Lack of interaction between the behavioral effects of ketamine and benzodiazepines in mice.
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The effect of co-administration of ketamine at the sub-effective dose with diazepam, chlordiazepoxide and clonazepam on their antinociceptive and protective efficacy against pentetrazole-induced seizures were studied in mice. Ketamine alone produces dose-dependent antinociception manifested as reduction in the number of writhing episodes evoked by acetic acid. In the writhing test, the antinociceptive effects of the threshold doses of diazepam, chlordiazepoxide or clonazepam were not changed by ketamine, whereas that of morphine was intensified by ketamine. In the hot plate test, slight antinociceptive effects of the threshold dose of diazepam, but not that of chlordiazepoxide (except the results at 120 min of observation), were significantly intensified by ketamine vs ketamine alone. Ketamine alone was able to protect mice, in the dose-related manner, against pentetrazole-induced seizures. The anticonvulsant effects of the threshold doses of diazepam, chlordiazepoxide and clonazepam were not changed by ketamine. These findings indicate that co-administration of ketamine (at the sub-effective dose) with diazepam, chlordiazepoxide and clonazepam (at non-effective doses) resulted in an intensification of neither antinociceptive nor protective effect against pentetrazole-induced seizures in mice. These data seem to indicate the lack of interaction between ketamine and benzodiazepines with respect to their antinociceptive and anticonvulsant efficacy. (+info)
Selective serotonin reuptake inhibitors decrease impulsive behavior as measured by an adjusting delay procedure in the pigeon.
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The inability to delay gratification (reinforcement or reward) is one index of impulsive behavior. In order to measure the willingness of pigeons to delay reinforcement, an adjustable delay schedule was developed that allowed daily approximations of an indifference point between immediate brief access to reinforcer and delayed, longer access to reinforcer. Acute administration of the anxiolytic alprazolam (5 mg/kg) decreased the length of delay tolerated before a larger reinforcement. Likewise, acute administration of the anxiolytic chlordiazepoxide (10 mg/kg) produced a similar, although not significant, effect. Neither acute nor five daily injections of 8-OH-DPAT, a 5-HT(1A) agonist, or WAY100635, a 5-HT(1A) antagonist, affected the length of the delay period. Chronic (17 day), but not acute injections of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (10 mg/kg), citalopram (10 mg/kg) and paroxetine (3 mg/kg) increased the delay period. When given in addition to 1 mg/kg of 8-OH-DPAT, but not 1 mg/kg WAY100635, the effect of fluoxetine was accelerated in that the increase in delay was observed earlier in the treatment. These data support the use of SSRIs to decrease impulsive behavior. Addition of a 5-HT(1A) agonist, but not a 5-HT(1A) antagonist, to the SSRI may hasten the therapeutic activity of the SSRI in treating impulsivity. (+info)
Immediate effects on human performance of a 1,5-genzodiazepine (clobazam) compared with the 1,4-benzodiazepines, chlordiazepoxide hydrochloride and diazepam.
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1 The immediate effects on human performance of the 1,5-benzodiazepine, clobazam (20 mg), and the 1,4-benzodiazepines, chlordiazepoxide hydrochloride (20 mg) and diazepam (10 mg), were studied by adaptive tracking and measurement of reaction time. Each drug was ingested at 09.00 h and performance was measured at 09 h 30 min (0.5 h), 11 h 30 min (2.5 h), 14 h 30 min (5.5 h) and 18 h 30 min (9.5 h after ingestion). 2 With diazepam decrements in performance on adaptive tracking were observed at 0.5 h and 2.5 h and performance was enhanced at 9.5 h after ingestion. With clobazam performance at individual times did not differ significantly from control, but there was evidence of an improvement in performance during the day. There was no evidence of impaired performance on adaptive tracking after chlordiazepoxide hydrochloride. 3 Reaction time was slowed at 0.5 h and 2.5 h after diazepam and chlordiazepoxide hydrochloride. A decrease in reaction time was observed at 9.5 h after diazepam. No changes in reaction time were observed after clobazam. 4 The subjects as a group differentiated correctly between performance decrements on adaptive tracking after diazepam and the absence of performance decrements after clobazam and chlordiazepoxide hydrochloride. The persistence of the decrement in performance after diazepam was accurately assessed. 5 It is evident that the nature and persistence of impaired performance and the ability to appreciate impaired performance vary considerably between the benzodiazepines, and that the choice of a benzodiazepine should include careful consideration of performance sequelae. (+info)
5-ethoxymethyl-7-fluoro-3-oxo-1,2,3,5-tetrahydrobenzo[4,5]imidazo[1,2a]pyridine-4 -N-(2-fluorophenyl)carboxamide (RWJ-51204), a new nonbenzodiazepine anxiolytic.
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5-ethoxymethyl-7-fluoro-3-oxo-1,2,3,5-tetrahydrobenzo[4,5] imidazo[1,2a]pyridine-4-N-(2-fluorophenyl)carboxamide) (RWJ-51204) binds selectively and with high affinity (K(i) = 0.2-2 nM) to the benzodiazepine site on GABA(A) receptors. Considering the GABA shift, the intrinsic modulatory activity of RWJ-51204 is lower than that of full agonist anxiolytics (lorazepam, diazepam, alprazolam, and clonazepam) but similar to partial agonists (bretazenil, abecarnil, panadiplon, and imidazenil). RWJ-51204 was orally active in anxiolytic efficacy tests; pentylenetetrazole induced seizure inhibition in mice (ED(50) = 0.04 mg/kg), Vogel conflict in rats (ED(50) = 0.36 mg/kg), elevated plus-maze in rats (minimal effective dose = 0.1 mg/kg), and conflict in squirrel monkeys (ED(50) = 0.49 mg/kg). RWJ-51204 attenuated chlordiazepoxide-induced motor impairment in mice. Usually, RWJ-51204 was more potent than reference anxiolytics in rodent efficacy tests but less potent in monkey conflict. Usually, the slope of the dose-response lines for RWJ-51204 was more shallow than the full agonist anxiolytics but steeper than partial agonists in efficacy tests but typically shallow in tests for central nervous system side effects. In monkeys only mild or moderate sedation was observed at doses equivalent to 20 or 40 times the anxiolytic ED(50). RWJ-51204 fits into the partial agonist class of GABA(A) receptor modulators. In conclusion, RWJ-51204 exhibits a profile in in vitro experiments and in animal models, in mice and monkeys (but not in rats), suggesting that it has a profile of anxiolytic activity associated with less sedation, motor impairment, or muscle relaxation than currently available GABA(A) receptor modulators, i.e., the benzodiazepines. (+info)
Benzodiazepines and central glycine receptors.
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1 In cats, anaesthetized with pentobarbitone, intravenous diazepam (minimum dose 3.0 mg/kg) enhanced dorsal root potentials but did not significantly diminish the reduction by electrophoretic strychnine of the inhibitory action of electrophoretic glycine on dorsal horn interneurones. 2 In mice, intraperitoneal diazepam (2.5 mg/kg) had no appreciable effect on the potency of strychnine as a convulsant, although providing some protection against bicuculline. 3 These observations, together with the failure of chlordiazepoxide to either inhibit the firing of spinal interneurones or reduce antagonism between strychnine and glycine when administered locally, provide no support for the interaction between benzodiazepines and mammalian central glycine receptors which has been proposed on the basis of in vitro studies of strychnine binding. (+info)
Thyrotropin-releasing hormone binding to the mouse pituitary receptor does not involve ionic interactions. A model for neutral peptide binding to G protein-coupled receptors.
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Thyrotropin-releasing hormone, TRH (< Glu-His-Proamide), and [N tau-Me-His]TRH (MeTRH) are present as neutral and positively charged forms at physiologic pH, and it was possible that they bind to the TRH receptor (TRH-R) as charged (protonated) species. Binding affinities of TRH and MeTRH to endogenous rat TRH-Rs and to transfected wild type mouse TRH-Rs decreased below pH 7.1. Half-maximal decreases in binding occurred at the approximate pK alpha values of these ligands. Asp to Ala mutations in extracellular loop 1, TM-4, and TM-5 did not decrease binding affinity, but an Asp to Ala mutation in TM-2 caused the affinity to decrease 8-fold. The pH dependences of binding of MeTRH, however, were similar in wild type and all mutant receptors and were consistent with the protonated form of MeTRH binding less well. Thus, the binding of TRH to its receptor does not involve ionic interactions and may be a prototype for binding of neutral peptide ligands to G protein-coupled receptors. (+info)
Two isoforms of the thyrotropin-releasing hormone receptor generated by alternative splicing have indistinguishable functional properties.
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Two cDNA clones encoding two different isoforms of the thyrotropin-releasing hormone receptor (TRH-R) from GH3 rat anterior pituitary cells have been isolated. One isoform corresponds to the TRH-R(412) receptor previously described (de la Pena, P., Delgado, L. M., del Camino, D., and Barros, F. (1992) Biochem. J. 284, 891-899). The second one, named TRH-R(387), contains a 52-base pair deletion, which yields a new variant of the receptor protein 25 amino acid shorter and which contains 12 new residues on its carboxyl terminus. This new isoform is produced by alternative splicing of a retained intron in the primary transcript of a gene represented only once in the rat genome. Furthermore, the perfect colinearity between genomic DNA and TRH-R(412) cDNA demonstrates that no other introns are present within the coding region of the TRH receptor gene. Functional expression in Xenopus laevis oocytes indicates that both cDNAs encode fully functional TRH receptors. Otherwise, indistinguishable electrophysiological responses to TRH are evoked in oocytes expressing both receptor isoforms. (+info)
Effect of a benzodiazepine (chlordiazepoxide) on a GABAA receptor from rat brain. Requirement of only one bound GABA molecule for channel opening.
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Chlordiazepoxide (CDPX) enhanced the rate of chloride exchange mediated by the major GABAA receptor found on sealed native membrane vesicles from rat cerebral cortex. The initial rate constant for chloride exchange for this receptor, (JA), a measure of open channel, was determined from the progress of GABA-mediated influx of 36Cl-. The dependence of JA on GABA concentration was hyperbolic in the presence of CDPX (150 microM, sufficient to give maximum enhancement of chloride exchange rate) but sigmoid in its absence. Enhancement of channel opening (10-fold at 0.3 microM GABA) decreased with increasing GABA concentration. The maximal response, above 1,000 microM GABA, was unaltered. The half-response concentration was reduced from 80 microM to 50 microM. CDPX alone caused no measurable 36Cl- exchange. In the presence of CDPX, channel opening occurred with only one bound GABA molecule, whereas in its absence, channel opening with two bound GABA molecules was much more favorable. This could not be direct allosteric modulation of the channel opening conformational change by binding of CDPX at effector sites, but could be explained by an additional change of the receptor on binding CDPX to give a closed state which gave channel opening mediated by a single GABA binding site. Another possibility is that CDPX could act at one of the channel opening binding sites without a postulated, second closed conformational state. (+info)