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)

There was no overt evidence of the development of physical dependence, as shown by a decrease in the body weight of rats following the abrupt withdrawal of dextropropoxyphene after two weeks administration. The ambulation and rearing scores in the 'open field' apparatus were increased after chronic, but not acute drug administration and returned to control values two days following drug withdrawal. GABA turnover, determined from the rise in GABA concentrations following GABA-transaminase inhibition, was reduced in the frontal and amygdaloid cortex after acute and chronic drug administration; a compensatory rise in GABA turnover in the amygdaloid cortex occurred two days after drug withdrawal. Na+, K+, ATP'ase activity, determined in a synaptosomal fraction from the mid-brain and hippocampus, was decreased in the latter region only during drug administration; a compensatory increase in the activity of this enzyme was found two days after drug withdrawal. These results support the view that chronically administered dextropropoxyphene may cause changes in inhibitory transmission and central neurotransmitter transport.
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PMID:Acute and chronic effects of dextropropoxyphene on behaviour and central inhibitory neurotransmission in the rat. 299 72

The previously-observed attenuation of withdrawal reactions in mice (group B) fed an ethanol diet containing chlordiazepoxide (CDP) was not due to a difference in the rate of disappearance of blood ethanol levels during chronic diet treatment in group B compared to mice which received only the ethanol diet (group A). Injection of group A mice with CDP or N-demethyl CDP (10 mg/kg) at the time of diet withdrawal did not result in any significant attenuation of withdrawal scores. Injection of the lactam metabolite of CDP (LCDP; 10 mg/kg) resulted in significantly attenuated withdrawal scores at 4 and 6 hr only, but the pattern of withdrawal scores were different from that for group B mice. Moreover, blood LCDP level, in mice injected with LCDP, at 4 hr was at least five times higher than that attained in group B mice (from diet containing CDP). These results support our previous conclusion that the presence of major metabolites of CDP during withdrawal could only account for a minor contribution to the protective effect. Mice in A and B did not differ in the degree of functional tolerance which developed as a result of ethanol intake. Thus, there was an apparent dissociation between tolerance and physical dependence in the mice which had consumed the CDP/ethanol diet. The magnitude of decrease of GABA levels in the cerebellum and cerebral cortex at 4 hr after withdrawal also did not differ between the two groups, suggesting the reduction in GABA levels could not be correlated with the intensity of withdrawal signs.
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PMID:Dissociation of tolerance and physical dependence after ethanol/chlordiazepoxide intake. 689 92

We studied the differences in alterations of GABAAergic receptor function between pentobarbital (PB)-dependent female Lewis (LEW) and Wistar-Kyoto (WKY) rats. The 36Cl- influx induced by 10 microM GABA in the PB-dependent WKY was significantly lower than that in the control, while there was no significant 36Cl- influx change in both PB-dependent and control LEW. The additions of PB, flunitrazepam (FZ) and ethanol (EtOH) enhanced the GABA-dependent 36Cl- influx in control rats of both strains. However, the enhancements of 36Cl- influx by PB, FZ, EtOH were not recognized in PB-dependent WKY. On the other hand, the enhancement of GABA-dependent 36Cl- influx was observed only with the addition of PB in PB-dependent LEW. The additions of bicuculline (BIC) and picrotoxin (PIC) inhibited GABA-dependent 36Cl- influx in control rats of both strains. However, inhibition of 36Cl- influx by BIC and PIC was not recognized in the PB-dependent WKY. These results suggest that physical dependence on PB in WKY may cause greater functional alterations of the GABA/benzodiazepine receptor complex than those in LEW, and that these changes in this receptor complex may relate to the difference in the development of physical dependence on PB between the two strains.
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PMID:[Changes in GABAA/benzodiazepine receptor complex function in the pentobarbital-dependent rat. II: Strain differences between Lewis and Wistar-Kyoto rats]. 758 29

Alcohol is known to be a CNS teratogenic factor interfering with neuronal and synaptic maturation. The purpose of this microiontophoretic study was to explore GABAergic and cholinergic central mechanisms in adult rats exposed to alcohol in the third phase of prenatal life (ADM), when their mothers were subjected to alcohol physical dependence induction (9.6 g/kg/day). Responses to acetylcholine and GABA were recorded in frontal and somatosensory cortical neurons. Adult rats, whose mothers had been administered placebo with identical procedures, were used as a control (C). Cholinergic responses were significantly decreased and GABAergic responses increased in ADM animals with respect to controls. After a single i.p. alcohol injection (1.6 g/kg) spontaneous firing was depressed in ADM animals to a lesser extent than in C rats. Cholinergic excitations were reduced in C group and potentiated with reversal of atropine antagonism in ADM animals. GABAergic inhibitions were slightly increased and bicuculline antagonism was blocked in C rats, while ADM animals showed decreased responses to GABA. The present results support the hyperactivity of GABAergic system and the hypoactivity of cholinergic system reported in previous studies on prenatally and postnatally alcohol-exposed animals. Microiontophoretic results following ethanol injection led to the hypothesis that a rapid tolerance/dependence may develop in the offspring of alcohol-dependent rats.
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PMID:Alterations of neocortical neuronal responses to acetylcholine and GABA in rats born to alcohol-dependent mothers. 781 46

The benzodiazepine receptor is an allosteric modulatory site present on most, if not all, gamma-aminobutyric acid A (GABAA) receptor channels (GABAA-R). The benzodiazepine receptor recognizes a large spectrum of compounds from different chemical classes that are grouped together as benzodiazepine receptor ligands--of benzodiazepine and non benzodiazepine structure. The GABAA-R is thought to be a heteropentameric protein complex composed of at least three different classes of subunits, with each subunit comprised of up to six structural variants. Binding of GABA to the extracellular domain of the receptor causes a conformational change that opens the channel pore to anions. A classical benzodiazepine achieves a positive allosteric modulation of the GABA channel gating function by increasing the affinity of the receptor for GABA and, possibly, by facilitating the conformational transition from the closed to the open form (benzodiazepine receptor agonists). Inverse agonists of benzodiazepine receptors cause negative allosteric modulation (a decrease in the GABA activity). Benzodiazepine receptor antagonists bind to the benzodiazepine receptor with little effect on GABAA-R functioning. The intrinsic efficacy of benzodiazepine receptor ligands determines the direction and magnitude of allosteric modulation. Benzodiazepine receptor agonists affect neuronal activity in all major neuronal networks. The classical pharmacological profile of benzodiazepine receptor agonists consists of anxiolytic, anticonvulsant, sedative, and myorelaxant activities. Partial agonists of benzodiazepine receptors conserve anxiolytic and anticonvulsant activity, with greatly reduced sedation and muscle relaxation. They promise to present therapeutic advantages, in particular for long term use. In initial studies. they have produced fewer side-effects and showed reduced tolerance development and physical dependence liability.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The multiplicity of actions of benzodiazepine receptor ligands. 830 40

The effect of diazepam on the development of physical dependence on morphine and on the naloxone-precipitated increase in cortical NA turnover were investigated in mice. Co-administration of diazepam (1-4 mg/kg, i.p.) during chronic morphine treatment suppressed the expression of naloxone (3 mg/kg, s.c.)-precipitated withdrawal signs (jumping, exploratory rearing and weight loss). However, a single injection of diazepam (4 mg/kg, i.p.) in morphine-dependent mice did not affect the expression of naloxone-precipitated withdrawal signs. The 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) level and noradrenaline (NA) turnover (MHPG/NA) in the cerebral cortex were increased by naloxone (3 mg/kg) challenge. These increases in the cortical MHPG level and NA turnover were significantly prevented by co-administration of diazepam (4 mg/kg, i.p.) during chronic morphine treatment. These findings suggest that the co-administration of diazepam during chronic morphine treatment may prevent some neurochemical changes in the central noradrenergic system during chronic morphine treatment, and may suppress the development of physical dependence on morphine. Therefore, the inhibitory action of GABA via benzodiazepine binding sites may play an important role in the development of physical dependence on morphine.
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PMID:Diazepam pretreatment suppresses morphine withdrawal signs in the mouse. 853 71

The impact of chronic ethanol treatment, sufficient to induce tolerance and physical dependence, on GABAA receptor function was studied in acutely isolated neurons from the medial septum/nucleus diagonal band (MS/nDB) of adult rats using whole cell, patch-clamp recordings. In ethanol-naive Controls, GABA (0.3-300 microM) induced concentration-dependent increases in Cl- current with a threshold of 0.3-1 microM, a mean maximal current of 7645 +/- 2148 pA at 100-300 microM, an EC50 of 11.3 +/- 1.3 microM and a slope of 1.53 +/- 0.07. GABA-activated currents in neurons from animals receiving two weeks of ethanol liquid diet treatment did not differ significantly on any of these measures. The rate of GABAA receptor desensitization (t1/2 = 6.49 +/- 1.19 s) estimated as the time required for loss of 50% of peak current during sustained application of 10 microM GABA, as well as the residual steady state current remaining following complete desensitization for controls was unchanged by chronic ethanol. The impact of chronic ethanol treatment on the GABAA receptor modulation by lanthanum and zinc which act as positive and negative allosteric modulators, respectively, was also evaluated. Test pulses of 3 microM GABA in control neurons showed maximal potentiation by 141 +/- 30% at approximately 1000 microM lanthanum with an EC50 of 107 +/- 34 microM and a slope of approximately 1. Lanthanum potentiation remained the same following chronic ethanol treatment. Initial estimates based on fitted concentration response curves suggested that maximal inhibition of 3 microM GABA responses by zinc at the level of 70.2 +/- 8.5% in control cells was significantly increased by chronic ethanol treatment to 95.3 +/- 2.5%, although the IC50 of 60.2 +/- 25 microM was not changed. However, this difference was not supported by direct tests of maximal 3-10 mM zinc concentrations. These results suggest that chronic ethanol treatment, sufficient to induce tolerance and physical dependence, probably does not lead to readily detectible changes in GABAA receptor function in MS/nDB neurons.
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PMID:Lanthanum and zinc sensitivity of GABAA-activated currents in adult medial septum/diagonal band neurons from ethanol dependent rats. 878 2

Prolonged occupancy of GABAA receptors by ligands, including GABA and benzodiazepine agonists, sets in motion a series of mechanisms that can be termed use-dependent regulation. These mechanisms can be subdivided into two distinct pathways, one for GABAA receptor downregulation and another for upregulation. Treatment of cortical neurons with GABA or benzodiazepines in cultures opens the pathway for GABAA receptor downregulation, which includes (in putative temporal order): (1) desensitization (tachyphylaxis), (2) sequestration (endocytosis) of subunit polypeptides and uncoupling of allosteric interactions between GABA and benzodiazepine binding sites, (3) subunit polypeptide degradation, and (4) repression of subunit gene expression. The end-point of GABAA receptor downregulation, a reduction in receptor number, is postulated to be established initially by degradation of the receptor protein and then maintained by a diminished level of de novo synthesis. Benzodiazepine treatment of many preparations, including cells expressing recombinant GABAA receptors, may elicit only desensitization, sequestration, or uncoupling, without a decline in receptor number. Components of the GABAA receptor downregulation pathway are also evoked by chronic administration of GABAmimetics, benzodiazepines, barbiturates, and neurosteroids in animals. This downregulation correlates with the establishment of tolerance to and physical dependence on the pharmacological effects of these drugs, suggesting a cellular model for this behavior. The upregulation of GABAA receptors is observed as one of the neurotrophic actions of GABA, primarily in cultured cerebellar granule cells. Upregulation in culture is caused by enhanced expression of genes for GABAA receptor subunits and correlates with the establishment of GABAergic circuitry in the developing cerebellum. Thus, both the upregulation and downregulation of GABAA receptors appear to represent use-dependent pathways for guiding synaptic plasticity in the vertebrate central nervous system.
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PMID:Use-dependent regulation of GABAA receptors. 889 44

This study investigated the ability of the benzodiazepine inverse agonist, Ro 15-4513, to alter the expression of physical dependence on pentobarbital. Male Sprague-Dawley rats were made physically dependent on pentobarbital by continuous. IP, infusion of escalating doses of pentobarbital for 12 days. In Experiment 1, pentobarbital dependent rats received either vehicle or Ro 15-4513, in doses of 5, 10, or 15 mg/kg, IP, periodically during the pentobarbital abstinence period. As expected, Ro 15-4513 produced a significant, dose-dependent, exacerbation of withdrawal signs in the pentobarbital dependent rats. In Experiment 2, either vehicle or Ro 15-4513, at a dose of 15 mg/ kg, was administered, IP, once daily during the 12 days of continuous pentobarbital infusion. During the subsequent pentobarbital abstinence period it was noted that the withdrawal signs were significantly reduced in the rats receiving the daily administration of Ro 15-4513. It is hypothesized that the benzodiazepine inverse agonist, Ro 15-4513, may inhibit the development of physical dependence on pentobarbital through an opposing action on the GABA-A receptor.
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PMID:Ro 15-4513 alteration of pentobarbital dependence. 895 79

PNU-101017 is a chemically novel ligand at the benzodiazepine recognition site of cloned GABAA receptors. It was reported to potentiate GABA-mediated chloride current in cultured cells with a moderate intrinsic activity and a biphasic dose-response relationship. In this study, we confirmed that PNU-101017 has a partial agonist-like effect in the antagonism of metrazole-induced seizures in mice. It produced no sedation or ataxia, but did antagonize diazepam-induced motor deficit of mice in the rotarod test. PNU-101017 was weakly active in anti-conflict anxiolytic tests, but attenuated the plasma corticosteroid response to mild stress in rats. It also antagonized stress-induced elevation of cerebellar cGMP levels in mice. Like chlordiazepoxide, it increased drinking of saline solution in thirsty rats. PNU-101017 did not potentiate the CNS-depressant effects of ethanol, and produced no evidence of physical dependence when administered repeatedly. Agonists with low intrinsic activity at the benzodiazepine receptor, such as PNU-101017, should be further explored for therapeutic uses.
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PMID:Anxiolytic-like effects of PNU-101017, a partial agonist at the benzodiazepine receptor. 920 36


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