Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. T-butyl-bicyclo-phosphorothionate (TBPS) is a prototypical representative of the cage-convulsants which act through a use-dependent block of the GABA(A)-receptor-ionophore complex. Using current recordings from cultured neurones of rat striatum the manner was investigated in which two antagonists, bicuculline and penicillin, presumably acting at the agonist binding site and in the ionic channel, respectively, modify the rate of block by TBPS. 2. Penicillin (5 or 10 mM) did not slow the rate of block by TBPS, but produced a significant enhancement of block rate, which, however, was inversely related to the degree of antagonism by penicillin of the GABA-induced current. 3. Bicuculline (10 microM) reduced the rate of block by TBPS. However, this effect was 3 fold weaker than its GABA-antagonistic action. The slowing of block rate and the current antagonism exhibited a biphasic, positive-negative relationship. Co-application of bicuculline (100 microM) in a concentration that produced nearly complete antagonism and TBPS (10 microM) resulted in a marked ( approximately 40%) reduction of subsequent GABA response amplitudes compatible with a direct, bicuculline-induced conformational change in the receptor required for the binding of and block by TBPS. 4. The lack of protection afforded by the channel blocker penicillin as well as the lack of correlation between bicuculline antagonism of the Cl(-)-current and its efficiency in protecting against TBPS block is evidence against an open channel blocking mechanism for TBPS. TBPS does, therefore, not appear to gain access to its binding site via the open pore but through alternative routes regulated from the agonist binding site.
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PMID:Modulation by bicuculline and penicillin of the block by t-butyl-bicyclo-phosphorothionate (TBPS) of GABA(A)-receptor mediated Cl(-)-current responses in rat striatal neurones. 1069 49

In the framework of the well-known regulatory role of the GABA-benzodiazepine (BZ) mechanisms of the brain in response to social and environmental challenges, we tested the hypothesis that developmental manipulation of this neurochemical system by prenatal BZ exposure can affect the social repertoire and neophobia level in infant mice. Outbred CD-1 mice were treated with either vehicle or oxazepam (15mg/kg p.o. to the dam, twice a day on Days 12-16 of foetal life), and fostered at birth to untreated dams. Two males plus two females were observed in the home cage, in the presence of a novel object, on Postnatal Days 16, 20 and 24. The expression of social and non-social behaviours increased with age. Prenatal oxazepam exposure reduced sex differences by having a more pronounced effect on males than on females; it also produced fairly specific, though subtle, behavioural changes. Oxazepam exposed mice appeared more involved than prenatal controls in behaviours related to the achievement and maintenance of a "passive" proximity with littermates. By contrast, they performed less active investigation and solicitation of littermates, and non-social behaviours such as locomotor-rotational play, cage exploration, and maintenance activities; they also showed a reduced frequency of approaching and making contact with the novel object. Analysis of social interactions of infant mice seems to represent a sensitive tool for early detection of subtle developmental changes in the CNS.
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PMID:Affiliation and neophobia in developing mice prenatally exposed to oxazepam. 1122 51

1. Trimethylolpropane phosphate (TMPP) is a potent cage convulsant, reported to act through binding to the picrotoxinin and/or benzodiazepine receptor sites of the gamma-aminobutyricA (GABA(A)) ionophore complex. 2. Adult male Fischer-344 rats were pretreated by intraperitoneal (i.p.) injection with either diazepam (DZP) [0.5-5.0 mg/kg], Phenobarbital (PB) [5-20 mg/kg], dizocilpine maleate (MK-801) [0.5-3.0 mg/kg], Tiagabine (TGB) [0.5-5.0 mg/kg], 6,7-dinitro-quinoxaline-2,3-dione (DNQX), [5-20 mg/kg], or scopolamine [SCP] (0.25-1.0 mg/kg) 30 min prior to i.p. injection with a convulsive dose of TMPP (0.6 mg/kg). 3. Rats were rated for occurrence of convulsive activity for 120 min post-injection. Time from TMPP injection to observation of subclinical seizures, generalized (tonic-clonic) seizures, and lethality was rated for each pretreatment group. 4. In general, DZP = PB > TGB in reduction of TMPP subclinical and/or clinical seizures. MK-801, at dose levels inducing near sedation, was also effective in modulation of TMPP-induced seizures. SCP or DNQX were generally ineffective in reducing or eliminating TMPP-induced seizures.
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PMID:Reduction of motor seizures in rats induced by the ethyl bicyclophosphate trimethylolpropane phosphate (TMPP). 1147 48

We determined whether functional integrity of neurons in the amygdala is necessary for sudden episodes of cutaneous vasoconstriction that occur when the conscious animal detects a salient alerting stimulus. To inhibit neuronal function, muscimol (5 nmol in 300 nl), a long acting and potent GABA-A receptor agonist that hyperpolarizes neurons, was injected bilaterally into the amygdala or into a more dorsal control site in conscious rabbits. Cutaneous blood flow was measured in the ear pinna flow using an ultrasonic Doppler probe chronically implanted around the central ear artery. Ear flow responses to salient unconditioned alerting stimuli (fur touch, slight cage movement. removal of drape covering cage) were examined before and after injection of the muscimol, and the effects compared with effects of muscimol on the ear flow response to more nociceptive stimuli, including ear pinch. Muscimol injections into the dorsal control site did not significantly alter alerting-related episodes of ear pinna vasoconstriction. Muscimol injections into the amygdala almost completely abolished ear vasoconstriction elicited by fur touch (0/5 positive responses), drape removal (0/7 positive responses) and cage movement (0/7 positive responses). Muscimol injections into the amygdala reduced the mean ear flow coefficient of variation for a 15 min observation period from 47+/-5 before injection to 15+/-33% after injection (P<0.01, n=7 rabbits). Muscimol injections into the amygdala did not alter the vigorous ear pinna vasoconstriction elicited by ear pinch (7/7 positive responses). Our results indicate that neuronal function in the amygdala, probably the central nucleus of the amygdala, is necessary for the occurrence of ear pinna vasoconstriction episodes elicited by unconditioned salient stimuli but not for the occurrence of corresponding vasoconstriction elicited by nociceptive stimuli.
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PMID:Neurons in amygdala mediate ear pinna vasoconstriction elicited by unconditioned salient stimuli in conscious rabbits. 1147 84

Testosterone (T) and pregnane neurosteroids can enhance conditioned place preference (CPP). The present experiment examined CPP produced by T and its androgenic metabolite dihydrotestosterone (DHT) and 3alpha-Androstanediol (3alpha-diol; an androstane neurosteroid). Administration of 3alpha-diol (>DHT>T) to intact male Long-Evans rats, 1.0 mg daily for six days, 30 min prior to exposure to the non-preferred side of the CPP chamber significantly increased preference for the non-preferred side of the chamber compared to that seen in home cage controls. Levels of circulating 3alpha-diol were increased significantly in 3alpha-diol>DHT>T-administered rats, compared to rats that had vehicle administered or androgen-administration discontinued. Androgen administration decreased seminal vesicle weight and intrahypothalamic androgen receptor (AR) binding compared to that seen in rats that had vehicle administered or androgen-administration discontinued. Testosterone, DHT, and 3alpha-diol decreased GABA-stimulated chloride influx in cortical synaptoneurosomes, and muscimol binding in the hippocampus compared to that seen in rats with vehicle administered or that had androgen-administration discontinued. These data indicate that administration of 3alpha-diol is more effective at enhancing CPP and increasing circulating 3alpha-diol levels than is DHT or T administration, and that all of the androgen regimens employed decreased peripheral and hypothalamic androgen receptor binding and cortical and hippocampal GABA(A) receptor function. Hence, whether the effects of 3 alpha-diol on CPP are mediated by differential actions at ARs or GABA(A) receptors in particular brain regions needs to be determined.
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PMID:The testosterone metabolite and neurosteroid 3alpha-androstanediol may mediate the effects of testosterone on conditioned place preference. 1150 Feb 54

We examined the effect of (+/-)-gamma-vinyl GABA (GVG, Vigabatrin), an irreversible inhibitor of the enzyme GABA transaminase, on the acquisition and expression of cocaine-induced sensitization in albino male Sprague-Dawley rats. Animals received a single injection of 1 ml/kg i.p. of 0.9% saline or 15 mg/kg i.p. of (-)-cocaine and locomotor activity was assessed using automated locomotor cages and stereotyped behaviors were scored using a 4-point rating scale (Day 1). Subsequently, animals were given 15 mg/kg i.p. of cocaine every 48 h in their home cage for 1 week (Days 3, 5, and 7) and then given no treatment for 1 week. A challenge injection of 15 mg/kg i.p. of cocaine, but not vehicle, produced a significant increase in locomotor activity and stereotyped behaviors on Day 15 compared to animals that received cocaine on Day 1. Administration of 75 mg/kg i.p. of GVG 2.5 h before the cocaine injections did not significantly alter the acquisition of cocaine-induced locomotor sensitization. However, 150 mg/kg i.p. of GVG significantly attenuated the acquisition of cocaine-induced locomotor sensitization. Administration of 150 mg/kg i.p. of GVG 2.5 h before the cocaine challenge injection on Day 15 significantly attenuated the expression of cocaine-induced locomotor sensitization. Acquisition and expression of cocaine-induced sensitization of stereotypy was also significantly attenuated by 150 mg/kg i.p. of GVG. Since sensitization may be one of the factors involved in relapse to drug use, the present results, in combination with previous findings that GVG blocks the rewarding and incentive motivating effects of cocaine, suggest that GVG might prove useful in the treatment of cocaine addiction.
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PMID:Gamma-vinyl GABA, an irreversible inhibitor of GABA transaminase, alters the acquisition and expression of cocaine-induced sensitization in male rats. 1237 39

(+)-Borneol is a bicyclic monoterpene used for analgesia and anaesthesia in traditional Chinese and Japanese medicine and is found in the essential oils of medicinal herbs, such as valerian. (+)-Borneol was found to have a highly efficacious positive modulating action at GABA(A) receptors, as did its enantiomer (-)-borneol. The effects of these bicyclic monoterpenes alone and with GABA were evaluated at recombinant human alpha(1)beta(2)gamma(2L) GABA(A) receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. (+)-Borneol (EC(50) 248microM) and (-)-borneol (EC(50) 237microM) enhanced the action of low concentrations of GABA by more than 1000%. These enhancing effects were highly dependent on the relative concentrations of the borneol enantiomer and GABA, and were insensitive to flumazenil indicating that (+)- and (-)-borneol were not acting at classical benzodiazepine sites. The maximal responses to GABA were enhanced 19% by (+)-borneol and reduced 21% by (-)-borneol. The borneol analogues isoborneol, (-)-bornyl acetate and camphor, produced less marked effects. At high concentrations (>1.5mM) (+)- and (-)-borneol directly activated GABA(A) receptors producing 89% and 84%, respectively, of the maximal GABA response indicative of a weak partial agonist action. Although of lower potency, the highly efficacious positive modulatory actions of (+)- and (-)-borneol on GABA responses were at least equivalent to that of the anaesthetic etomidate and much greater than that of diazepam or 5alpha-pregnan-3alpha-ol-20-one. The relatively rigid cage structure of these bicyclic monoterpenes and their high efficacy may aid in a greater understanding of molecular aspects of positive modulation of the activation of GABA(A) receptors.
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PMID:(+)- And (-)-borneol: efficacious positive modulators of GABA action at human recombinant alpha1beta2gamma2L GABA(A) receptors. 1576 46

Several studies have shown that sleep deprivation produces deficits in learning tasks, but mechanisms underlying these effects remain unclear. Other lines of evidence indicate an involvement of brain GABA systems in cognitive processes. Here, we investigated the possibility that alterations in GABA(A) or benzodiazepine (BDZ) receptor binding might underlie avoidance deficits induced by sleep deprivation. Rats were deprived of sleep for 96 h using the platform method and then trained in a step-through inhibitory avoidance task, or allowed to recover sleep for 24 h before training (sleep rebound group). Thirty minutes after training, animals were given a retention test. Both sleep-deprived and sleep-recovered animals showed a significant impairment in avoidance responding compared to cage controls, and the sleep-deprived group performed significant worse than the sleep-recovered group. A separate group of animals was sacrificed either immediately after 96 h of sleep deprivation or after 96 h of sleep deprivation followed by 24 h of sleep recovery. [(3)H]muscimol and [(3)H]flunitrazepam binding were examined by quantitative autoradiography in 42 brain regions, including areas involved in cognitive processes. No significant differences among groups were found in any brain region, except for a reduction in [(3)H]flunitrazepam binding in the frontal cortex of sleep-recovered animals. These results confirm the deleterious effects of sleep loss on inhibitory avoidance learning, but suggest that such deficits cannot be attributed to altered GABA(A) or BDZ binding in brain.
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PMID:Learning deficits induced by sleep deprivation and recovery are not associated with altered [(3)H]muscimol and [(3)H]flunitrazepam binding. 1577 64

GABA transporter subtype 1 (GAT1) knock-out (KO) mice display normal reproduction and life span but have reduced body weight (female, -10%; male, -20%) and higher body temperature fluctuations in the 0.2-1.5/h frequency range. Mouse GAT1 (mGAT1) KO mice exhibit motor disorders, including gait abnormality, constant 25-32 Hz tremor, which is aggravated by flunitrazepam, reduced rotarod performance, and reduced locomotor activity in the home cage. Open-field tests show delayed exploratory activity, reduced rearing, and reduced visits to the central area, with no change in the total distance traveled. The mGAT1 KO mice display no difference in acoustic startle response but exhibit a deficiency in prepulse inhibition. These open-field and prepulse inhibition results suggest that the mGAT1 KO mice display mild anxiety or nervousness. The compromised GABA uptake in mGAT1 KO mice results in an increased GABA(A) receptor-mediated tonic conductance in both cerebellar granule and Purkinje cells. The reduced rate of GABA clearance from the synaptic cleft is probably responsible for the slower decay of spontaneous IPSCs in cerebellar granule cells. There is little or no compensatory change in other proteins or structures related to GABA transmission in the mGAT1 KO mice, including GAT1-independent GABA uptake, number of GABAergic interneurons, and GABA(A)-, vesicular GABA transporter-, GAD65-, and GAT3-immunoreactive structures in cerebellum or hippocampus. Therefore, the excessive extracellular GABA present in mGAT1 KO mice results in behaviors that partially phenocopy the clinical side effects of tiagabine, suggesting that these side effects are inherent to a therapeutic strategy that targets the widely expressed GAT1 transporter system.
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PMID:GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum. 1578 81

The present study investigated the role of the alpha1-containing GABA(A) receptors in the neurobehavioral actions of alcohol. In Experiment 1, mice lacking the alpha1 subunit (alpha1 (-/-)) were tested for their capacity to initiate operant-lever press responding for alcohol or sucrose. Alcohol intake in the home cage was also measured. In Experiment 2, the alpha1 (-/-) mice were injected with a range of alcohol doses (0.875-4.0 g/kg; i.p.) to evaluate the significance of the alpha1 subunit in alcohol's stimulant actions. In Experiment 3, we determined if the alcohol-induced stimulant effects were regulated via dopaminergic (DA) or benzodiazepine (BDZ)-dependent mechanisms. To accomplish this, we investigated the capacity of DA (eticlopride, SCH 23390) and BDZ (flumazenil, betaCCt) receptor antagonists to attenuate the alcohol-induced stimulant actions. Compared with wild-type mice (alpha1 (+/+)), the null mutants showed marked reductions in both EtOH and sucrose-maintained responding, and home-cage alcohol drinking. The null mutants also showed significant increases in locomotor behaviors after injections of low-moderate alcohol doses (1.75-3.0 g/kg). betaCCt, flumazenil, eticlopride, and SCH 23390 were able to attenuate the alcohol-induced stimulation in mutant mice, in the absence of intrinsic effects. These data suggest the alpha1 receptor plays an important role in alcohol-motivated behaviors; however, it also appears crucial in regulating the reinforcing properties associated with normal ingestive behaviors. Deleting the alpha1 subunit of the GABA(A) receptor appears to unmask alcohol's stimulatory effects; these effects appear to be regulated via an interaction of both DA- and GABA(A) BDZ-dependent mechanisms.
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PMID:Dopamine and benzodiazepine-dependent mechanisms regulate the EtOH-enhanced locomotor stimulation in the GABAA alpha1 subunit null mutant mice. 1671 Mar 15


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