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Biomedical subjects

G Biggio

Publications and source records attributed to G Biggio.

At least 55 records · Page 3Linked to original sources
PubMed1998

Role of brain allopregnanolone in the plasticity of gamma-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery.

The relation between changes in brain and plasma concentrations of neurosteroids and the function and structure of gamma-aminobutyric acid type A (GABAA) receptors in the brain during pregnancy and after delivery was investigated in rats. In contrast with plasma, where all steroids increased in parallel, the kinetics of changes in the cerebrocortical concentrations of progesterone, allopregnanolone (AP), and allotetrahydrodeoxycorticosterone (THDOC) diverged during pregnancy. Progesterone was already maximally increased between days 10 and 15, whereas AP and allotetrahydrodeoxycorticosterone peaked around day 19. The stimulatory effect of muscimol on 36Cl- uptake by cerebrocortical membrane vesicles was decreased on days 15 and 19 of pregnancy and increased 2 days after delivery. Moreover, the expression in cerebral cortex and hippocampus of the mRNA encoding for gamma2L GABAA receptor subunit decreased during pregnancy and had returned to control values 2 days after delivery. Also alpha1, alpha2, alpha3, alpha4, beta1, beta2, beta3, and gamma2S mRNAs were measured and failed to change during pregnancy. Subchronic administration of finasteride, a 5alpha-reductase inhibitor, to pregnant rats reduced the concentrations of AP more in brain than in plasma as well as prevented the decreases in both the stimulatory effect of muscimol on 36Cl- uptake and the decrease of gamma2L mRNA observed during pregnancy. These results indicate that the plasticity of GABAA receptors during pregnancy and after delivery is functionally related to fluctuations in endogenous brain concentrations of AP whose rate of synthesis/metabolism appears to differ in the brain, compared with plasma, in pregnant rats.

Animals↗
PubMed1998

Propofol analogues. Synthesis, relationships between structure and affinity at GABAA receptor in rat brain, and differential electrophysiological profile at recombinant human GABAA receptors.

A number of propofol (2,6-diisopropylphenol) congeners and derivatives were synthesized and their in vitro capability to affect GABAA receptors determined by the inhibition of the specific [35S]-tert-butylbicyclophosphorothionate ([35S]TBPS) binding to rat whole brain membranes. Introduction of halogen (Cl, Br, and I) and benzoyl substituents in the para position of the phenyl group resulted in ligands with higher potency at inhibiting [35S]TBPS binding. A quantitative structure-affinity relationship (QSAR) study demonstrated that affinity is enhanced by increases in lipophilicity of the ligand whereas affinity is adversely affected by increases in size of the substituent para to the phenolic hydroxyl group. Consistent with the displacement of [35S]TBPS and with the activation of GABAA receptors, we demonstrate that ligands displaying high affinity (i.e., 2-4, and 8) are able to increase GABA-stimulated chloride currents in oocytes expressing human GABAA receptors and to directly activate chloride currents in an electrophysiological assay. Among them, compound 4 showed a rather peculiar profile in the electrophysiological examination with cloned alpha1beta2gamma2 GABAA receptors. Indeed, compared to propofol, it displayed a much greater efficacy at potentiating GABA-elicited chloride currents, but a much lower efficacy at producing a direct activation of the chloride channel in the absence of GABA. This behavior may give to compound 4 pharmacological properties that are more similar to anxiolytic and anticonvulsant drugs than to those of general anesthetics.

Anesthetics, Intravenous↗
PubMed1998

Rapid increase in basal acetylcholine release in the hippocampus of freely moving rats induced by withdrawal from long-term ethanol intoxication.

The effect of ethanol withdrawal on hippocampal acetylcholine (ACh) release was investigated by brain microdialysis in rats rendered ethanol dependent by repeated forced administration of a 20% ethanol solution for 7 days. The behavioral signs of ethanol withdrawal were accompanied by an increase in hippocampal ACh output that was significantly 6 h after the last ethanol administration, reached a maximum (fourfold) at 12 h, and persisted for >72 h. Administration of diazepam (5 mg/kg, i.p.) or gamma-hydroxybutyrate (1 g/kg, intragastric) 12 h after the last ethanol administration completely antagonized, within 30 min, the increase in ACh output induced by ethanol withdrawal. Thus, the rapid and marked increase in ACh output might contribute to the changes in cognitive function associated with ethanol withdrawal, and the septohippocampal cholinergic system may play a major role in the response to withdrawal of addictive drugs.

Acetylcholine↗
PubMed1998

Antagonism by abecarnil of enhanced acetylcholine release in the rat brain during anticipation but not consumption of food.

Changes in the extracellular concentration of acetylcholine (ACh) were evaluated in the prefrontal cortex and hippocampus of freely moving rats habituated for 35 days to consume their daily meal during a fixed 2-h period. During the 40 min immediately before presentation, ACh output increased by 49 and 55% in the prefrontal cortex and hippocampus, respectively. ACh release increased further during the first 40 min of consumption phase in the prefrontal cortex (+220%) and hippocampus (175%). Administration of abecarnil (0.1 mg/kg, IP) 40 min before food presentation prevented the increase in ACh output in both brain regions during the anticipatory phase. In contrast, although abecarnil reduced the ACh content achieved during the consummatory phase, it did not prevent the increase in ACh release in the prefrontal cortex or hippocampus induced by food intake. Finally, the binding of [35S]TPBS to cerebral cortex, hippocampus, or septum of rats killed 20 min before food presentation was significantly higher than the values for animals killed 2 h after food presentation. These results suggest that during ingestive behavior ACh release is regulated by at least two independent mechanisms: one, associated with the anticipatory phase, that is sensitive to the activation of GABA(A) receptors. and a second, associated with the consummatory phase, that is insensitive to abecarnil.

Acetylcholine↗
PubMed1998

Modulation of gamma-aminobutyric acid (GABA) receptors and the feeding response by neurosteroids in Hydra vulgaris.

Gamma-Aminobutyric acid (GABA) receptors are present in membrane preparations from Hydra vulgaris, one of the most primitive organisms with a nervous system. These receptors are sensitive to muscimol and benzodiazepines and appear to be important in the regulation of the feeding response. The effects of neurosteroids, general anaesthetics, and GABA antagonists on GABA(A) receptors in membranes prepared from Hydra and on the feeding response have now been investigated. The neurosteroids tetrahydroprogesterone and tetrahydrodeoxycorticosterone increased [3H]GABA binding to hydra membranes with nanomolar potency (EC50, 141+/-11 and 623+/-36 nM, respectively) and high efficacy (maximal increase 79+/-6.5 and 62+/-4%, respectively), whereas the 3beta-hydroxy epimer of tetrahydroprogesterone was ineffective. The benzodiazepine receptor ligands diazepam (100 microM), clonazepam (100 microM) and abecarnil (30 microM) enhanced [3H]GABA binding to Hydra membranes by 22, 20 and 24%, respectively; effects abolished by the specific benzodiazepine antagonist flumazenil (100 microM). On the contrary, the peripheral benzodiazepine receptor ligand 4'chlorodiazepam failed to affect [3H]GABA binding to Hydra membranes. The general anaesthetics propofol and alphaxalone similarly increased (+38% and +30% respectively) [3H]GABA binding. Moreover, [3H]GABA binding to Hydra membranes was completely inhibited by the GABA(A) receptor antagonist SR 95531, whereas bicuculline was without effect. The modulation of GABA(A) receptors in vitro by these various drugs correlated with their effects on the glutathione-induced feeding response in the living animals. Tetrahydroprogesterone and tetrahydrodeoxy-corticosterone (1 to 10 microM) prolonged, in a dose-dependent manner, the duration of mouth opening induced by 10 microM glutathione, with maximal effects of +33 and +29%, respectively, apparent at 10 microM neurosteroid. Alphaxalone (10 microM) similarly increased (+33%) the effect of glutathione. The effects of steroids on the feeding response were inhibited by SR 95531 in a dose-dependent manner; t-butylbyclophosphorothyonate (1 microM), a specific Cl- channel blocker, which per se, like picrotoxin but not bicuculline, shortened the duration of the response, also counteracted the steroids effects at 1 microM. These results suggest that the modulation of GABA(A) receptors by steroids is an ancient characteristic of the animal kingdom and that the pharmacological properties of these receptors have been highly conserved through evolution.

Anesthetics↗
PubMed1998

High affinity central benzodiazepine receptor ligands: synthesis and structure-activity relationship studies of a new series of pyrazolo[4,3-c]quinolin-3-ones.

A large series of 2-aryl(heteroaryl)-2,5-dihydropyrazolo[4,3-c]quinolin- 3-(3H)-ones, carrying appropriate substituents at the quinoline and N2-phenyl rings, were prepared and tested as central benzodiazepine receptor ligands. Results from structure-affinity relationship studies were in full agreement with previously proposed pharmacophore models and, in addition, quantitative structure-activity analysis gave further significant insight into the main molecular determinants of high benzodiazepine receptor affinity. The intrinsic activity of some active ligands was also determined and preliminary discussed.

Animals↗
PubMed1998

Functional changes in rat nigral GABA(A) receptors induced by degeneration of the striatonigral GABAergic pathway: an electrophysiological study of receptors incorporated into Xenopus oocytes.

Expression of rat brain gamma-aminobutyric acid type A (GABA(A)) receptors in Xenopus laevis oocytes can be achieved by injection of the oocytes with synaptosomes. This approach has now been applied to evaluate changes in the function of nigral GABA(A) receptors after degeneration of the striatonigral GABAergic pathway induced by the unilateral infusion of kainic acid into the rat striatum. Ten days after striatal injection, synaptosomal membranes were prepared from the substantia nigra and introduced into oocytes. Nigral GABA(A) receptors incorporated into the oocyte cell membrane were then characterized electrophysiologically under voltage-clamp conditions. The maximal amplitude of GABA-induced Cl- currents in oocytes injected with synaptosomes from denervated substantia nigra was twice that observed in oocytes injected with synaptosomes from control substantia nigra. The concentration of GABA required for the half-maximal response did not differ between the two groups of oocytes. In addition, the potentiation of GABA-induced currents by the benzodiazepine diazepam (1 microM) and the steroid derivative allopregnanolone (3 microM) was increased by approximately 65 and 60%, respectively, in oocytes injected with synaptosomes from denervated substantia nigra compared with those injected with control synaptosomes. The concentrations of diazepam and allopregnanolone giving half-maximal responses were not affected by denervation. In contrast, the inhibitory effects of the benzodiazepine receptor inverse agonists FG 7142 (10 microM) and 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylic acid ethyl ester (1 microM) were reduced by 48 and 38%, respectively, after denervation. These results indicate that the up-regulation of nigral GABA(A) receptors induced by degeneration of the striatonigral GABAergic pathway is associated with an increased efficacy of positive allosteric modulators, such as benzodiazepines and steroids, and with a reduced efficacy of negative allosteric modulators such as beta-carbolines.

Animals↗
PubMed1998

Molecular and functional adaptation of the GABA(A) receptor complex during pregnancy and after delivery in the rat brain.

The abundance of gamma-aminobutyric acid receptor type A (GABAA receptor) subunit mRNAs and polypeptides as well as muscimol-stimulated 36Cl- uptake were measured in rat cerebral cortex or hippocampus at various times during pregnancy and after delivery. RNase protection assays revealed that the amount of the gamma2L subunit mRNA decreased progressively during pregnancy, in the cerebral cortex and hippocampus, and then returned to control values around the time of delivery. A similar pattern was observed for the alpha5 subunit mRNA in the cerebral cortex, whereas no significant changes were apparent for alpha1, alpha2, alpha3, alpha4, beta1, beta2, beta3 and gamma2S subunit mRNAs. The amounts of gamma2 and alpha1 proteins in the cerebral cortex were measured by immunoblot analysis; whereas the abundance of gamma2 protein decreased during pregnancy, no change was detected in the amount of alpha1 protein. Evaluation for functional significance of the down-regulated gamma2 and alpha5 subunit was made by determining the GABAA receptor function assessed by measurement of muscimol-stimulated 36Cl- uptake in cerebral cortical membrane vesicles. Muscimol-induced 36Cl- uptake was markedly reduced during of pregnancy compared with rats in oestrus. At this same time, the potentiating effects of diazepam and allopregnanolone on muscimol stimulation of 36Cl- uptake also were reduced. In contrast, the effects of muscimol, allopregnanolone and diazepam were significantly increased, relative to animals in oestrus, after delivery.

Allosteric Regulation↗
PubMed1997

Synthesis and binding affinity of 2-phenylimidazo[1,2-alpha]pyridine derivatives for both central and peripheral benzodiazepine receptors. A new series of high-affinity and selective ligands for the peripheral type.

A number of 6-substituted or 6,8-disubstituted alkyl 2-phenylimidazo[1,2-alpha]pyridine-3-carboxylates 5a-h, -acetates 5i-s, 6a-g, and -propionates 5t, 6h and of N,N-dialkyl-2-phenylimidazo[1,2-alpha]pyridine-3-carboxamides 7a-d,-acetamides 7e-t or -propionamide 7u were prepared following new synthetic methods, and their affinities for both the central (CBR) and the peripheral (PBR) benzodiazepine receptors evaluated. The compounds of the ester series displayed low affinity for both receptor types. Conversely, most of N,N-dialkyl(2-phenylimidazo[1,2-alpha]pyridin-3-yl)acetamides 7e-t proved to possess high affinity and selectivity for CBR or PBR depending on the nature of substituents at C(6)- and/or C(8) on the heterocyclic ring system. In particular, the 6-substituted compounds 7f-n displayed ratios of IC50 values (IC50(CBR)/IC50(PBR)) ranging from 0.32 (7m) to 232 (7k), while the 6,8-disubstituted compounds 7o-t were more than 1000-fold more selective for PBR versus CBR. Compounds 7f,m were examined in several different benzodiazepine receptor subtypes. Expression of specific GABAA, receptor subunit assemblies in Xenopus oocytes was utilized to evaluate functionally both the efficacy and potency of the positive modulation of GABA-evoked Cl- currents by 7f and 7m in comparison with Zolpidem. The rank order of potencies of these drugs was 7f (EC50 = 3.2 x 10(-8) M) > Zolpidem (EC50 = 3.6 x 10(-8) M) > 7m (EC50 = 2.2 x 10(-7) M). The actions of these compounds were also tested on alpha 2 beta 2 gamma 2s, receptors. However, the EC50 of these compounds was increased, compared to alpha 1 beta 2 gamma 2s receptors, by 30-, 4-, and 5-fold for 7m, 7f, and Zolpidem, respectively. Finally, these compounds were almost completely devoid of activity at receptors containing the alpha 5 subunit.

Animals↗
PubMed1997

Modulation of 6-hydroxydopamine oxidation by various proteins.

The spontaneous autoxidation of the neurotoxin 6-hydroxydopamine proceeds by a free radical chain reaction involving the superoxide anion radical and produces the corresponding chromogen 6-hydroxydopamine quinone and hydrogen peroxide. The rate of this reaction is increased in the presence of ceruloplasmin and peroxidase, and reduced by superoxide dismutase, catalase, and DT-diaphorase. We report some explanations of why these proteins may increase or reduce the rate of autoxidation of 6-hydroxydopamine.

Animals↗
PubMed1997

Reversal of a selective decrease in hippocampal acetylcholine release, but not of the persistence of kindling, after discontinuation of long-term pentylenetetrazol administration in rats.

The time course of the effect of pentylenetetrazol (PTZ)-induced kindling on acetylcholine release in the hippocampus of freely moving rats was investigated with the transversal microdialysis technique. The basal extracellular concentration of acetylcholine in the hippocampus was reduced significantly (-29%, P < 0.05) after 3 weeks, and the effect was maximal (-52%, P < 0.01) after 4 weeks and remained essentially unchanged during the remaining 4 weeks of PTZ treatment (30 mg/kg, i.p., 3 times/week), relative to vehicle-treated rats. The basal release of acetylcholine in the prefrontal cortex and in the striatum of kindled rats was unchanged compared with that of vehicle-treated rats. The specific binding of [3H]quinuclidinyl benzilate, a non-selective ligand of muscarinic receptors, was significantly increased (+29%, P < 0.01) in hippocampal membrane, but not in membranes prepared from the prefrontal cortex or striatum, of PTZ-kindled rats. Thirty days after discontinuation of PTZ treatment, both hippocampal acetylcholine output and the density of muscarinic receptors had returned to values characteristic of vehicle-treated rats, whereas seizure susceptibility did not differ significantly from that apparent 4 days after PTZ administration. These results suggest that the selective and transient decrease in acetylcholine output and the parallel increase in the density of postsynaptic muscarinic receptors in the hippocampus may play a role in facilitating the development of kindling rather than in the maintenance of the kindled state.

Acetylcholine↗
PubMed1997

Enhancement of basal and pentylenetetrazol (PTZ)-stimulated dopamine release in the brain of freely moving rats by PTZ-induced kindling.

The effects of pentylenetetrazol (PTZ)-induced kindling on the activity of mesocortical, mesoaccumbens, and nigrostriatal dopaminergic neurons was investigated with the transversal microdialysis technique in freely moving rats. Four days after the last chronic administration of PTZ, the basal extracellular concentrations of dopamine in the prefrontal cortex, nucleus accumbens, and striatum of kindled rats were significantly increased (+76, +36, +49%, respectively) relative to those of animals chronically treated with saline. Moreover, dopamine output was markedly more sensitive to the effect of a challenge injection of PTZ (20 mg/kg ip) in the prefrontal cortex (+93 vs. +50%, relative to basal values), the nucleus accumbens (+36 vs. +4%), and the striatum (+50 vs. + 35%) of kindled rats relative to that in the control animals. Because kindled rats and their controls are habituated to handling, the neurochemical mechanisms that underlie the effects of chemical kindling on the sensitivity of dopaminergic neurons to PTZ were investigated by comparing the effects of an acute administration of PTZ (20 mg/kg ip) between naive and handling-habituated animals. The sensitivity of dopamine output to PTZ in naive rats was markedly greater than that in handling-habituated animals for the prefrontal cortex (+83 vs. +50%) and nucleus accumbens (+35 vs. +4%), but not for the striatum (+35 vs. +32%). These results indicate that PTZ kindling enhances the basal activity and the sensitivity to PTZ of dopamine neurons in rat brain and suggest that mesocortical, mesoaccumbens, and nigrostriatal dopaminergic neurons contribute to the central alterations associated with experimental epilepsy.

Animals↗
PubMed1997

Enhancement by flumazenil of dopamine release in the nucleus accumbens of rats repeatedly exposed to diazepam or imidazenil.

The effect of long-term treatment (three times daily for 3 weeks) with a behaviorally relevant dose of the benzodiazepine receptor partial agonist imidazenil (0.5 mg/kg, IP) on basal dopamine release in the nucleus accumbens of freely moving rats was compared with that of diazepam (3 mg/kg, IP), a benzodiazepine receptor full agonist. Challenge doses of imidazenil and diazepam decreased the extracellular dopamine concentration in the nucleus accumbens by approximately the same extent in animals repeatedly exposed to vehicle or to the respective drug. Moreover, the abrupt discontinuation of long-term treatment with diazepam or imidazenil failed to affect basal dopamine release in this brain area during the first 5 days of withdrawal. In contrast, administration of the benzodiazepine receptor antagonist flumazenil (4 mg/kg, IP) elicited a marked increase (95 or 60%) in dopamine release in the nucleus accumbens 6 h after withdrawal of diazepam or imidazenil, respectively. Flumazenil induced a similar but smaller effect (50% increase) 5 days after diazepam withdrawal but had no effect 5 days after discontinuation of imidazenil treatment. The results support an involvement of the mesoaccumbens dopaminergic neurons in the withdrawal syndrome precipitated by flumazenil and allow further differentiation of benzodiazepine receptor partial and full agonists with respect to dependence liability of dopaminergic neurons in the nucleus accumbens.

Animals↗
PubMed1997

Antagonism of convulsions but failure to enhance GABA(A) receptor function by felbamate in mice tolerant to diazepam.

The transfer of tolerance between drugs may indicate a common mode of action. The development of cross-tolerance to the anticonvulsant effect of felbamate after long-term treatment of mice with diazepam, a positive modulator of gamma-aminobutyric acid (GABA)-mediated transmission, was therefore studied in order to clarify the mechanism of this action of felbamate. A challenge injection of felbamate, administered 36 h after the last dose of chronic diazepam treatment, antagonized convulsions elicited by administration of isoniazid. In contrast, felbamate had no effect on the isoniazid-induced increase in t-[35S]butylbicyclophosphorothionate binding to cerebral cortical membranes of diazepam-tolerant mice. These results suggest that the action of felbamate on GABAergic transmission is not required for the anticonvulsant effect of this drug. This conclusion is consistent with studies that have indicated that the antiepileptic activity of felbamate depends on its modulatory activity at excitatory amino acid receptors.

Animals↗
PubMed1997

The effects of inhibitors of GABAergic transmission and stress on brain and plasma allopregnanolone concentrations.

1. This study was undertaken to investigate the relationship between a reduction in brain GABAA receptor function and the cerebro-cortical content of 3 alpha-hydroxy-5 alpha-pregnan-20 one (allopregnanolone, AP), a potent endogenous positive modulator of 7-aminobutyric acid (GABA) action at GABAA receptors, with anticonflict and anticonvulsant effects in rodents. 2. An acute depletion of the cerebral content of GABA or an attenuation of GABAA receptor-mediated transmission by systemic injections of isoniazid (375 mg kg-1, s.c.) or FG 7142 (15 mg kg-1, i.p.) induced a transient increase in the cerebro-cortical and plasma concentrations of AP in handling-habituated (not stressed) rats. 3. Two stress paradigms, handling in naive rats and mild foot shock in handling-habituated rats, that reduce central GABAergic tone mimicked the effects of isoniazid and FG 7142 on cortical AP content; foot shock in handling-habituated rats, but not handling in naive animals, also increased plasma AP. Isoniazid, FG 7142, and foot shock also each increased the concentrations of the AP precursors, pregnenolone and progesterone, in both brain and plasma of handling-habituated rats, whereas handling in naive rats increased the concentrations of these steroids only in brain. 4. Pretreatment of handling-habituated rats with the anxiolytic beta-carboline derivative abecarnil, a positive allosteric modulator of GABAA receptors, which per se failed to affect the AP concentration in brain or plasma, prevented the increase in brain and plasma AP induced by foot shock or isoniazid. 5. In adrenalectomized and castrated rats foot shock or isoniazid failed to increase AP both in brain cortex and plasma. 6. These observations indicate that inhibition of GABAergic transmission, induced by foot shock or pharmacological manipulations, results in an increase in the concentrations of AP in brain and plasma, possibly via a modulation of hypothalamic-pituitary-adrenal (HPA) axis. 7. Given that AP enhances GABAA receptor function with high efficacy and potency, an increase in brain AP concentration may be important in the fine tuning of the GABA-mediated inhibitory transmission in the central nervous system.

Adrenalectomy↗
PubMed1997

Effect of pentylenetetrazole-induced kindling on acetylcholine release in the hippocampus of freely moving rats.

The role of gamma-aminobutyric acid (GABA) modulation of septohippocampal cholinergic neurons in kindling was investigated. Hippocampal acetylcholine release was evaluated with the microdialysis technique in freely moving rats either after acute administration of isoniazid (an inhibitor of GABA synthesis) or pentylenetetrazole (PTZ) (a blocker of the GABAA receptor-associated Cl- channel) or after chronic administration of PTZ. Short-term treatment with PTZ (5-50 mg/kg, i.p.) or isoniazid (150-250 mg/kg, s.c.) increased hippocampal acetylcholine release in a dose-dependent manner. In contrast, the basal concentration of acetylcholine in the dialysate from the hippocampus of rats chronically treated with PTZ (kindled animals) was significantly reduced relative to that of vehicle-treated rats (2.39 +/- 0.21 vs. 4.2 +/- 0.31 pmol per 20-min sample; p < 0.01). Moreover, the release of acetylcholine was markedly more sensitive to the effect of a challenge injection of PTZ (10 or 20 mg/kg, i.p.) in kindled rats than in naive rats or rats chronically treated with vehicle. Abecarnil, a selective benzodiazepine receptor agonist with marked anticonvulsant activity, was administered together with chronic PTZ to evaluate whether persistent activation of GABAA receptors and suppression of seizures during kindling might affect the sensitivity of septohippocampal cholinergic neurons to a challenge dose of PTZ. Abecarnil (1 mg/kg, i.p.) administered 40 min before each PTZ injection neither antagonized the decrease in basal acetylcholine release (2.26 +/- 0.19 pmol per 20-min sample) nor prevented the development of kindling. In contrast, abecarnil prevented the chronic PTZ-induced increase in the sensitivity of acetylcholine release to a challenge dose of PTZ. These results provide novel in vivo data concerning the role of hippocampal acetylcholine function in the development of kindling and potentially in the learning and memory deficits associated with this phenomenon.

Acetylcholine↗
PubMed1997

Differential subunit dependence of the actions of the general anesthetics alphaxalone and etomidate at gamma-aminobutyric acid type A receptors expressed in Xenopus laevis oocytes.

The effects of subunit composition of the gamma-aminobutyric acid (GABA) type A receptor on the multiple actions of the general anesthetics alphaxalone and etomidate were investigated. The abilities of the two drugs to activate directly Cl- currents and to modulate GABA-evoked Cl- currents mediated by human recombinant GABA(A) receptors composed of alpha1, gamma2S, and either beta1, beta2, or beta3 subunit expressed in Xenopus laevis oocytes were compared. Both alphaxalone and etomidate evoked Cl currents in alpha1 beta1 gamma2S, alpha1 beta2 gamma2S, and alpha1 beta3 gamma2S receptors, an action that was blocked by both SR 95531 and picrotoxin. However, although maximal current activation by alphaxalone varied only slightly with the specific beta subunit isoform present, the efficacy of etomidate showed a rank order of beta3 > beta2 >>> beta1. In addition, beta1 homomeric receptors were markedly activated by etomidate but not by alphaxalone. Conversely, receptors consisting of alpha1 and gamma2S subunits were markedly activated by alphaxalone but not by etomidate. The modulatory effect of alphaxalone was also not markedly influenced by the beta-specific subunit isoform, whereas the modulatory efficacy of etomidate showed a rank order of beta3 > beta2 >> beta1. These results further demonstrate that the actions of general anesthetics at GABA(A) receptors are influenced by receptor subunit composition, and they suggest that the effects of alphaxalone and etomidate are mediated by different binding sites on the receptor complex.

Anesthetics↗