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Biomedical subjects

M K Ticku

Publications and source records attributed to M K Ticku.

At least 127 records · Page 7Linked to original sources
PubMed1983

GABA receptor binding and hemodynamic responses to ICV GABA in adult spontaneously hypertensive rats.

Blood pressure and heart rate responses after central administration of GABA (100-1000 micrograms, ICV) and after ganglionic blockade with hexamethonium (25 mg/kg, i.a.) were compared in conscious 12 week-old spontaneously hypertensive (SH) and age-matched Wistar-Kyoto (WKY) rats. Ganglionic blockade produced an equivalent change in mean arterial pressure between SH and WKY rats. Thus, the total functional sympathetic nervous system contribution to blood pressure is equivalent in these two strains. Intraventricularly-administered GABA produced a greater absolute decrease in mean arterial pressure in the SHR compared to the WKY. However, the percent changes in arterial pressure produced by GABA were not different between these strains. This greater absolute depressor effect of GABA does not appear to be due to differences in GABA receptor binding constants since GABA receptor affinity and number of binding sites were not significantly different in the forebrain, cerebellum or pons-medulla between SH and WKY rats.

Animals↗
PubMed1983

Benzodiazepine-GABA receptor-ionophore complex. Current concepts.

The benzodiazepine--gamma-aminobutyric acid (GABA) receptor--ionophore system is an oligomeric complex, composed of at least three interacting components. These three components have been well characterized in vitro by radioreceptor binding assays. A variety of centrally acting anxiolytic, depressant, anticonvulsant and convulsant drugs, which affect GABAergic transmission, bind to one of the sites and modulate the binding of ligands at the other sites. Thus, depressant barbiturates, nonbarbiturate hypnotics (like etomidate) and pyrazolopyridines (like etazolate), while inhibiting the binding of alpha-dihydropicrotoxinin (DHP), enhance the binding of GABA and benzodiazepines. These enhancing effects are blocked by convulsant drugs that inhibit the binding of dihydropicrotoxinin and also by bicuculline. These interactions involving barbiturates and other modulatory drugs, exhibit stereoselectivity, anion dependence and brain regional selectivity. Several classes of drugs which facilitate GABAergic transmission appear to interact with the sites for GABA and benzodiazepines allosterically via the dihydropicrotoxinin site of the oligomeric complex. The GABA system has also been implicated in a variety of pathological conditions, including anxiety, seizure activity, movement disorders, cardiovascular control, pain and in drug dependence. Since most of the GABA agonists do not pass the blood-brain barrier, future trends in the pharmacology of GABA may be the development of drugs that will activate the GABA receptor system via picrotoxinin or benzodiazepine sites.

Animals↗
PubMed1983

The effects of chronic haloperidol administration on GABA receptor binding.

The effect of chronic administration of haloperidol for 30 days and its subsequent withdrawal for 0, 4 and 8 days on the binding of [3H]-GABA and [3H]-muscimol to GABA binding sites in rat brain membranes obtained from six discrete regions of the brain and spinal cord was investigated. The chronic administration of haloperidol resulted in a marked increase in the number of GABA binding sites within the substantia nigra, but did not affect GABA binding sites in other regions of rat brain or spinal cord. The increase in GABA binding sites in the substantia nigra was evident for at least 4 days following termination of haloperidol treatment; however, 8 days following withdrawal from haloperidol, when dopaminergic supersensitivity had become maximally expressed, the number of GABA binding sites in the substantia nigra had declined and was the same as that observed in the control rats. These observations suggest that blockade of dopamine receptors in the striatum by haloperidol results in a compensatory decrease in the activity of the GABAergic strionigral system that leads to an increase in the number of GABA binding sites within the substantia nigra. This increase in the number of GABA binding sites is gradually reversed when dopamine is again allowed to interact with its receptors.

Animals↗
PubMed1983

The interactions of ethanol with the benzodiazepine-GABA receptor-ionophore complex.

Ethanol, barbiturates and benzodiazepines have similar pharmacological effects. All of these drugs facilitate the inhibitory transmission mediated by GABA. Drugs that facilitate GABAergic transmission are effective in alleviating ethanol withdrawal symptoms. Acute ethanol administration increases the number of low affinity GABA receptor sites, while, during ethanol withdrawal, the affinity of this site is decreased. This decreased affinity during withdrawal correlated with the audiogenic seizure activity. These results indicate that in vivo ethanol interacts with GABA receptors, and this interaction may be responsible for some of the effects of ethanol and for some symptoms of withdrawal. Ethanol, like pentobarbital, also enhances [3H]diazepam binding to the Lubrol-solubilized membrane fraction in vitro. This effect was dose-related and was blocked by picrotoxinin and other GABA antagonists. Enhancement of [3H]diazepam binding by various alcohols did not correlate with lipid:water partition coefficients. Ethanol also partially inhibited the binding of [3H]-alpha-dihydropicrotoxinin in the Lubrol-solubilized fraction. These results indicate that ethanol, like pentobarbital, may modulate the benzodiazepine binding component of the benzodiazepine-GABA receptor-ionophore complex via the picrotoxinin site. The possible interpretation of these results, in relation to the GABAergic transmission, is discussed.

Animals↗
PubMed1983

Enhancement of diazepam and gamma-aminobutyric acid binding by (+)etomidate and pentobarbital.

(+)Etomidate and pentobarbital enhance [3H]diazepam and [3H]gamma-aminobutyric acid [( 3H]GABA) binding to cerebral cortex membranes. Both (+)etomidate and pentobarbital increase the affinity of [3H]diazepam for its binding sites. In contrast, they increase the Bmax of both the high- and low-affinity GABA receptor sites. The enhancement of [3H]diazepam and [3H]GABA by (+)etomidate and pentobarbital is blocked by GABA antagonists. These results indicate that hypnotic drugs such as (+)etomidate and pentobarbital, which are not structurally related, modulate diazepam and GABA binding sites via similar mechanisms.

Animals↗
PubMed1983

Group-selective reagent modification of the benzodiazepine-gamma-aminobutyric acid receptor-ionophore complex reveals that low-affinity gamma-aminobutyric acid receptors stimulate benzodiazepine binding.

The modification of membrane proteins with diethylpyrocarbonate (DEP) and diazotized sulfanilate was investigated on the binding of three benzodiazepine radioligands in three brain regions. Both of these reagents produced a dose-dependent inactivation of [3H] diazepam, [3H]flunitrazepam, and [3H]propyl beta-carboline-3-carboxylate binding to cortex, cerebellum, and hippocampus. Both DEP and diazotized sulfanilate decrease the Bmax of the benzodiazepine binding sites without altering the KD. The ability of muscimol and pentobarbital to enhance [3H]diazepam binding was not altered by DEP pretreatment in any of the three regions. Scatchard analysis indicated that, following the inactivation of 40-50% of [3H]diazepam binding by 1 mM DEP, pentobarbital and muscimol were still able to increase the affinity of [3H]diazepam binding in cortex, cerebellum, and hippocampus. In contrast, diazotized sulfanilate pretreatment abolishes the ability of muscimol and pentobarbital to enhance [3H]diazepam binding in these three regions. The effects of these reagents on [3H] gamma-aminobutyric acid (GABA) binding revealed that sulfanilate but not DEP eliminates the low-affinity GABA receptor sites in cortex and cerebellum. Thus, while both DEP and sulfanilate inactivate benzodiazepine binding sites, only sulfanilate abolishes the low-affinity GABA binding sites and the ability of the GABA agonists to enhance [3H]diazepam binding. These results suggest that the stimulation of benzodiazepine binding appears to be mediated by the low-affinity GABA receptors.

Animals↗
PubMed1982

Molecular interactions of etazolate with benzodiazepine and picrotoxinin binding sites.

Pyrazolopyridines, such as etazolate (SQ 20009), enhance [3H]diazepam binding to a Lubrol-solubilized fraction that has specific binding sites for 3H benzodiazepines, [alpha-3H]dihydropicrotoxinin (DHP) and [3H]muscimol. Etazolate enhancement of [3H]diazepam binding was inhibited by picrotoxinin. Furthermore, etazolate inhibited the [3H]DHP binding in a Lubrol-solubilized fraction with an IC50 value of 6-8 microM. These results provide evidence that etazolate, like pentobarbital, modulates benzodiazepine binding via the DHP-sensitive site of the benzodiazepine-GABA receptor-ionophore complex.

Animals↗
PubMed1981

Pentobarbital enhances [3H]diazepam binding to soluble receptors at the benzodiazepine--GABA-receptor-ionophore complex.

Pentobarbital enhances [3H]diazepam binding to soluble receptors in a dose-dependent and saturable manner. Half-maximal enhancement occurred at 110 micrometers pentobarbital. This enhancement was due to an increase in the affinity of diazepam to its receptor sites. Pentobarbital enhancement was blocked by picrotoxinin and bicuculline. These results are similar to those reported for membranes and suggest that various components of the benzodiazepine--GABA-receptor-ionophore complex are intimately associated.

Animals↗
PubMed1981

Interaction of stereoisomers of barbiturates with [3H]alpha-dihydropicrotoxinin binding sites.

Racemic depressant barbiturates inhibit the binding of gamma-aminobutyric acid antagonist [3H]alpha-dihydropicrotoxinin (DHP) to rat brain membranes with IC50 values ranging from 5 to 50 microM. The (-) isomers of pentobarbital and secobarbital were three to four-fold more potent that their (+) isomers in inhibiting [3H]DHP binding. In contrast, the (+) isomer of hexobarbital was a better inhibitor than (-) hexobarbital. The stereoisomers of 1-methyl-5-phenyl-5-propylbarbituric acid (MPPB), which show opposite pharmacological activity, inhibited [3H]DHP binding in a biphasic manner with a plateau at 4-100 nM MPPB. These results suggest heterogeneity of DHP binding sites. The possibility that depressant and convulsant barbiturates may act at the level of DHP site at the GABA synapse is discussed.

Animals↗
PubMed1981

Histidine modification with diethyl pyrocarbonate shows heterogeneity of benzodiazepine receptors.

The effect of diethyl pyrocarbonate modification of histidine on the specific binding of [3H]diazepam and its enhancement with muscimol and (+/-)-pentobarbital was investigated. Diethyl pyrocarbonate treatment produced a dose-related inhibition of specific [3H]diazepam binding to rat brain membranes with a maximal inhibition of approximately 40% at 1 mM. Scatchard analysis of the binding data showed that diethyl pyrocarbonate, while having no effect on the affinity (Kd), decreased the binding capacity (Bmax) of diazepam from a control value of 1543 +/- 116 fmol/mg of protein to 789 +/- 79 fmol/mg of protein (mean +/- SD; P less than 0.005; n = 4). Under conditions in which approximately 40% of the diazepam binding sites were modified by diethyl pyrocarbonate treatment, the ability of muscimol and pentobarbital to enhance diazepam binding was not altered. These results suggest that a histidine residue is critical for a part (approximately 40%) of the benzodiazepine binding sites and that there may exist a heterogeneity of benzodiazepine binding sites. Furthermore, these results indicate that perhaps only a portion of the benzodiazepine binding sites are functionally coupled to the gamma-aminobutyric acid receptor-ionophore complex.

Animals↗
PubMed1981

Solubilization of the picrotoxinin binding receptor from mammalian brain.

The binding sites for alpha-dihydropicrotoxinin (DHP), which is a ligand for the picrotoxin-sensitive component at the benzodiazepine-gamma-aminobutyric acid-receptor-ionophore complex, has been solubilized from rat brain, using 1% Lubrol. A new assay, which involves precipitation of the [3H]DHP-soluble protein complex by gamma-globulin and polyethylene glycol (PEG), followed by centrifugation, is described. The solubilized material bound DHP to two sites with apparent affinities of 0.038 and 1.85 microM. The binding of DHP to the solubilized receptors was inhibited by convulsant and depressant drugs with potencies similar to those required for membrane receptors. The ability of barbiturates to inhibit DHP binding to both solubilized and membrane receptors strongly suggests that barbiturates may interact with the picrotoxin binding component. These data suggest that ligand recognition properties of the picrotoxinin binding are not altered by solubilization. The binding was abolished by urea and partially destroyed by heating the soluble extract at 65 degrees C for 30 min. This new method of measuring the binding of ligands to the solubilized receptors by PEG centrifugation might be used successfully in other solubilization studies.

Animals↗
PubMed1981

Picrotoxinin and diazepam bind to two distinct proteins: further evidence that pentobarbital may act at the picrotoxinin site.

alpha-[3H]Dihydropicrotoxinin (DHP) and [3H]diazepam binding proteins were solubilized from rat brain membranes with 1% Lubrol-Px. Gel filtration of the Lubrol-solubilized fraction revealed that [3H]DHP and [3H]diazepam bind to two distinct peaks with apparent molecular weights of 185,000 and 61,000, respectively. The signal-to-noise ratio of [3H]DHP binding to 185,000-dalton fractions was improved significantly. [3H]DHP bound to the 185,000-dalton fraction with two binding constants. Muscimol and pentobarbital, while enhancing [3H]diazepam binding to membrane and crude Lubrol-solubilized fractions, failed to enhance [3H]diazepam binding to the 61,000-dalton fraction. Pentobarbital inhibited the binding of [3H]DHP to the 185,000-dalton fraction with an IC50 value of 60 +/- 12 micro M. The binding of [3H]DHP alos was inhibited by several depressant and convulsant drugs which affect gamma-aminobutyric acid (GABA)-mediated transmission. These results provide strong evidence that picrotoxinin and diazepam bind to two distinct proteins and that pentobarbital may act at the picrotoxinin-sensitive site of the benzodiazepine . GABA receptor . ionophore complex.

Animals↗