral but not contralateral to the lesion, whereas responses to iontophoretically applied GABA are not modified. In contrast the responsiveness of histamine-sensitive cyclic AMP generating systems is not modified, neither in the cerebral cortex nor in the hippocampus after this type of lesion. Similar conclusions are reached from the data obtained with specific agonists of the two classes of histaminergic receptors and measurements in the presence of a phosphodiesterase inhibitor. Several hypotheses are discussed in order to reconcile the finding of a denervation hypersensitivity revealed by iontophoresis contrasting with an unaltered responsiveness of the histaminergic receptors linked to the adenylate cyclase.
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PMID:Hypersensitivity to histamine in the guinea-pig brain: microiontophoretic and biochemical studies. 21 64

Homogenization of rabbit retina in isotonic sucrose and differential rate centrifugation yielded two morphologically distinct synaptosomal fractions. One fraction was enriched in photoreceptor cell synaptosomes; the second fraction contained small synaptosomes derived from conventional sized synapses most abundant in the inner plexiform layer. Attempts to further purify these fractions using a variety of density gradients proved unsuccessful due to poor viability of photoreceptor cell synaptosomes. The synaptosomes prepared by our method are functionally stable as they demonstrate high affinity uptake for putative retinal neurotransmitters, neurotransmitter-sensitive adenylate cyclase activity, and calcium-dependent, potassium-stimulated release of [14C]GABA and [3H]dopamine.
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PMID:Isolation of synaptosomal fractions from rabbit retina. 54 67

Brain-derived neurotrophic factor (BDNF) and NGF are both expressed by neurons in the hippocampus. In previous studies, it has been demonstrated that both BDNF and NGF mRNA levels are regulated by neuronal activity. Upregulation is predominantly regulated by the glutamate (NMDA and non-NMDA receptors); downregulation, predominantly by the GABA system (Zafra et al., 1990, 1991). In neuronal cultures of the rat hippocampus, potassium depolarization and kainic acid-mediated increases in BDNF and NGF mRNA were eliminated in a dose-dependent manner by the calcium channel blocker nifedipine. Conversely, calcium ionophores (Bay-K8644 and ionomycin) augmented BDNF and NGF mRNA levels by a calmodulin-mediated mechanism. In view of the fact that many potential modulators (conventional transmitters and neuropeptides) of neuronal and astrocytic BDNF and NGF mRNA synthesis may act via the adenylate cyclase system, we studied the effect of forskolin, an activator of adenylate cyclase. Indeed, forskolin enhanced the effects of calcium ionophores and kainic acid on BDNF and NGF mRNA levels. Cytokines, such as interleukin-1 and transforming growth factor-beta 1, which have previously been shown to increase NGF mRNA markedly in astrocytes, were without effect on neuronal BDNF and NGF mRNA levels. In contrast to neuronal cultures, where the regulation of BDNF and NGF mRNA was generally very similar, the regulation in astrocytes was distinctly different. All the cytokines that produce a marked increase in NGF mRNA were without effect on astrocyte BDNF mRNA levels, which under basic conditions were below the detection limit. However, norepinephrine produced a marked elevation of BDNF mRNA in astrocytes, an effect that was further enhanced by glutamate receptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of brain-derived neurotrophic factor and nerve growth factor mRNA in primary cultures of hippocampal neurons and astrocytes. 128 95

The in vivo effects of GABA-ergic drugs on the activity of serotonin N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT), two enzymes involved in melatonin biosynthesis, were investigated in light-exposed chicken retina. The ip administration of muscimol and baclofen (direct agonists of GABA-A and GABA-B receptors, respectively), aminooxyacetic acid (an inhibitor of GABA transaminase), and nipecotic acid (an inhibitor of GABA reuptake), significantly increased the retinal NAT activity by 50-100%. Similar rises in NAT activity were observed following intraocular treatment of ether-anesthetized chickens with muscimol, baclofen and GABA. In contrast to NAT, there was no effect of the tested drugs on the retinal HIOMT activity. Aminophylline (a phosphodiesterase inhibitor) markedly elevated the retinal NAT activity, and a combined treatment with the GABA-ergic drugs and aminophylline resulted in additive effects. The actions of both muscimol and baclofen were antagonized by picrotoxin and bicuculline (two GABA-A receptor blockers), whereas the effect of baclofen was not changed by a selective GABA-B receptor blocker, CGP 35,348. Melatonin given ip significantly raised NAT activity, and its combination with muscimol further stimulated the enzyme. Picrotoxin and bicuculline given to chickens during the dark phase of 12 h light--12 h dark illumination cycle significantly suppressed the nocturnal NAT activity in retina. Neither GABA nor muscimol and baclofen significantly affected basal and forskolin (1 microM)-stimulated adenylate cyclase activity in vitro in light-exposed chicken retina. It is concluded that a GABA signal (acting through type A of GABA receptors) plays an important role in a complex mechanism regulating the rhythmic melatonin biosynthesis in vertebrate retina.
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PMID:The role of GABA-ergic signal in the regulation of melatonin biosynthesis in vertebrate retina. 130 60

Three effects of NT were observed on midbrain DA cells. The modulatory effect of NT, that is, the attenuation of DA-induced inhibition, has been most extensively examined. Studies indicate that this effect of NT was not simply due to a nonspecific excitation. NT selectively attenuated DA-induced inhibition without affecting either GABA-induced inhibition or glutamate-induced excitation of the same cells, and the attenuation of DA-induced inhibition could be observed at the doses at which the basal activity of DA cells was not changed by NT. The attenuation of DA-induced inhibition by NT is also unlikely to result from the formation of a DA-NT complex, since neuromedin N, which competes with NT for the same receptor but does not bind to DA, mimicked the effects, and neurotensin(1-11), which forms a complex with DA but is inactive in competing for NT receptors, did not. The similarities between the effects of NT and those of 8-bromo-cAMP and forskolin suggest that intracellular cAMP and protein kinase A may be involved. This suggestion was supported by the findings that IBMX (an inhibitor of phosphodiesterases) potentiated the effect of NT; and SQ22536 (an inhibitor of adenylate cyclase) and H8 (an inhibitor of protein kinase A) antagonized it. Phorbal-12,13-dibutyrate (an activator of protein kinase C) did not mimic the effect of neurotensin, and H7 (an inhibitor of protein kinase C) did not reduce the effect, suggesting that protein kinase C is unlikely to be involved in the modulatory effect of neurotensin. Experiments in vitro indicated that the excitatory effect of NT on DA cells occurred at higher concentrations (> 10 nM) than those needed for producing the modulatory effect. Its persistence during DA receptor blockade by sulpiride suggests that this effect was not entirely mediated by an attenuation of the inhibition induced by endogenously released DA. At even higher concentrations (> 100 nM), a sudden cessation of cell activity preceded by an increase in firing rate was observed. Whether this effect of NT was due to depolarization inactivation or a toxic effect of the peptide at high concentrations remains to be determined. In most other areas studied, the excitatory effect of NT was most commonly observed. In many areas, this excitatory effect was apparently a direct postsynaptic effect of NT. However, different mechanisms may be involved (see Table 1). For example, in some areas NT acted through a decrease in membrane conductance, while in others no change or an increase in the membrane conductance was observed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Actions of neurotensin: a review of the electrophysiological studies. 146 69


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