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PubMed2004

Effects of galantamine, a nicotinic allosteric potentiating ligand, on nicotine-induced catecholamine release in hippocampus and nucleus accumbens of rats.

Galantamine, a drug for treatment of Alzheimer's disease, is a novel cholinergic agent with a dual mode of action that inhibits acetylcholinesterase and allosterically modulates nicotinic cholinergic receptors (nAChRs). Nicotine stimulates catecholamine secretion, inducing hippocampal norepinephrine (NE) release, and improves memory consolidation. Thus, the effect of galantamine on nicotine-induced hippocampal NE secretion was investigated. This was compared with the effect of galantamine on nicotine-induced dopamine (DA) release within the nucleus accumbens of the same rat. Nicotine (0.025-0.09 mg/kg i.v.) dose dependently increased NE and DA levels in microdialysates from the hippocampus and nucleus accumbens, respectively, of freely moving rats. Pretreatment with galantamine (3.0 mg/kg s.c.) 3 h before nicotine either potentiated NE responses to doses of nicotine that were ineffective alone (0.025-0.045 mg/kg) or significantly enhanced (0.065 mg/kg) NE responses, whereas galantamine was ineffective when administered 2 or 4 h before nicotine. In contrast to its effects on NE, galantamine did not alter accumbal DA responses to any dose of nicotine. These selective effects of galantamine on nicotine-stimulated NE secretion may reflect differences in local neural circuits that use nAChRs to modulate hippocampal NE versus accumbal DA release.

Allosteric Regulation↗
PubMed2005

[The role of neurosteroids in the central nervous system function].

Neurosteroids--important modulators of the central nervous system activity--have been biochemically and functionally well characterized in recent years. Inhibitory neurosteroids are positive allosteric modulators of GABAA receptors which show anxiolytic and anticonvulsant properties, whereas negative modulators of GABAA receptors facilitate memory processes and at high doses show proconvulsant activity. Allopregnanolone is the most potent inhibitory neurosteroid, and the reduced metabolites of deoxycorticosterone and androgens have similar though weaker action. Pregnenolone, dehydroepiandrosterone and their sulfate derivatives, belong to stimulating neurosteroids, that besides the inhibitory effect on GABAA receptors enhance activity of glutamatergic NMDA receptors and sigma1 receptors which leads to an increase in acetylcholine release, in consequence, strengthening cognitive processes. Neurosteroids seem to be also involved in neuronal cell regeneration, regulation of hypothalamic-pituitary-adrenal axis activity and in the mechanism of drug dependence and depression. In contrast to well-documented beneficial effects of some neurosteroids on animal brain function, scarce clinical data do not allow to draw final conclusions about potential usefulness of these compounds in diagnosis or treatment of neurological and psychiatric disorders.

Central Nervous System↗
PubMed2006

An interaction between benzodiazepines and neuroactive steroids at GABA A receptors in cultured hippocampal neurons.

Neurosteroids are modulators of several receptors and ion channels and are implicated in the pathophysiology of several neuropsychiatric diseases including hepatic encephalopathy (HE). The neurosteroid, allopregnanolone, a positive allosteric modulator of GABA(A) receptors, accumulates in the brains of HE patients where it can potentiate GABA(A) receptor-mediated responses. Attenuation of the effects of neurosteroids on GABA-ergic neurotransmission is therefore of interest for the management of HE. In the present study, we determined the effect of the benzodiazepine partial inverse agonist, Ro15-4513, and the benzodiazepine antagonist, flumazenil on modulation of the GABA(A) mediated chloride currents by allopregnanolone and on spontaneous synaptic activity in cultured hippocampal neurons using the patch-clamp technique. Allopregnanolone (0.03-0.3 microM), dose-dependently potentiated GABA-induced currents, an action significantly reduced by Ro15-4513 (10 microM). In contrast, flumazenil (10 microM) had no effect on the ability of allopregnanolone to potentiate GABA(A) currents but it blocked the effects of Ro15-4513. The frequency of spontaneous synaptic activity was significantly reduced in the presence of allopregnanolone (0.1 microM) from 1.5+/-0.7 to 0.1+/-0.04Hz. This action was partially reversed by Ro15-4513 (10 microM) but was not significantly influenced by flumazenil (10 microM). These findings suggest that the beneficial affects of Ro15-4513 in experimental HE result from attenuation of the effects of neurosteroids at GABA(A) receptors. Our results may provide a rational basis for the use of benzodiazepine inverse agonists in the management and treatment of hepatic encephalopathy in patients with liver failure.

Affinity Labels↗
PubMed2003

Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties.

Steroids influence neuronal function through binding to cognate intracellular receptors which may act as transcription factors in the regulation of gene expression. In addition, certain so-called neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially distinct 3alpha-reduced metabolites of progesterone and deoxycorticosterone are potent positive allosteric modulators of gamma-aminobutyric acid type A (GABA(A)) receptors. However, also classical steroid hormones such as 17beta-estradiol, testosterone and progesterone are neuroactive steroids because they may act as functional antagonists at the 5-hydroxytryptamine type 3 (5-HT(3)) receptor, a ligand-gated ion channel or distinct glutamate receptors. A structure-activity relationship for the actions of a variety of steroids at the 5-HT(3) receptor was elaborated that differed considerably from that known for GABA(A) receptors. Although a bindings site for steroids at GABA(A) receptors is still a matter of debate, meanwhile there is also evidence that steroids interact allosterically with ligand-gated ion channels at the receptor membrane interface. On the other hand, also 3alpha-reduced neuroactive steroids may regulate gene expression via the progesterone receptor after intracellular oxidation into 5alpha-pregnane steroids. Animal studies showed that progesterone is converted rapidly into GABAergic neuroactive steroids in vivo. Progesterone reduces locomotor activity in a dose-dependent fashion in male Wistar rats. Moreover, progesterone and 3alpha-reduced neuroactive steroids produce a benzodiazepine-like sleep EEG profile in rats and humans. During major depression, there is a disequilibrium of such 3alpha-reduced neuroactive steroids which is corrected by successful treatment with antidepressant drugs. Neuroactive steroids may further be involved in the treatment of depression and anxiety with antidepressants in patients during ethanol withdrawal. Studies in patients with panic disorder suggest that neuroactive steroids may also play a role in modulating human anxiety. Both the genomic and non-genomic effects of steroids in the brain may contribute to the pathophysiology of psychiatric disorders and the mechanisms of action of antidepressants. Neuroactive steroids affect a broad spectrum of behavioral functions through their unique molecular properties and may represent a new treatment strategy for neuropsychiatric disorders.

Anesthesia↗
PubMed1996

Tetrodotoxin reverses brevetoxin allosteric inhibition of scorpion alpha-toxin binding on rat brain sodium channels.

Voltage-sensitive sodium channels are responsible for the initiation of action potentials in many excitable cells. Several neurotoxins bind to distinct receptor sites on sodium channels and reveal strong allosteric interactions among them. Scorpion alpha toxins, which inhibit sodium channel inactivation by binding to receptor site 3, have been very important tools to study sodium channel structure and function. Recently, we have shown that brevetoxin induce a strong negative allosteric modulation on scorpion alpha-toxin binding on rat brain sodium channels, in contrast to previously published studies. In this report we have examined the reasons for this discrepancy and found new, unexpected allosteric interactions between the tetrodotoxin and brevetoxin receptor sites, using scorpion alpha-toxin as sensitive probe for subtle conformational changes on sodium channels. Tetrodotoxin reverses the negative modulation induced by brevetoxin on scorpion alpha-toxin binding, revealing new dynamic interactions in sodium channel structure.

Allosteric Site↗
PubMed1994

Correlation of neuroactive steroid modulation of [35S]t-butylbicyclophosphorothionate and [3H]flunitrazepam binding and gamma-aminobutyric acidA receptor function.

Neuroactive steroids, including endogenously occurring metabolites of progesterone and deoxycorticosterone as well as their synthetic derivatives, are positive allosteric modulators of the gamma-aminobutyric acid (GABA)A receptor complex. They inhibit the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS), enhance the binding of [3H]flunitrazepam, and potentiate GABA-evoked chloride currents and agonist-stimulated 36Cl- uptake. The structure-activity relationship for 31 neuroactive steroids and related compounds was explored by examining their relative ability to inhibit [35S]TBPS binding in rat brain cortical membranes. A free 3 alpha-hydroxy group is necessary for high potency inhibition. Whereas hydroxylation in the 21-position and subsequent esterification maintain activity, 11 alpha- or 12 alpha-hydroxylation greatly reduces activity. The rank order of potency for 17-position substitutions in the 5 alpha-reduced series is 17 beta-acetyl > 17 beta-cyano > 17 beta-methoxycarbonyl > 17 alpha-acetyl > 17-one > or = 17-oxime > or = 17 alpha-cyano. Introduction of a double bond between the 9- and 11-positions reduces potency, whereas a double bond in the 4-position reduces the maximal extent of inhibition. Comparing the activities of these neuroactive steroids and related compounds in the [35S]TBPS and [3H]flunitrazepam assays, there is a strong correlation between potency (r = 0.90, n = 17) and magnitude of modulation (r = 0.95, n = 31), indicating that the neuroactive steroid binding site is similarly coupled to the TBPS and benzodiazepine sites in rat cortex. However, there is a weaker correlation (r = 0.74-0.78, n = 31) between the degree of modulation in either binding assay and potentiation of muscimol-stimulated 36Cl- uptake in rat cortical synaptoneurosomes. Using an electrophysiological approach, stronger correlations (r = 0.89-0.94, n = 15) were observed between the magnitude of modulation in the binding assays and potentiation of GABA-evoked chloride currents in Xenopus oocytes expressing human alpha 1 beta 1 gamma 2L receptor complexes. Thus, neuroactive steroid modulation of [35S]TBPS and [3H]flunitrazepam binding is predictive of functional activity at the GABAA receptor complex.

Allosteric Regulation↗
PubMed2006

From electric patterns to drugs: perspectives of computational neuroscience in drug design.

A novel way of computational modeling by integrating compartmental neural techniques and detailed kinetic description of pharmacological modulation of transmitter-receptor interaction is offered as a method to test the electro-physiological and behavioral effects of potential drugs. Even more, an inverse method is suggested as a method for controlling a neural system to realize a prescribed temporal pattern. Generation and pharamcological modulation of theta rhythm in area CA1 of the hippocampus related to anxiety is analyzed. Integrative modeling might help to find positive allosteric modulators of alpha1 subunits as potential candidates for being selective anxyolitics.

Computer-Aided Design↗
PubMed2000

Modulation of [3H]MK-801 binding to NMDA receptors in vivo and in vitro.

[3H]MK-801 binding in vivo was used to determine the occupancy of NMDA receptor ligands shown to allosterically modulate binding in vitro. ED(50) values (mg/kg) were obtained for the channel blockers (+)-5-methyl-10,11-dihydro-5,4-dibenzo[a,d]cyclohepten-5,10-imine maleate ((+)-MK-801, 0.2), 1-(1-phenylcyclohexyl)piperidine (phencyclidine, PCP, 1.7) and ketamine (4.4). Antagonists at the glutamate (DL-(2-carboxypiperazine-4-yl)propyl-1-phosphonate (DL-CPP, 5.7)) and glycine site (7-Chloro-4-hydroxy-3-(3-phenoxy)-phenyl-2(H)quinolinone (L-701,324, 14.1), 3R(+)cis-4-methyl-pyrrollid-2-one (L-687,414, 15.1)) inhibited [3H]MK-801 binding in vivo to varying maximum levels (69%, 103% and 45%, respectively). NR2B subunit-selective compounds acting at the ifenprodil site inhibited [3H]MK-801 in vivo by a maximum of 52-72% and gave ED(50) values (mg/kg) of: (+/-)-(1S*, 2S*)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol ((+/-)CP-101,606), 1.9; (+/-)-(3R, 4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol ((+/-)CP-283,097), 1.8; (+/-)-(R*, S*)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propanol ((+/-)Ro 25-6981), 1.0; ifenprodil, 6.0. The glycine site agonist D-serine stimulated binding to 151% of control with an ED(50) of 1.7 mg/kg. Results show that [3H]MK-801 binding in vivo may be used to measure receptor occupancy of ligands acting not only within the ion channel but also at modulatory sites on the NMDA receptor complex.

Animals↗
PubMed2004

Alanine-scanning mutagenesis in the signature disulfide loop of the glycine receptor alpha 1 subunit: critical residues for activation and modulation.

The glycine receptor enables the generation of inhibitory postsynaptic currents at synapses via neurotransmitter-dependent activation. These receptors belong to the ligand-gated ion channel gene superfamily, in which all members are comprised of five subunits, each of which possesses a signature 13-residue disulfide loop (Cys loop) in the extracellular domain. In this study, we used alanine-scanning mutagenesis of the residues between C138 and C152 of the Cys loop of the glycine receptor alpha1 subunit to identify residues critical for receptor activation and allosteric modulation. Mutation of L142, F145, or P146 to alanine produced decreases in the potency, maximal amplitude, and Hill coefficient for currents elicited by glycine and impaired receptor activation by the agonist taurine. These residues, along with D148, are positionally conserved in the family of LGIC subunits. Mutation at several other positions had little or no effect. The inhaled anesthetics halothane and isoflurane potentiate submaximal agonist responses at wild-type receptors, via an allosteric site. The mutations L142A, F145A, P146A, and D148A abolished positive modulation by these anesthetics, in some cases revealing a small inhibitory effect. A molecular model of the glycine receptor alpha1 subunit suggests that the Cys loop is positioned in a region of the receptor at the interface between the extracellular and transmembrane domains and that the critical functional residues identified here lie along the face of a predominantly hydrophobic surface. The present data implicate the Cys loop as an important functional moiety in the process of glycine receptor activation and allosteric regulation by anesthetics.

Alanine↗
PubMed2000

Progesterone-metabolite prevents protein kinase C-dependent modulation of gamma-aminobutyric acid type A receptors in oxytocin neurons.

Gonadal steroid feedback to oxytocin neurons during pregnancy is in part mediated via the neurosteroid allopregnanolone (3alpha-OH-DHP), acting as allosteric modulator of postsynaptic gamma-aminobutyric acid type A (GABA(A)) receptors. We describe here a form of nongenomic progesterone signaling by showing that 3alpha-OH-DHP not only potentiates GABA(A) receptor-channel activity but also prevents its modulation by protein kinase C (PKC). Application of oxytocin or stimulation of PKC suppressed the postsynaptic GABA responses of oxytocin neurons in the absence, but not in the presence of 3alpha-OH-DHP. This finding was true at the juvenile stage and during late pregnancy, when the GABA(A) receptor is sensitive to 3alpha-OH-DHP. In contrast, after parturition, when the GABA(A) receptors expressed by oxytocin neurons are less sensitive to 3alpha-OH-DHP, this neurosteroid no longer counteracts PKC. The change in GABA(A)-receptor responsiveness to 3alpha-OH-DHP helps to explain the onset of firing activity and thus the induction of oxytocin release at parturition.

Allosteric Regulation↗
PubMed1998

Comparative modulation by 3 alpha,5 alpha and 3 beta,5 beta neurosteroids of GABA binding sites during avian central nervous system development.

Neurosteroids are endogenous Central Nervous System (CNS) compounds which act mainly by allosteric modulation of the GABAA receptor complex. The presence of a 3 alpha-hydroxyl group and a 5 alpha-hydrogen atom have been found to be essential structural requirements for biological activity in mammals. In the present work we report the enhancing activity on [3H]GABA binding to its receptor sites in chick optic lobe produced by progesterone metabolites 3 alpha-hydroxy,5 alpha-pregnan-20-one (3 alpha,5 alpha-P) and 3 beta-hydroxy,5 beta-pregnan-20-one (3 beta,5 beta-P). Both steroids were found able to enhance [3H]GABA binding along ontogeny, displaying a similar profile at early developmental stages, while in adulthood 3 alpha,5 alpha-P had greater potency (EC50 0.22 microM) and enhancing effect (Emax: 122%). In adult synaptic membranes, the two compounds displayed a complex interaction with the GABAA receptor, disclosed by a Schild plot with slope below one and an incomplete displacement of 3 alpha,5 alpha-P by its 3 beta,5 beta isomer. Such complexity could be related to the steroidogenic profile in avian CNS, with 5 alpha-reduced progesterone metabolites present since early development, while 3 alpha,5 alpha-P is found only in adulthood. Bearing in mind differences between avian and mammalian steroidogenic profiles and the relevance of 5 beta-steroids in early avian development, we propose that 3 beta,5 beta-P, instead of the classical potent 3 alpha,5 alpha-steroids, may be the endogenous modulator of GABAergic activity in developing avian brain.

Animals↗
PubMed1997

Kinetic studies of co-operativity at atrial muscarinic M2 receptors with an "infinite dilution" procedure.

The effects of two competitive antagonists and two allosteric ligands on the rate of dissociation of [3H]N-methylscopolamine ([3H]NMS) were studied at atrial muscarinic acetylcholine M2 receptors by the technique of "infinite dilution." The dissociation rate for [3H]NMS, initiated by diluting the incubation mixture in a 100-fold volume of buffer, was 0.61 +/- 0.10 min-1. Addition of the competitive antagonists, atropine or NMS, to the dilution medium did not alter the observed [3H]NMS dissociation rate. In contrast, gallamine and the bisquaternary, heptane-1,7-bis-(dimethyl-3'-phthalimidopropyl-ammonium bromide) (C7/3'-phth), produced a concentration-dependent slowing of the dissociation rate of [3H]NMS, with IC50 values of 7.5 microM and 196 nM, respectively. Gallamine exhibited an increased modulatory potency when equilibration with the tissue was allowed prior to dilution. The findings showed that the influence of low concentrations of allosteric modulators on the [3H]NMS dissociation rate may be demonstrated separately from any effects on association rate, and that the contact time with the allosteric ligand may influence the extent of these effects.

Allosteric Regulation↗
PubMed1992

Interactions of cocaine with primary and secondary recognition sites on muscarinic receptors.

Several lines of evidence have suggested that muscarinic receptors may possess more than one ligand binding site. In this study, the interactions of cocaine with primary and secondary (allosteric) sites on muscarinic receptors in membrane homogenates from post-mortem human brainstem were examined. (-)-Cocaine inhibited the binding of the tritiated muscarinic antagonists N-methylscopolamine (NMS) and pirenzepine to an apparent single class of sites, with Ki values of 200-300 microM. The binding of the muscarinic agonist [3H]oxotremorine-M was inhibited with a similar Ki value (200 microM). (+)-Cocaine, although not the naturally occurring stereoisomer, was 10-20-fold more potent than (-)-cocaine in competing for binding to the primary muscarinic recognition site. The binding of cocaine was unaffected by guanine nucleotides or N-ethylmaleimide, consistent with its purported action as a competitive antagonist. Cocaine was not selective for muscarinic receptor subtypes. Rosenthal analysis of the [3H]NMS saturation binding data in the presence of increasing concentrations of either (-)-cocaine or (+)-cocaine indicated that both isomers produced an apparent competitive-like reduction in the [3H]NMS affinity. Schild regression analysis of the saturation binding data resulted in curvilinear plots suggestive of cooperative or allosteric interactions of (-)-cocaine with the [3H]NMS-labeled receptors. The effects of (-)-cocaine on the kinetics of [3H]NMS binding were consistent with an allosteric interaction with the receptor. Increasing concentrations of cocaine markedly slowed the rate of [3H]NMS dissociation from the primary recognition site. The allosteric modulation of [3H] NMS binding by (-)-cocaine was abolished with increasing ionic strength. Taken together, these data demonstrate that (-)-cocaine interacts with primary and allosteric recognition sites on muscarinic receptors.

Adult↗
PubMed1998

Felbamate increases [3H]glycine binding in rat brain and sections of human postmortem brain.

The anticonvulsant compound felbamate (2-phenyl-1,3-propanediol dicarbamate; FBM) appears to inhibit the function of the N-methyl-D-aspartate (NMDA) receptor complex through an interaction with the strychnine-insensitive glycine recognition site. Since we have demonstrated previously that FBM inhibits the binding of [3H]5, 7-dichlorokynurenic acid (DCKA), a competitive antagonist at the glycine site, we assessed the ability of FBM to modulate the binding of an agonist, [3H]glycine, to rat forebrain membranes and human brain sections. In contrast to its ability to inhibit [3H]5,7-DCKA binding, FBM increased [3H]glycine binding (20 nM; EC50 = 485 microM; Emax = 211% of control; nH = 1.8). FBM, but not carbamazepine, phenytoin, valproic acid or phenobarbital, also increased [3H]glycine binding (50 nM; EC50 = 142 microM; Emax = 157% of control; nH = 1.6) in human cortex sections. Autoradiographic analysis of human brain slices demonstrated that FBM produced the largest increases in [3H]glycine binding in the cortex, hippocampus and the parahippocampal gyrus. Because various ions can influence the binding of glycine-site ligands, we assessed their effects on FBM-modulation of [3H]glycine binding. FBM-enhanced [3H]glycine binding was attenuated by Zn++ and not inhibited by Mg++ in human brain. These results suggest that FBM increases [3H]glycine binding in a manner sensitive to ions which modulate the NMDA receptor. These data support the hypothesis that FBM produces anticonvulsant and neuroprotective effects by inhibiting NMDA receptor function, likely through an allosteric modulation of the glycine site.

Animals↗
PubMed1999

Solute modulation of conformational equilibria in intrinsic membrane proteins: apparent "cooperativity" without binding.

The activity of many membrane proteins depends on a conformational transition that is often strongly influenced by small membrane-soluble solutes. This allosteric modulation may be direct, involving binding to the protein at localized sites of varying specificity, or may be indirect, resulting from altered membrane properties. In the present paper, a general expression for solute-protein titration curves is predicted, using an indirect mechanism that couples solute-induced changes in the lateral pressure profile of the bilayer to a shift in protein conformational equilibrium. When the common practice of fitting dose-response data to the Hill equation is applied to these curves, the fits are found to be reasonably good, with large Hill coefficients. Because this would commonly be interpreted as evidence of the existence of multiple sites with strong positive cooperativity, it is argued that caution must therefore be exercised in the interpretation of titration data in the absence of direct evidence of the existence of binding sites. The form of the titration curve predicted from this lateral pressure mechanism is shown to be quite general for indirect mechanisms. It is also shown that this form is the same as would be obtained from classical models of binding cooperativity, such as that of Monod, Wyman, and Changeux, in the limit of an infinite number of sites with vanishingly small site affinity.

Allosteric Regulation↗
PubMed2002

Potentiation of human alpha4beta2 neuronal nicotinic acetylcholine receptor by estradiol.

The modulation of neurotransmitter receptors by various substances can reflect important physiological mechanisms involved in the regulation of neural function. Furthermore, such substances, in particular specific allosteric modulators, can reveal promising therapeutic targets for diseases of the nervous system. From this perspective, we investigated the effects of the steroid hormone estradiol on human neuronal nicotinic acetylcholine receptors expressed either in Xenopus laevis oocytes or human embryonic kidney cells. Acetylcholine-evoked currents were potentiated both by pre- and coapplications of estradiol in alpha4beta2 and alpha4beta4 receptors, but not in alpha3beta2 or alpha3beta4 receptors. The reversible potentiation of alpha4-containing receptors could be induced within seconds in X. laevis oocytes and at micromolar concentrations of estradiol. The potentiation was greatest for responses evoked by low concentrations of acetylcholine, resulting in an apparent increase of receptor affinity. At the single channel level, estradiol potentiation resulted from an increase in opening probability. Finally, the use of functional chimeric or truncated alpha4 subunits demonstrated that a site at the C-terminal tail of the alpha4 subunit is required for estradiol potentiation. These results suggest the presence of a specific site at the human nicotinic acetylcholine receptor alpha4 subunit through which estradiol can cause an allosteric potentiation of acetylcholine-evoked responses.

Acetylcholine↗
PubMed2006

[Sleep-modulation and hypnotics: effects of benzodiazepine-receptor's agonists].

As binding sites of the alpha-amino butyric acid receptor complexes benzodiazepine-receptors offer a possibility to enhance hyperpolarization-based inhibition by allosteric modulation. Most of the hypnotic drugs are compounds that bind to benzodiazepine receptors. The effects of these drugs are usually characterized at a descriptive level, without deliberation of the basic processes involved in sleep regulation. This review follows the analysis of hypnotic's effect from a perspective of homeostatic, circadian, ultradian and microstructural regulation of sleep. In contrast to their expected effect benzodiazepines produce a decrease in most of the markers of homeostatic sleep regulation. Ligands with non-benzodiazepine structure (cyclopyrrolones, imidazopyridines, pyrazolopyrimidines) have a permissive or even stimulating effect in some measures of homeostatic sleep regulation. Some benzodiazepines have marked chronobiotic effects, while others interfere with circadian rhythms. The non- benzodiazepine-type hypnotics are mostly free of chronobiotic effects, although zaleplon may increase melatonin release. Given their acute hypothermic effect all hypnotic sedatives mimic the circadian signal of sleep initiation. Ultradian sleep regulation is largely unaffected by hypnotics. The microstructure of sleep as quantified by arousal instability is a sensitive measure of the effect of most of the hypnotics. Hypnotic sedatives decrease arousal instability. Zolpidem has the strongest effects in microstructural terms.

Animals↗
PubMedDate not supplied

Tagetone modulates the coupling of flunitrazepam and GABA binding sites at GABAA receptor from chick brain membranes.

The effects of tagetone on flunitrazepam (FNTZ) binding to synaptosomal membranes from chick brains in the presence and absence of allosteric modulations induced by gamma-aminobutyric acid (GABA) were investigated. Tagetone, at 50 micrograms/ml (final concentration), decreased the binding affinity of [3H]FNTZ to synaptosomal membranes form chick brain (Kd = 3.34 +/- 0.36 nM without tagetone and Kd,t = 5.86 +/- 0.86 nM with tagetone; p < 0.05, two tailed Student's t-test) without affecting maximal binding (Bmax = 488 +/- 24 fmoles/mg protein, and Bmax,t = 500 +/- 25 fmoles/mg protein in the absence and in the presence of tagetone respectively). The potency of GABA to stimulate [3H]FNTZ binding increased in the presence of tagetone (EC50 values were 2.78 and 1.12 microM with and without tagetone respectively). GABA was able to decrease merocyanine delta A570-610 values in a concentration dependent manner; half maximal effect was attained at a GABA concentration of 34 +/- 13 microM. Tagetone, at a concentration of 50 micrograms/ml and in the presence of GABA 30 microM or 60 microM, enhanced the ability of GABA alone on decreasing delta A570-610. Tagetone alone did not change delta A570-610 values. FNTZ, a well known GABA modulator, could also potentiate the effect of GABA. Theoretical calculations indicate that the effects on merocyanine delta A570-610 value are mainly exerted at the membrane potential level (delta psi m). The present results strongly suggest that tagetone affected the function of GABAA receptor in a complex way: on the one hand it impaired FNTZ binding: on the other hand tagetone improved both the coupling between FNTZ and GABA binding sites and it enhanced GABA-induced chloride permeability. Changes in the geometrical and electrostatic properties of the self-organized membrane structure may account for these effects of tagetone.

Acyclic Monoterpenes↗