Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A-86929 ((-)-trans-9,10-dihydroxy-2-propyl-4,5,5a,6,7,11b-hexahydro-3- thia-5-azacyclopent-1-ena[c]phenanthrene) is a potent and selective full agonist at the dopamine D1 receptor. Both A-86929 and ABT-431 ((-)-trans-9,10-diacetyloxy-2-propyl-4,5,5a,6,7,11b- hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride), the diacetyl prodrug derivative of A-86929, were evaluated for their effects on behavioral excitability in rodents. In rats, A-86929 produced a dose-dependent increase in locomotor activity that was attenuated by the selective dopamine D1 receptor antagonist, SCH 23390, as well as by higher doses of the dopamine D2 receptor antagonist, haloperidol. Repeated administration of A-86929 over 6 days produced hyperactivity which did not change in magnitude across days. Acute administration of A-86929 and ABT-431 to mice produced behavioral seizure activity, with ED50 values of 7.1 and 2.7 mumol/kg, s.c., respectively, that was blocked by SCH 23390. Young rats (35-37 days) exhibited behavioral seizures following A-86929 and ABT-431 treatment (ED50 = 34.2 and 35.6 mumol/kg, s.c., respectively), but at doses higher than those required in mice. Moreover, adult rats (3 months) were less sensitive (ED50 = 345 mumol/kg, s.c.) to A-86929-induced seizures than young rats. Comparison of the ED50 values that produced behavioral seizure activity in rats with those previously established to produce contralateral rotation (ED50 = 0.24 mumol/kg, s.c.) in 6-hydroxydopamine-lesioned rat indicates that a significant dose separation exists between these two properties of A-86929.
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PMID:Hyperactivity and behavioral seizures in rodents following treatment with the dopamine D1 receptor agonists A-86929 and ABT-431. 899 99

The effects of repeated administration of the selective adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), the selective adenosine A2 receptor agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA), the non-selective adenosine A1/A2 receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA), the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3 dipropylxanthine (DPCPX) and the selective adenosine A2 receptor antagonist 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-(4,3-e)1,2,4-triazolo(1,5 -c)pyrimidine (SCH 58261) on the anticonvulsant activity of 3-(2-carboxypiperazine-4y)propenyl-1-phosphonic acid (CPPene), a selective N-methyl-D-aspartate receptor antagonist, were evaluated in audiogenic sensible dilute brown agouti mice DBA/2J (DBA/2). Mice were treated intraperitoneally twice daily for 7 days with CCPA 0.11 mg/kg, 2HE-NECA 0.056 mg/kg, NECA 0.11 mg/kg, DPCPX 0.5 mg/kg and SCH 58261 0.5 mg/kg followed by 2 vehicle injections (the wash-out period of 1 day) and subsequently CPPene was administered intracerebroventricularly. Audiogenic seizures were delivered 30 min after CPPene administration. Repeated treatment with CCPA significantly reduced the anticonvulsant properties of CPPene against audiogenic seizures. A weak and not significant reduction of anticonvulsant effects of CPPene was observed following repeated administration of NECA, whilst the repeated administration of 2HE-NECA did not decrease the antiseizure activity of CPPene. Conversely, repeated administration of DPCPX markedly potentiated the anticonvulsant properties of CPPene, whilst the repeated treatment with SCH 58261 did not increase the anticonvulsant activity of CPPene. The present results indicate that repeated treatment with CPPA, a selective adenosine A1 receptor agonist, decreases the anticonvulsant properties of CPPene, whilst the repeated administration of DPCPX, a selective adenosine A1 receptor antagonist, potentiates the anticonvulsant effects of CPPene. The compounds acting as selective agonists or antagonists of adenosine A2 receptors do not affect the antiseizure activity of CPPene. In conclusion, the repeated interaction of agonists or antagonists with adenosine A1 receptors seems to induce changes on anticonvulsant activity of CPPene, whereas drugs acting at adenosine A2 receptors do not.
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PMID:Repeated treatment with adenosine A1 receptor agonist and antagonist modifies the anticonvulsant properties of CPPene. 899 6

In adult rat brain, adenosine A2A receptors and dopamine D2 receptors are known to be located on the same cells where they interact in an antagonistic manner. In the present study we wanted to examine when this situation develops and compared the postnatal ontogeny of the binding of the adenosine A2A receptor agonist [3H]CGS 21680, the binding of the dopamine D1 receptor antagonist [3H]SCH 23390 and the dopamine D2 receptor antagonist [3H]raclopride. All three radioligands bound to the striatum at birth and this binding increased several-fold during the postnatal period. [3H]SCH 23390 binding developed first (mostly during the first week), followed by [3H]raclopride binding (first to third week) and [3H]CGS 21680 binding (only during second and third week). For all three radioligands the binding tended to decrease between 21 days and adulthood. This occurred earlier and was more pronounced in the globus pallidus than in the other examined structures. The increase in [3H]CGS 21680 binding from newborn to adult was mainly due to four-fold increase in the number of binding sites. The pharmacology of [3H]CGS 21680 binding to caudate-putamen was similar in newborn, one-week-old and adult animals, and was indicative of A2A receptors. The binding was inhibited by guanylyl imidodiphosphate at all ages, indicating that A2A receptors are G-protein-coupled already at birth. In contrast to the large increase in [3H]CGS 21680 binding, there was a decrease in the levels of A2A messenger RNA during the postnatal period in the caudate-putamen. In cerebral cortex [3H]CGS 21680 bound to a different site than the A2A receptor. From birth to adulthood cortical binding of [3H]CGS 21680 increased four-fold and that of the adenosine A1 agonist [3H]cyclohexyladenosine 19-fold. During early postnatal development [3H]SCH 23390 binding was higher in deep than in superficial cortical layers, but this difference disappeared in adult animals. There was binding of both [3H]CGS 21680 and [3H]cyclohexyladenosine to the olfactory bulb, suggesting a role of the two adenosine receptors in processing of olfactory information. [3H]CGS 21680 binding was present in the external plexiform layer and glomerular layer, and increased during development, but the density of binding sites was about one tenth of that seen in caudate putamen. [3H]cyclohexyladenosine showed a very different labelling pattern, resembling that observed with [3H]SCH 23390. Postnatal changes in adenosine receptors may explain age-dependent differences in stimulatory caffeine effects and endogenous protection against seizures. Since A2A receptors show a co-distribution with D2 receptors throughout development, caffeine may partly exert such actions by regulating the activity of D2 receptor-containing striatopallidal neurons.
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PMID:Distribution and postnatal ontogeny of adenosine A2A receptors in rat brain: comparison with dopamine receptors. 928 70

The effects of selective dopaminergic agonists and antagonists on epileptic activity were tested in rats using the lithium/pilocarpine seizure model. Systemic administration of the D1 agonist SKF-38,393 reduced the latency of onset of forelimb clonus with rearing, whereas the D1 antagonist SCH-23,390 and the D2 agonist B-HT 920 prevented the convulsive activity in a dose-dependent manner. Mixed agonists like apomorphine offered partial protection. Haloperidol (D1, D2 blocker, with antimuscarinic property) reduced the threshold for convulsions. The effects of SKF-38,393 and B-HT 920 could be partially blocked by pretreating the rats with SCH-23,390 and sulpiride, respectively. Neither D1 nor D2 antagonists could alter the limbic stereotypies induced by lithium/pilocarpine. These results indicate that dopamine receptor subtypes exert opposite effects on the regulation of convulsive activity. Lipid peroxidation levels (MDA formed) in rat brain homogenates were found to be concomitant with the development of epileptiform activity.
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PMID:Dopaminergic modulation of lithium/pilocarpine-induced status epilepticus in rats. 941 31

The present study evaluated in mice the central inhibitory effects of a water extract of shichangpu (Acori graminei rhizoma (AGR), the dry rhizome of Acorus gramineus Soland. (Araceae)). AGR (0.5-5.0 g/kg) dose-dependently decreased the locomotor activity and increased the pentobarbital-induced sleeping time, but had no significant effect on the treadmill performance. AGR also dose-dependently inhibited the intensity of apomorphine-induced stereotypic behavior. At the highest dose (5.0 g/kg), AGR had a weak anticonvulsant effect on the pentylenetetrazol-induced seizures. Receptor binding assays showed that AGR competed with [3H]SCH-23390 and [3H]YM-09151-2 for specific binding to striatal dopamine D1 and D2 receptors with Ki values of 5.6 and 4.2 mg/ml, respectively. AGR also competed with [3H]muscimol for specific binding to the gamma-aminobutyric acid (GABA) binding site of cortex GABA(A) receptors with a Ki value of 0.31 mg/ml. It also increased the specific binding of [3H]flunitrazepam to the benzodiazepine binding site of the GABA(A) receptors, suggesting a GABA agonist-like action. These results suggested that the central inhibitory effects of AGR were probably effected through an action on the central dopamine receptors and GABA(A) receptors. The principle of AGR acting at these ligand binding sites was not alpha-asarone, one of the important principles of AGR, since that alpha-asarone (10(-6)-10(-4) M) had no significant interactions with these binding sites.
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PMID:Central inhibitory effects of water extract of Acori graminei rhizoma in mice. 970 9

We have studied the effects of selective and non-selective adenosine receptor agonists and antagonists in audiogenic-seizure-sensitive DBA/2 mice, an animal model of generalized reflex epilepsy. With the exception of the adenosine A3 receptor agonist, N6-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine (IB-MECA), all the agonists studied prevented the development of audiogenic seizures in a dose-dependent manner. The ED50 values against the clonic phase of the audiogenic seizures were low, that is: 0.06 mg/kg, i.p., for the adenosine A1 receptor agonist, 2-chloro-N6-cyclopentyladenosine (CCPA), 0.02 and 0.03 mg/kg, i.p., for the adenosine A2A receptor agonists, 2-(4-(2-carboxyethyl)-phenylamino)-5'-N-ethylcarboxamidoadenosine (CGS 21680) and 2-hexynyl-5'-N-ethyl-carboxamidoadenosine (2-HE-NECA), and 0.7 mg/kg, i.p., for the adenosine A1/A3 receptor agonist, N6-2-(4-aminophenyl)ethyladenosine (APNEA). Conversely, the non-selective agonist, N-ethyl-carboxamidoadenosine (NECA), was highly potent, the ED50 being 0.0005 mg/kg, i.p. In the absence of auditory stimulation, the adenosine receptor antagonists increased the incidence of both clonic and tonic seizures in DBA/2 mice. The ED50 values were: for caffeine, 207.5 mg/kg, i.p., for the adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), 327.8 mg/kg i.p., for the adenosine A2A receptor antagonists, 3,7-dimethyl-1-propylxanthine (DPMX), 86.7 mg/kg i.p., for the (E,18%-Z,82%)7-methyl-8-(3,4-dimethoxystyryl)-1,3-dipropylxanthine (KF 17837), 69.1 mg/kg i.p., and 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-(4,3-c)1,2,4-triazolo(1,5 -c)-pyrimidine (SCH 58261), 321.8 mg/kg i.p. The rank order of convulsant potency in our epileptic model, following intracerebroventricular administration, was DPCPX > DMPX > 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (CSC) > KF 17837 > Caffeine > SCH 58261 > 5-amino-9-chloro-2-(2-furyl)-1,2,4-triazolo(1,5-c)quinazoline (CGS 15943). Following a subconvulsant audiogenic stimulus of 83 dB, all adenosine receptor antagonists induced both tonic and clonic seizures. The ED50 values for such proconvulsant effects were: for caffeine 0.04 mg/kg, i.p., for the adenosine A receptor antagonist, DPCPX, 5.84 mg/kg, i.p., for the adenosine A2A receptor antagonists, DMPX, 0.02 mg/kg, i.p., CGS 15943, 0.29 mg/kg i.p., KF 17837, 0.57 mg/kg, i.p., CSC 0.12 mg/kg, i.p. and SCH 58261 0.07 mg/kg, i.p., respectively. These data suggest that stimulation of adenosine A1 and A2A receptors is involved in the suppression of seizures.
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PMID:Effects of adenosine receptor agonists and antagonists on audiogenic seizure-sensible DBA/2 mice. 1035 50

A large number of ligand binding studies have shown that clozapine has a number of receptor affinities, including those of the dopamine (DA) D1 and D2 receptor families. The study of intrinsic efficacy at these receptors is less straight-forward. In the experiments summarised here, evidence is presented that clozapine behaves as an agonist at DA D1 receptors. Thus, the hypothermia produced by clozapine (2.5 mg kg(-1)) in the rat is fully antagonised by either of the selective DA D1 receptor antagonists SCH-23390 (0.1 mg kg(-1)) or NNC-687 (4 mg kg(-1)). These results provide an intriguing explanation for the clinical profile of clozapine as an atypical antipsychotic drug. Thus, there are supporting clinical and laboratory observations implicating DA D1 receptors in the prefrontal cortex in cognitive functions. Finally, clozapine displays features with regard to extrapyramidal motor mechanisms, and seizure thresholds, that could be explained by its properties as a DA D1 receptor agonist.
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PMID:Clozapine: dopamine D1 receptor agonism in the prefrontal cortex as the code to decipher a Rosetta stone of antipsychotic drugs. 1036 74

1. The effects of dopaminergic agonists and antagonists were investigated on withdrawal signs in lorazepam-dependent rats. Physical dependence was developed by giving lorazepam admixed with food in the following dose schedules: 10 x 4, 20 x 4, 40 x 4, 80 x 4 and 120 x 7 mg/kg, daily for x days. 2. The parameters observed during the periods of administration of lorazepam and after its withdrawal were spontaneous locomotor activity (SLA), reaction time to pain, foot shock aggression (FSA) and audiogenic seizures. 3. During the withdrawal period, rats were divided into groups of 10 rats each. One group did not receive any drug and served as the control withdrawal groups. Three other groups received, separately, one of the following dopamimetic drugs: (i) 200 mg/kg per day, i.m., L-dihydroxyphenylalanine (DOPA; +50 mg/kg per day, i.m., carbidopa); (ii) 2 mg/kg per day, i.m., amphetamine; or (iii) 1 mg/kg per day, i.m., apomorphine. The remaining groups received one of the following dopamine antagonists: (i) 0.1 mg/kg per day, i.m., SCH 23390; (ii) 0.5 mg/kg per day, i.m., haloperidol; (iii) 0.5 mg/kg per day, i.m., centbutindol; and (iv) either 1 or 20 mg/kg per day, i.m., clozapine. 4. The withdrawal signs observed in the control group were hyperkinesia, hyperaggression and audiogenic seizures. 5. L-Dihydroxyphenylalanine (+ carbidopa), amphetamine and apomorphine potentiated hyperaggression and audiogenic seizures. The dopamine D2 receptor antagonists haloperidol, centbutindol and clozapine (at 20 mg/kg, i.m.) blocked all withdrawal signs. The D1 receptor antagonist SCH 23390 inhibited hyperkinesia and hyperaggression. The D4 receptor antagonist clozapine (at 1 mg/kg, i.m.) had no effect on any of the withdrawal signs. 6. It may be concluded that dopamine D2 receptors exert a dominant facilitatory influence, with partial contribution of D1 receptors, on the benzodiazepine withdrawal syndrome.
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PMID:Effect of dopamine agonists and antagonists on the lorazepam withdrawal syndrome in rats. 1074 42

The substantia nigra pars reticulata (SNpr) has been proposed to play an important role in the control of the propagation and/or the generation of epileptic seizures. Earlier studies have shown differential effects of the lesion of the SNpr on seizure genesis that demonstrated a regional difference in the anterior and posterior parts of the SNpr in preconvulsive behavior induced by unilateral reticulata injection of dopamine (DA). This study was aimed to investigate some of the underlying mechanisms of the preconvulsive behavior elicited by unilateral SNpr DA injection by the study of changes in the gene expression of glutamate receptor subunits (GluR1, GluR2 and NMDAR1) and of changes in animal behavior following coinfusion of DA and a DA D1 antagonist SCH 23390 into the SNpr. Unilateral injection of exogenous DA into the anterior region of the SNpr induced rapid and short lasting preconvulsive behavior up to wet dog shakes stage and a significant reduction of gene expression for GluR1, GluR2 and NMDAR1 subunits in rat hippocampal subfields including CA1 through CA4 and dentate gyrus (DG) at 1 day after nigral DA injection. The effect was long lasting and persisted for at least 3 weeks. Both preconvulsive behavior and downregulation of glutamate receptor subunit genes were completely blocked by simultaneous coinfusion of DA and SCH 23390. The results suggest, for the first time, that DA D1 receptor in the SNpr may mediate the nigral-involved seizure development. Glutamate desensitization, and/or selective early neuronal damage might be responsible for the downregulation of glutamate receptor subunits by transient preconvulsive activity.
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PMID:Substantia nigra pars reticulata lesion induces preconvulsive behavior and changes in glutamate receptor gene expression in the rat brain. 1083 96

The present microdialysis study was aimed at evaluating the anticonvulsant effect of the adenosine A(1) receptor agonist 2-chloroadenosine (2-CADO) against pilocarpine-induced seizures in rats. The hippocampal neurotransmitter modulation on the action of 2-CADO and its possible activation of hippocampal adenosine A(2a) receptors was also assessed. Intrahippocampal perfusion of 2-CADO (100 microM) produced a sustained attenuation of baseline dopamine levels, while eliciting a delayed augmentation of both glutamate and GABA efflux. When co-perfused with pilocarpine (10 mM) or injected systemically (7.5 mg/kg), 2-CADO prevented the development of seizures as well as pilocarpine-evoked augmentation of the glutamate and dopamine levels. However, the delayed increase in glutamate overflow with intrahippocampal 2-CADO was still observed. Intraperitoneal injection of selective adenosine A(2a) receptor antagonist SCH 58261 reversed the 2-CADO-elicited attenuation of pilocarpine-induced increment in dopamine efflux and completely abolished the delayed augmentation of glutamate levels, irrespective of perfusion with pilocarpine. Intraperitoneal injection of 5 mg/kg 2-CADO mostly prevented the elevation of pilocarpine-induced glutamate efflux but could not confer adequate protection. We conclude that 2-CADO can prevent pilocarpine-induced seizures by both intrahippocampal perfusion and systemic administration. The attenuation of pilocarpine-induced dopamine efflux and the late elevations of glutamate are likely to be mediated by hippocampal A(2a) receptors. Inhibition of presynaptic glutamate release does not appear to be sufficient for the anticonvulsant action. Postsynaptic events could play a more important role.
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PMID:Anticonvulsant effect and neurotransmitter modulation of focal and systemic 2-chloroadenosine against the development of pilocarpine-induced seizures. 1097 26


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