Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tranylcypromine, a monoamine oxidase inhititor, was administered to rats during chronic ethanol treatment. The severity of the hyperactive withdrawal behavior observed upon removal of ethanol was, during the first 60 hours of treatment, similar in both ethanol and ethanol + tranylcypromine treated animals. However, after 84 hours of ethanol treatment, tranylcypromine slightly depressed the withdrawal severity. Rises in cerebral cortical cyclic adenosine 3',5'-monophosphate (cAMP) levels and adenylate cyclase activity associated with withdrawal behavior in ethanol-treated rats, though, were not observed. (Adenylate cyclase activity used throughout this paper refers to % conversion of 3H-adenine into 3H-cAMP). Based on this and previous data, a model invoking two neurochemical adaptations--one in adenylate cyclase and one, as yet, unknown-is proposed for the mechanism of physical dependence.
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PMID:Cyclic adenosine 3',5'-monophosphate, adenylate cyclase and physical dependence on ethanol: studies with tranylcypromine. 19 7

Repeated administrations of ethanol and of phenobarbital to rats led to characteristic withdrawal symptoms when the drug had been stopped. Since both drugs affect brain dopamine metabolism, the postjunctional sensitivity to dopamine in the corpora striata was tested during ethanol or phenobarbital withdrawal. This was done by studying the dopamine-sensitive adenylate cyclase in homogenates of the copora striata of ethanol- or phenobarbital-dependent rats. The results demonstrated a slight postjunctional subsensitivity to dopamine in withdrawal from both ethanol and phenobarbital. Both drugs, when added in vitro, did not affect the postjunctionsl sensitivity to dopamine. The results do not support the hypothesis, at least not in the case of dopamine, that a postjunctional supersensitivity to neurotransmitters is important for withdrawal symptoms after chronic administration of drugs inducing physical dependence.
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PMID:Dopamine-sensitive adenylate cyclase in homogenates of rat striata during ethanol and barbiturate withdrawal. 98 95

Chronic ingestion of ethanol, which produced tolerance and physical dependence, resulted in altered function of the cerebral cortical beta-adrenergic receptor-coupled adenylate cyclase system in mice. Although there was no change in basal adenylate cyclase activity, or in the activity of the digitonin-solubilized catalytic unit, stimulation of adenylate cyclase activity by the nonhydrolyzable guanine nucleotide analog guanylylimidodiphosphate [Gpp(NH)p] was reduced in brains of ethanol-fed animals. Ethanol added in vitro increased adenylate cyclase activity, and this enhancement, in the presence of Gpp(NH)p, was also reduced in cortical membranes of ethanol-fed mice. Furthermore, the maximal response to isoproterenol was decreased, and the EC50 for isoproterenol stimulation of adenylate cyclase activity was increased in ethanol-fed animals. The results are consistent with a qualitative or quantitative defect in the function of the stimulatory guanine nucleotide-binding protein (Ns), as well as in the beta-adrenergic receptor, after chronic ethanol exposure. In part, these changes appear to be similar to those that occur during heterologous desensitization of various receptor systems, and may be associated with dependence on or tolerance to ethanol.
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PMID:Effects of chronic ethanol treatment on the beta-adrenergic receptor-coupled adenylate cyclase system of mouse cerebral cortex. 303 51

1. The half-time for maximal withdrawal scores in the rat is 30 to 36 hours following around the clock intubation with ethanol. 2. Cyclic AMP levels in all brain areas decline with ethanol treatment and rise again to control levels during withdrawal. 3. Norepinephrine-stimulated adenylate cyclase activity is increased by chronic treatment with ethanol. However, it is unlikely that this change is related to physical dependence, as it occurs 50 to 60 hours following the development of half-maximal withdrawal scores. 4. Ethanol had no effect on the concentration of beta-receptors in the cerebral cortex.
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PMID:Cyclic AMP and beta-adrenergic receptors during the development of physical dependence on ethanol in the rat. 625 Mar 27

A progressive increase in activity of some brain membrane-bound enzymes is shown after 2 and 4 weeks of ethanol administration. After 4 weeks the activities in brain homogenate of (Na+, K+) ATPase, Ca++ ATPase, 5'-nucleotidase, acetylcholinesterase and adenylate cyclase increased 150, 200, 140, 125 and 129 percent, respectively. Arrhenius plots of synaptosomal (Na+, K+) ATPase and acetylcholinesterase from alcohol-treated rats showed a lower transition temperature than control rats after two weeks, and this changed to a higher transition temperature after 4 and 8 weeks. Also, when ethanol was added in vitro to the control membranes, the transition temperature was lowered. However, if the alcohol was added to the membranes from alcohol-treated animals, the transition temperature was lowered to a value similar to that of controls. Fluorescence studies with l-anilinonaphthalene-8-sulfonate (ANS) demonstrate that ethanol induces a decrease in the fluorescence of ANS bound to brain synaptic membranes. This decrease in fluorescence is less than when these membranes are derived from chronically ethanol-treated rats. Also, when the synaptosomal enzymes were exposed to exogenous agents such as detergents, the enzyme obtained from alcohol-treated rats was more stable than that from control rats. These findings indicate a protein conformation change, probably due to the alteration of the physical properties of membrane lipids following chronic ethanol administration. These findings also demonstrate that there is a resistance to the effect of ethanol in membranes of animals habituated to ethanol that may be related to the adaptative modifications that underlie tolerance to and physical dependence on alcohol.
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PMID:Chronic ethanol treatment affects synaptosomal membrane-bound enzymes. 631 83

In mice ascorbate, when co-administered with morphine, suppresses the development of tolerance and physical dependence on the drug, without significantly affecting its analgesic properties as inferred from unaltered ED50 values. The duration of morphine-induced analgesia, however, is progressively reduced with an increase in the amounts of ascorbate. Ascorbate at 1g/kg body weight does not alter the pH of blood, and has no effect on the levels of lipid-peroxides in blood and brain. Studies presented in this paper suggest the potential use of ascorbate in the prevention of development of tolerance in therapeutic applications of narcotics as analgesics. Cultured Neuroblastoma X Glioma hybrid cells (NG 108-15) respond to opiates in two different ways. The rapid receptor mediated inhibition of adenylate cyclase is followed by a long-lived compensatory increase in its activity (1-4). In a recent report (5) we have shown that ascorbate suppresses the delayed etorphine-induced compensatory increase in cAMP levels in NG 108-15 cells without affecting the short-term inhibitory response of cells to the drug. It has been suggested that while the former may be the basis of narcotic dependence and tolerance, the latter is responsible for the analgesic effect. These observations, based on a model system, prompted us to examine the effect of ascorbate on the pharmacological properties of morphine at the organismal level.
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PMID:Megadoses of vitamin C prevent the development of tolerance and physical dependence on morphine in mice. 668 37

After the intravenous injection of butorphanol or norbutorphanol in rats every 1 hr for 3 days, naloxone-induced body weight loss and withdrawal syndrome were observed to some degree. A slow-released emulsion containing each of the test drugs was injected subcutaneously in guinea-pigs, and naloxone was administered after 2 or 3 days. BT caused little jumping response even at a dose of 600 mg/kg, and the reaction was significantly weaker than that of pentazocine. No jumping responses were recognized in the cases of NB (600 mg/kg). In morphinized rats, the injection of BT or HB caused potent body weight loss, and these rats exhibited withdrawal syndrome which was more potent than that by pentazocine at the same dose. The body weight losses by the injection of NB and pentazocine were to the same degree, and these changes were significantly different from that of the saline control. BT inhibited the adenylate cyclase activity of the rat caudate nuclei, and the effect was weaker than that of pentazocine. NB showed a slight inhibition, and HB had no effect on the activity. These results suggest that the physical dependence liability of butorphanol is less than that of pentazocine, and the potent mu-antagonistic character of butorphanol is based on the liability. NB, a mu-agonist, makes dependence production possible. The ability of HB is negligible.
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PMID:[Physical dependence liabilities of butorphanol, a narcotic antagonist, and its main metabolites, norbutorphanol and hydroxybutorphanol]. 668 28

The existence of mu, delta and kappa opioid receptors in the central nervous system is well documented. The present review focuses on the relationships between opioid receptor types and physical and psychic dependences. Mu and delta, but not kappa opioid receptor agonists produce physical dependence. From behavioral, biochemical and molecular biological studies, it is suggested so far that development of physical dependence on morphine results predominantly from an activation of mu 1 and mu 2 opioid receptors which causes functional changes in Gi/o, adenylate cyclase, protein kinases A and C, beta-adrenoceptor and NMDA receptor in the locus coeruleus. Recently, there have been significant advances in studies on psychic dependence. Mu and delta opioid receptor agonists produce psychic dependence, but kappa opioid receptor agonists rather produce an aversive effect. Activation of the mesolimbic dopamine system may lead to psychic dependence on opioids. Mu and delta 1 opioid receptor agonists activate the mesolimbic dopamine system to induce a rewarding effect, whereas the rewarding effect of delta 2 opioid receptor agonists may be produced through a non-dopaminergic system. There are complicated interactions among opioid receptor types. The activation of kappa opioid receptor suppresses physical and psychic dependences on mu and delta opioid receptor agonists, but the activation of delta opioid receptor potentiates the dependence on mu opioid receptor agonists. The clinical use of morphine in patients with cancer pain won't develop dependence probably due to the balance of the opioid system coming from these interactions.
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PMID:[Opioid receptor types and dependence]. 916 Mar 46

These studies were designed to examine the effect of chronic administration of pentobarbital on activity of adenylate cyclase (AC) and protein kinase C (PKC) in the rat brain by autoradiography. Recently, it has been suggested that the phosphorylation of specific proteins may be involved in the development of physical dependence. An experimental model of barbiturate tolerance and dependence was developed using i.c.v. infusion of pentobarbital (300 microg/10 microl/hr for 7 days) by osmotic minipumps and abrupt withdrawal from pentobarbital. The levels of [3H]forskolin binding were elevated (28-67%) in cortex, thalamus, dentate gyrus, hippocampal CA3 and cerebellum of the pentobarbital withdrawal animals, while these changes were not observed in tolerant rats. The levels of [3H]phorbol dibutyrate binding were highly elevated (38-65%) in the region of cortex, caudate putamen, septum, thalamus, dentate gyrus, and cerebellum of rats withdrawal from pentobarbital. These results show that the levels of AC and PKC were significantly elevated in pentobarbital withdrawal rats, and suggest that the levels of AC and PKC are altered in a region-specific manner during pentobarbital withdrawal.
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PMID:Changes in [3H]forskolin binding to adenylate cyclase and [3H]phorbol dibutyrate binding to protein kinase C in pentobarbital tolerant/dependent rats. 956 79

Acute morphine administration produces analgesia and reward, but prolonged use may lead to analgesic tolerance in patients chronically treated for pain and to compulsive intake in opioid addicts. Moreover, long-term exposure may induce physical dependence, manifested as somatic withdrawal symptoms in the absence of the drug. We set up three behavioral paradigms to model these adaptations in mice, using distinct regimens of repeated morphine injections to induce either analgesic tolerance, locomotor sensitization or physical dependence. Interestingly, mice tolerant to analgesia were not sensitized to hyperlocomotion, whereas sensitized mice displayed some analgesic tolerance. We then examined candidate molecular modifications that could underlie the development of each behavioral adaptation. First, analgesic tolerance was not accompanied by mu opioid receptor desensitization in the periaqueductal gray. Second, cdk5 and p35 protein levels were unchanged in caudate-putamen, nucleus accumbens and prefrontal cortex of mice displaying locomotor sensitization. Finally, naloxone-precipitated morphine withdrawal did not enhance basal or forskolin-stimulated adenylate cyclase activity in nucleus accumbens, prefrontal cortex, amygdala, bed nucleus of stria terminalis or periaqueductal gray. Therefore, the expression of behavioral adaptations to chronic morphine treatment was not associated with the regulation of micro opioid receptor, cdk5 or adenylate cyclase activity in relevant brain areas. Although we cannot exclude that these modifications were not detected under our experimental conditions, another hypothesis is that alternative molecular mechanisms, yet to be discovered, underlie analgesic tolerance, locomotor sensitization and physical dependence induced by chronic morphine administration.
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PMID:Morphine-induced analgesic tolerance, locomotor sensitization and physical dependence do not require modification of mu opioid receptor, cdk5 and adenylate cyclase activity. 1808 50


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