Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pentylenetetrazol (PTZ) and sodium valproate (VPA) produce acutely in the naive rat various behavioural effects resembling signs of opiate withdrawal in the morphine-treated subject. Suggestions in the literature that these substances may activate directly some of the neural consequences of opiate and drug withdrawal prompted us to look for and examine possible aversive effects of these substances at non-toxic doses. With a sensitive two-flavour, three-trial taste aversion procedure, relatively low doses of PTZ and VPA (5 and 160 mg/kg, respectively) do indeed have aversive effects. The maximum aversions were produced by 10 and 20 mg/kg PTZ and 320 mg/kg VPA and were equivalent to those of morphine withdrawal precipitated by 0.01-0.03 mg/kg naloxone in a morphine pellet-implanted animal. Moreover, the maximum aversions with PTZ and VPA were significantly higher than the maximum aversions seen with naloxone in the drug-naive animal under the same training conditions. Thus, the data from the present study confirmed the notion that low doses of PTZ and VPA in the naive animal may activate processes activated by drug withdrawal, including those important for the motivational effect of withdrawal. However, it was also pointed out that the lowest dose VPA producing aversion was higher than that found here to produce writhes and ataxia (80 mg/kg) but the same as that required for shaking (160 mg/kg), while the PTZ aversion was at a dose lower than that known to produce a PTZ cue. Implications were discussed for using withdrawal-like phenomena as a model in the non-treated organism of clinically-relevant withdrawal effects.
Drug Alcohol Depend 1995 Jul
PMID:Withdrawal-like effects of pentylenetetrazol and valproate in the naive organism: a model of motivation produced by opiate withdrawal? 758 68

Imidazenil is a highly potent partial allosteric modulator of gamma-aminobutyric acid action at a great variety of gamma-aminobutyric acid(A) receptors, whereas alprazolam is a full allosteric modulator at these receptors. Data in rats indicate that imidazenil, like alprazolam, has pharmacological effects in animals indicative of anxiolytic, antipanic and anticonvulsant activity in humans, but unlike alprazolam, in animals imidazenil does not produce ataxia, sedation, tolerance or dependence nor does it potentiate the effects of ethanol. To extend the study of the imidazenil pharmacological profile, we administered this drug and alprazolam, alone and in combination, in monkeys working in a complex behavioral task. In one component of a multiple schedule (repeated acquisition or "learning"), patas monkeys acquired a different four-response chain each session by responding sequentially on three keys in the presence of four discriminative stimuli (geometric forms or numerals). In the other component (performance), the four-response chain was the same each session. The response chain in each component was maintained by food presentation under a fixed-ratio schedule. When alprazolam (0.01-0.32 mg/kg, p.o.) was administered alone, the overall response rate in both learning and performance decreased and the percent errors in both components increased with increasing doses. Learning, however, was more sensitive than performance; i.e., error-increasing effects were seen in learning at doses that had no effect on performance accuracy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Imidazenil, a new anxiolytic and anticonvulsant drug, attenuates a benzodiazepine-induced cognition deficit in monkeys. 779 Nov 2

Up to now, clinical predictors for the course of the alcohol withdrawal syndrome, especially for the occurrence of a delirium, are lacking. Thus, this study was undertaken to examine whether clinical routine investigations at admission before the withdrawal syndrome can reveal factors indicating a higher risk for the development of a delirium. Our results showed that decreased serum electrolyte concentrations (i.e., chloride and potassium), elevated ALT, and gamma-glutamyltransferase serum levels, as well as ataxia and polyneuropathy at the neurological examination, indicate a higher risk for the development of an alcohol withdrawal delirium.
Alcohol Clin Exp Res 1994 Oct
PMID:Clinical predictors of alcohol withdrawal delirium. 784 90

To study the role of the striatum in modulating the effects of adenosine agonists and benzodiazepine inverse agonists on acute ethanol-induced motor impairment, we evaluated the effect of direct intrastriatal Ro15-4513 [0.625, 1.25 and 2.5 ng], a partial inverse agonist of benzodiazepine receptor, on ethanol-induced motor incoordination. A significant and nearly dose-dependent antagonism by Ro15-4513 was observed, which suggests involvement of the striatum in ethanol-induced motor incoordination. No effect of IST Ro15-4513 on motor incoordination induced by Na-pentobarbital (10 mg/kg, i.p.) was noted, indicating the selectivity of the antiethanol action of Ro15-4513. The IST adenosine agonist N6-cyclohexyladenosine (CHA) markedly accentuated ethanol-induced motor incoordination in a dose-related manner, suggesting a striatal adenosinergic modulation of ethanol-induced motor incoordination. The IST Ro15-4513 also significantly antagonized the accentuating effects of CHA on ethanol-induced motor incoordination. No change in normal motor coordination was observed after IST CHA or Ro15-4513 when followed by saline administration instead of ethanol. No accentuating effect by intrahippocampal CHA on ethanol-induced motor incoordination was seen, which suggests the selectivity of striatal adenosinergic modulation of ethanol-induced motor incoordination. There was no significant radioactivity present in the systemic circulation, in the CSF or in brain areas other than striatum after intrastriatal [3H]Ro15-4513 or [3H]CHA and ethanol injection. Data obtained so far support the involvement of striatum in ethanol's ataxia as well as striatal adenosinergic modulation of the central effect(s) of ethanol, possibly through Ro15-4513-sensitive mechanism(s).
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PMID:Intrastriatal Ro15-4513 functionally antagonizes ethanol-induced motor incoordination and striatal adenosinergic modulation of ethanol-induced motor incoordination in rats. 796 52

The behavioral pharmacology of tandospirone (SM 3997), a novel anxiolytic/antidepressant pyrimidinylpiperazine compound with selective pharmacological effects at the 5-HT1A binding site, was investigated in baboons. Animals administered 50 mg/kg/day i.g. tandospirone, showed few behavioral changes (lip droop, ataxia), which decreased over 2 weeks. Substitution of vehicle for tandospirone after 7 weeks produced time-limited suppression of food intake, suggesting a mild withdrawal syndrome. Under an i.v. self-injection procedure, tandospirone (1.0-32 mg/kg/injection) did not maintain responding greater than vehicle, although cocaine and triazolam did. Under a drug discrimination procedure, tandospirone (1-3.2 mg/kg p.o.; 0.1-32 mg/kg, i.m.) did not occasion drug-appropriate responding in baboons trained to discriminate lorazepam or pentobarbital and buspirone (1-18 mg/kg, p.o.; 0.1-1.0 mg/kg, i.m.) did not occasion drug-appropriate responding in the pentobarbital-training group. Tandospirone's profile of effects differs from those for barbiturates and benzodiazepines and suggests low abuse liability.
Drug Alcohol Depend 1993 May
PMID:Behavioral pharmacology of tandospirone in baboons: chronic administration and withdrawal, self-injection and drug discrimination. 810 30

Mice from 15 inbred strains differed in sensitivity to ethanol-induced effects on open-field activity, hypothermia, rotarod ataxia, and anesthesia. Sensitivities to the different behavioral responses were generally uncorrelated. This suggests that the genetic determinants of behavioral sensitivity to one domain of ethanol effects are unrelated to those determining other responses. On the other hand, some variables were genetically related. For example, those strains sensitive to the loss of righting reflex induced by higher doses of ethanol showed reduced activity in the open field at lower doses and were more sensitive to ethanol-induced decreases in rearing. More generally, the pattern of results suggests that genetically influenced sensitivity to ethanol is not a monolithic phenomenon. Rather, it is specific to the particular response variable studied.
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PMID:Genetic determinants of sensitivity to ethanol in inbred mice. 819 44

Female F344 rats of three different ages (4, 13, and 25 months) were tested for sensitivity to the ataxic, hypothermic, and hypnotic effects of injected ethanol. Challenges with ethanol sufficient to produce similar blood alcohol concentrations (BACs) in all age groups at the time of testing were observed to produce greater ataxia in old rats (25 months > 13 months > 4 months). Old rats also were observed to recover the righting reflex at lower BACs than those present in young or middle age rats. BAC at a target rectal temperature of 36 degrees C was observed to be lower in old than in young or middle-age rats when measured as body temperature was falling after doses of 3.0 g/kg to old and 3.5 g/kg to young and middle rats. However, no differences among groups in BAC at target temperature (36 degrees C) were observed as body temperature was recovering from peak hypothermia back up to 36 degrees C. With the exception of the last observation cited, these findings appear to confirm and extend earlier reports of increased target tissue sensitivity to ethanol with advancing age in rodents.
Alcohol Clin Exp Res 1993 Aug
PMID:Age-related differences in sensitivity to alcohol in the rat. 821 28

Consumption of large amounts of ethanol (EtOH) in a single drinking episode is common, but very little is known about the immunological effects of such occurrences. Exposure to EtOH for several days is immunosuppressive in rodent models, and a single dose of EtOH causes substantial increases in endogenous glucocorticoid levels which might have immunosuppressive effects. In the present study, the effects of a single dose of EtOH on the thymus and the role of endogenous glucocorticoids in these effects were examined in B6C3F1 female mice. A single dose of EtOH decreased thymus weight and cellularity, predominantly by elimination of CD4+CD8+ (immature) thymocytes. This occurred over a broad range of EtOH doses and was associated with behavioral effects (ranging from mild ataxia to unresponsiveness) similar to those noted in human binge drinkers. Several lines of evidence indicate that the effects of EtOH on the thymus are mediated by endogenous glucocorticoids: (1) corticosterone levels in EtOH-treated mice increased more than 10-fold and remained significantly elevated for up to 12 hr; (2) the most glucocorticoid-sensitive thymocytes (CD4+CD8+ cells) were preferentially depleted by EtOH; (3) before thymocyte depletion was evident, substantial DNA fragmentation occurred in the thymus as would be expected in the case of glucocorticoid-induced apoptosis; (4) the glucocorticoid antagonist, RU 486, blocked thymic atrophy and DNA fragmentation in EtOH-treated mice; (5) EtOH and its major metabolites at concentrations comparable to or greater than expected in vivo did not decrease thymocyte viability in 20-hr cultures, indicating that direct action of EtOH or its metabolites on thymocytes does not play an important role in EtOH-induced thymic atrophy. These results suggest that a single dose of EtOH induces thymic atrophy which is predominantly mediated by increased levels of endogenous glucocorticoids. The mouse model described here should be useful in evaluating other effects of binge drinking on the immune system, and the experimental strategy described should be applicable in investigating the role of endogenous glucocorticoids in thymic atrophy induced by other chemicals and drugs.
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PMID:Thymic atrophy caused by ethanol in a mouse model for binge drinking: involvement of endogenous glucocorticoids. 823 55

The purpose of present experiment was to investigate the pharmacological effects of ethanol on morphine tolerant rats. We found that chronic morphine injection diminished the duration of ataxia induced by ethanol in rats. Using enzymatic and spectrophotometric methods, we found that chronic injection of morphine did not affect the metabolism of ethanol. On the other hand, the sensitivity to ethanol was decreased in the cerebellar Purkinje neurons. These suggested that behavior tolerance to ethanol in chronic morphine treated rats may possibly involve the desensitization of ethanol in the CNS.
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PMID:Chronic morphine treatment diminished ethanol mediated responses in the CNS. 828 14

Positive allosteric modulators of gamma-aminobutyric acid (GABA)A receptors, including benzodiazepines and congeners, can be classified into three categories: 1) full allosteric modulators (i.e., triazolam and alprazolam) that act with high potency and efficacy at many GABAA receptors; 2) selective allosteric modulators (i.e., diazepam) that act with high potency and high efficacy at selected GABAA receptors; and 3) partial allosteric modulators (i.e., bretazenil) that act with high potency but low efficacy at many GABAA receptors. Imidazenil, an imidazobenzodiazepine carboxamide, has been characterized as a novel representative of the partial allosteric modulator class. When tested on a broad spectrum (native and recombinant) of GABAA receptors, imidazenil positively modulates the GABA-elicited Cl- currents with a 4- to 5-fold higher potency but an efficacy (30-50%) lower than that of diazepam, and it antagonizes the effects of the latter drug. Imidazenil in vitro (Ki = 5 x 10(-10) M) and in vivo (ID50 = 0.2 mumol/kg i.v.) displaces [3H]flumazenil from its brain binding sites and in vivo it possesses a marked anticonflict profile in the rat Vogel conflict-punishment test and is 10 times more potent than bretazenil and 100 times more potent than diazepam or alprazolam in antagonizing bicuculline- and pentylenetetrazol-induced seizures. Unlike diazepam and alprazolam, which induce sedation and ataxia and potentiate the effects of ethanol and thiopental at doses similar to those that produce anticonflict effects and occupy 50% of brain flumazenil binding sites, imidazenil does not produce ataxia or sedation in rats nor does it potentiate the effects of ethanol or thiopental in doses 30- to 50-fold higher than those required for the anticonflict effect and for 100% occupancy of brain flumazenil binding sites. Furthermore, when administered with diazepam, imidazenil blocks in a dose-related fashion the sedative, ataxic effects of this drug and thus acts on these unwanted responses as an antagonist (i.e., like flumazenil). In all tests, imidazenil has the pharmacological profile of a partial allosteric modulator, but is more potent than bretazenil, has a longer biological half-life and, in rodents, is virtually unable to cause sedation, ataxia or to potentiate ethanol toxicity.
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PMID:Imidazenil: a new partial positive allosteric modulator of gamma-aminobutyric acid (GABA) action at GABAA receptors. 839 2


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