Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The additive drugs alcohol, morphine, cocaine, and amphetamine are each associated with the development of tolerance and physical dependence. Changes in gene expression occur in cell culture and in vivo with the administration of these centrally-acting drugs. This article reviews those experiments that have studied drug-induced alterations in gene transcription. Ethanol has diverse effects on the amounts of messenger RNA molecules within the central nervous system. Ion channels, neuropeptides, membrane receptors, and immediate early genes represent several regulated mRNAs. The effects are selective, however, as many other specific products are not altered. Evidence for a genetic predisposition to ethanol use reinforces the importance of the genotype. Opioids, cocaine, and amphetamine also affect gene transcription. Messenger RNAs studied have included many of those demonstrated to be altered by alcohol use. Interestingly, use of any of these drugs alters the expression of immediate early genes. These genes may represent an initial step in the pathway that leads to drug addiction. The composite of drug-induced changes in gene expression results in the cellular responses of tolerance and dependence. The characterization of these changes should provide a better understanding of the molecular mechanisms of drug addiction.
Mol Neurobiol 1991
PMID:The molecular biology of addictive drugs. 172 3

Intracellular recordings of membrane potassium current were made from rat locus coeruleus in vitro. The effects of agonists at mu-opioid receptors were studied on neurons from rats that had been chronically treated with morphine; these were compared with actions on neurons from control rats. Tolerance to the opioid-induced increase in potassium conductance was observed, and this was more pronounced for normorphine than for [Met5]enkephalin and [D-Ala2, Mephe4, Gly5-ol]enkephalin: experiments with the irreversible receptor blocker beta-chlornaltrexamine indicated that normorphine had lower intrinsic efficacy than [Met5]enkephalin and [D-Ala2 MePhe4, Gly5-ol]enkephalin. This adaptation was not due to any change of the properties of the potassium conductance activated by mu-receptors because both full and partial agonists at alpha 2-adrenoceptors, which couple to the same potassium conductance, were unchanged in their effectiveness; nor was it associated with any change in the affinity of mu-receptors for the antagonist naloxone. Naloxone had no effect on the neurons other than simple competitive reversal of the action of the mu-receptor agonists. These results demonstrate that 1) the mechanism responsible for tolerance in locus coeruleus neurons is specifically associated with mu-receptors and/or their coupling to potassium channels, 2) the intrinsic efficacy of an opioid determines the degree of tolerance observed, and 3) tolerance and physical dependence can be dissociated at the cellular level.
Mol Pharmacol 1987 Nov
PMID:Cellular mechanisms of opioid tolerance: studies in single brain neurons. 282 80

The effects of ethanol ingestion on the lipids of the synaptic plasma membrane (SPM) have been measured and correlated with the time frame for the development of physical dependence. Alterations were observed in three of the phospholipid fractions: phosphatidylcholine (PC) increased, and the phosphatidylethanolamine (PE) and phosphatidylserine (PS) plus phosphatidylinositol (PI) fractions decreased. These alterations occurred after the animals showed signs of dependence. Because PC can be synthesized from PE by the methyltransferase pathway, synaptosomal methyl group incorporation was measured. Rats were fed ethanol for 6 days before an increase was observed in methyl incorporation, a shorter length of time than was necessary to demonstrate physical dependence or phospholipid alterations (10 to 14 days). After ethanol withdrawal, 7 days of control diet feeding were required for methyl group incorporation to return to control values. In vitro ethanol (10-250 mM) additions to the methyltransferase incubations resulted in a slight increase in methyl incorporation. These data suggest that synaptic membrane lipid alterations may be related to ethanol dependence and that changes in the PC/PE ratio may be the result of an increase in the incorporation of methyl groups into synaptosomal phospholipids.
Mol Pharmacol 1985 Feb
PMID:Ethanol-induced alterations in rat synaptosomal plasma membrane phospholipids. Relationship to changes in the phospholipid methyltransferases. 403 42

Previous studies have implicated the N-methyl-D-aspartate receptor (NMDAR) complex in the physical dependence and withdrawal effects of chronic ethanol administration. In this study, we examined the effect of chronic ethanol administration and ethanol withdrawal on the NMDAR subunit R1, R2A, R2B, and R2C mRNA levels in rat hippocampus, cerebral cortex, and cerebellum. Using the RNase protection assay, we compared the levels of the NMDAR subunits mRNAs in ethanol-treated and control rats. Our results indicate that chronic ethanol administration and ethanol withdrawal do not change the NMDAR R1 subunit mRNA levels in cerebral cortex, hippocampus, or cerebellum at any time point. In contrast, 9 h after the last ethanol administration the R2A and R2B mRNA subunits were elevated by approximately 40% in cerebral cortex, and approximately 30% in hippocampus with respect to the levels in control animals. At 48 h the mRNA levels returned to the control levels. The chronic ethanol treatment did not alter R1, R2A, and R2C subunit mRNA levels in cerebellum. Our results demonstrate that chronic ethanol administration produces a differential regulation of the genes encoding the various subunits of the NMDAR.
Brain Res Mol Brain Res 1995 Mar
PMID:Chronic ethanol treatment differentially regulates NMDA receptor subunit mRNA expression in rat brain. 777 6

Morphine dependence is a long lasting form of neuronal plasticity. Naloxone-precipitated morphine withdrawal, a model of opioid dependence, induces brain region-specific changes in activator protein-1 (AP-1) transcription factor gene expression. Rapid increases in c-fos, fos-B, jun-B, and c-jun mRNA levels accompany withdrawal, with the relative level of induction correlating with the severity of physical dependence. Altered patterns of c-fos mRNA expression were limited to neuronal circuits mediating stress responses, motivation, and cognition. AP-1 DNA-binding activity and dimer composition also exhibited regulation after withdrawal, presumably as a result of both transcriptional and post-translational events. Thus, morphine dependence results in the alteration of diverse, brain region-specific, signal transcription pathways involving AP-1 transcription factors.
Mol Pharmacol 1995 Jan
PMID:Precipitated morphine withdrawal stimulates multiple activator protein-1 signaling pathways in rat brain. 783 31

The effect of acute and chronic morphine administration on calbindin-D28K (calbindin) gene expression has been studied. One group of adult male rats received a single injection of morphine (10 mg/kg, s.c.) or saline and were sacrificed 1 or 4 h later. Another group was injected with escalating doses of morphine sulfate twice daily for 15 days to induce tolerance and physical dependence. Rats were sacrificed 1 h after the last injection. In a third group, the effect of naloxone-precipitated withdrawal on gene expression in morphine-addicted rats was also analyzed 1 h after naloxone (1 mg/kg, i.p.). The cerebellum and remaining brain (minus the cerebellum) were removed, and total RNA was extracted and used for analysis. Calbindin mRNA levels in cerebellum were decreased to 30%-40% control at 1 and 4 h after a single morphine injection. Co-administration of the opiate antagonist, naloxone, reversed the effect of morphine. Tolerance developed to the acute effects in that levels were not altered significantly 1 h after morphine injection in chronically-treated rats. Unlike the cerebellum, calbindin mRNA in the remainder of the brain (minus the cerebellum) was unchanged 1 and 4 h following morphine administration to drug-naive rats, but was increased more than 2-fold compared to controls 1 h after morphine injection in chronically treated animals. Naloxone-precipitated withdrawal caused a small (20%) but significant decrease in calbindin mRNA in the cerebellum, with no change in the brain (minus the cerebellum).(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1994 Apr
PMID:Regulation of calbindin-D28K gene expression in response to acute and chronic morphine administration. 802 77

The molecular mechanisms associated with ethanol-induced tolerance and physical dependence have yet to be elucidated. In previous studies we have demonstrated that chronic ethanol administration produced a decrease in the GABAA receptor mRNA level of alpha 1, alpha 2, alpha 5 subunits, and a decrease in the polypeptide (alpha 1, alpha 2, and alpha 3) expression in the rat cerebral cortex. In this study we examined the effect of chronic ethanol treatment on the mRNA levels and the expressions of the beta-subunits of the GABAA receptors in rat cerebral cortex. The results indicate that chronic ethanol administration produced an upregulation of the beta 1 subunit mRNA (12 kb) by 29 +/- 10%, beta 2 mRNA (8 kb) by 55 +/- 6% and the beta 3-subunit (6 kb) mRNA by 72 +/- 9% in cerebral cortex. The levels of the beta 2 and beta 3 subunit mRNAs remains elevated at 24 hr withdrawal. We also investigated the effect of chronic ethanol administration on the beta-subunit polypeptide expression using monoclonal antibody BD17, which recognizes the beta 2 (P56) and beta 3 (P58) polypeptides. Chronic ethanol treatment increased the levels of both of these polypeptides in cerebral cortex. Taken together, chronic ethanol administration produced an upregulation of the beta-subunit mRNA and the polypeptide expression of these subunits in rat cerebral cortex. In contrast, chronic ethanol treatment decreased the expression of various alpha-subunits in the cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1994 May
PMID:Chronic ethanol treatment upregulates the GABA receptor beta subunit expression. 805 81

Male Mol: SPRD rats were treated with 5 or 20 mg/kg of diazepam for 4 days. The treatment was repeated at two different ages. Diazepam was either dissolved in Intralipid (KABI, Sweden) or dispersed in gummi arabicum. Tolerance induced by the treatment was tested with an EEG-threshold technique where hexobarbital was infused intravenously on day 1, 4, 7 and 14 of the abstinence. The threshold was the dose of hexobarbital needed to induce a burst suppression of 1 sec. or more (silent second). After the first diazepam treatment significant increase in the hexobarbital threshold doses were recorded in all but one of the diazepam treated groups. The pattern varied depending on dose, age and solvent. After the second treatment tolerance was seen only when diazepam had been dissolved in Intralipid. Short term treatment with diazepam can induce cross-tolerance to hexobarbital which probably is due to an increased excitation (physical dependence) in abstinence after treatment with diazepam.
 ...
PMID:Tolerance to hexobarbital induced by short-term treatments with diazepam and tested with an EEG-threshold test in male rats. 847 66

Melanocortin peptides are reported to antagonize opiate dependence and tolerance, but the neural substrates underlying these actions are unknown. In this study, we characterize the rat melanocortin-4 receptor (MC4-R) and demonstrate that this receptor is regulated by opiate administration. The rat MC4-R is 95% identical to the human MC4-R, and the potency of melanocortin peptides to stimulate cAMP production is similar in these two species homologs (alpha-melanocyte-stimulating hormone = adrenocorticotropic hormone > gamma-melanocyte-stimulating hormone). Expression of MC4-R mRNA was found to be enriched in the striatum, nucleus accumbens, and periaque-ductal gray, all of which are regions implicated in the behavioral effects of opiates. In contrast, MC1-, MC3-, and MC5-R are expressed at very low or undetectable levels in these brain regions. Chronic administration of morphine (5 days) resulted in a time-dependent down-regulation of MC4-R mRNA expression in the striatum and periaqueductal gray. Expression of MC4-R mRNA was also decreased in the nucleus accumbens/ olfactory tubercle, but this effect was observed after 1 or 3 days of morphine treatment. In the striatum, the reduction of MC4-R mRNA was accompanied by a concomitant decrease in melanocortin receptor levels, shown by quantitative radioligand binding and autoradiography. In contrast, morphine administration did not influence levels of MC4-R mRNA in several other brain regions, including frontal cortex, olfactory bulb, hypothalamus, and ventral tegmentum/substantia nigra. In light of previous findings that melanocortins antagonize opiate self-administration, analgesic tolerance, and physical dependence, we hypothesize that decreased melanocortin function, via down-regulation of MC4-R expression, may contribute to the development of these opiate-induced behaviors.
Mol Pharmacol 1996 Sep
PMID:Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction. 879 97

Chronic ethanol treatment of mice has been shown to result in increased binding of dizocilpine and glutamate to hippocampal NMDA receptors. These changes were suggested to reflect an increase in NMDA receptor number that may underlie certain signs of the ethanol withdrawal syndrome. However, there was no change in binding of a competitive NMDA receptor antagonist, or of ligand binding to the glycine co-agonist site on the receptor after chronic ethanol treatment. Differential changes in the binding of particular ligands at the NMDA receptor suggested the possibility that chronic ethanol ingestion might selectively affect the expression of particular NMDA receptor subunits. Our current work demonstrates that chronic ethanol ingestion by mice, which results in the generation of physical dependence, also produces increases in the NMDA receptor NR1 subunit protein in the hippocampus and cerebellum (approximately 50% and 95%, respectively), and produces increases in the NR2A subunit protein in the hippocampus and cortex (approximately 25% and 40%, respectively). However, the mRNA levels for these subunits were not increased in the respective brain areas by the same ethanol treatment. The changes in NMDA receptor subunit expression in discrete areas of the brain may contribute to the previously observed changes in ligand binding and, possibly, signs of ethanol withdrawal.
Brain Res Mol Brain Res 1996 Aug
PMID:Regional and subunit specific changes in NMDA receptor mRNA and immunoreactivity in mouse brain following chronic ethanol ingestion. 884 15


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