Biomedical subjects

R Zini

Publications and source records attributed to R Zini.

At least 19 recordsLinked to original sources

PubMed1999

A GppNHp-insensitivity factor modulates the activation of beta-adrenoceptor-coupled Gs protein in rat cortex and cerebellum.

The effect known as the GTP-shift refers to the complete conversion of receptors from the high- to the low agonist-affinity state in the presence of an excess of GTP or one of its analogs. 5'-Guanylylimidodiphosphate (GppNHp) was able to fully suppress the high (-)-isoproterenol-affinity of beta-adrenoceptors (beta AR) in cultured rat brain astrocytes. In contrast, a proportion of beta AR in rat cortex and cerebellum synaptosomes was found to be insensitive to this GTP analog. This GppNHp-insensitivity was due to a membrane-associated factor, presumably interacting with Gs proteins and not present in a functional form in cultured astrocytes. Here we assessed the effect of this factor on the beta AR-mediated activation of Gs proteins. The removal of the GppNHp-insensitivity factor from the synaptosomes was achieved using 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), a mild detergent. The activation of Gs proteins was monitored by the binding of another non-hydrolysable GTP-analog, guanylyl 5'-[gamma-[35S]thio]-triphosphate ([35S]GTP gamma S). The beta AR-Gs protein coupling was at least twofold less efficient in synaptosomes relative to cultured astrocytes. The CHAPS treatment induced a twofold increase in the coupling efficiency in cortex and cerebellum synaptosomes, but had no effect in cultured astrocytes. It undoubtedly indicated the inhibitory effect of the GppNHp-insensitivity factor on the activation of Gs proteins in the synaptosomes. Using CHAPS-soluble material extracted from synaptosomes, it was possible to reconstitute the GppNHp-insensitivity of CHAPS-treated membranes or even to induce it in cultured astrocytes. This effect correlated with the amount of CHAPS-soluble material according to a sigmoid curve, but it was abolished by the heat of CHAPS-soluble material. Successful crossed reconstitutions of the GppNHp-insensitivity suggest that the GppNHp-insensitivity factor is the same regardless of its originating area, and that it might play a general role in the central nervous system. Further investigations should help to identify the GppNHp-insensitivity factor.

Adrenergic beta-Agonists↗

PubMed1999

Effects of resveratrol on the rat brain respiratory chain.

The aim of this work was to investigate the possible effects of resveratrol on the mitochondrial respiratory chain in rat brains. Isolation of mitochondria was performed at 4 degrees C using differential centrifugation. Mitochondrial respiration rate (0.4 mg of protein/ml) was determined by measuring mitochondrial oxygen consumption with a Clark electrode at 37 degrees C. Respiratory control ratio (RCR) was evaluated as the state 3/state 4 ratio of oxidative phosphorylation with substrates adenosine 5'-diphosphate (ADP) and malate plus glutamate, respectively in the presence and in the absence of resveratrol. The rate of oxygen consumption by the different complexes was checked using rotenone (2 microM), malonate (10 mM), antimycin A (1 microM), potassium cyanide (KCN) (0.3 mM) and oligomycin (10 microM) to inhibit complexes II, III, IV, V and I, respectively. Moreover, enzyme activity determinations were checked as follows: the activities of complexes II-III were measured as the rate of cytochrome c reduction at 550 nm (37 degrees C) successively triggered either by succinate (complexes II and III) or by decylubiquinol (DUQH2) (complex III), in the presence and in the absence of resveratrol. Adenosine 5'-triphosphate (ATP) synthase activity was checked as ATP hydrolysis (ATPase) at 37 degrees C for 10 min from purified mitochondria on Percoll gradient. The inorganic phosphate (Pi) concentration was measured by the Fiske and Subbarow method. When complexes I to V were activated by glutamate plus malate, resveratrol (10(-11) - 10(-4) M) significantly decreased RC (p < 0.001) following a biphasic curve with two EC50 values, 0.162 +/- 0.072 microM and 24.5 +/- 4.0 microM, representing about 56% of total oxygen consumption inhibition. We also observed a concentration-dependent effect on state 3 with two EC50 values, 2.28 +/- 0.87 nM and 27 +/- 5 microM respectively. On the other hand, resveratrol inhibited state 4 following a concentration-dependent curve with an EC50 of 37 +/- 11 microM. When complex IV operated alone, resveratrol (100 microM) did not modify oxygen consumption compared with control, indicating that this molecule did not inhibit complex IV. Thus resveratrol inhibits the mitochondrial respiratory chain through complexes I to III. In order to confirm these data, we measured the enzymatic activity of ubiquinol cytochrome c reductase alone and in the presence of resveratrol. In the presence of disrupted mitochondria, after freeze thawing cycles (three times), resveratrol inhibited about 20% of complex III activity. These results suggest that resveratrol and DUQH2 could be competitive on complex III. Resveratrol significantly inhibited ATPase activity (p < 0.001) following a biphasic curve with two EC50 values, 0.39 +/- 0.15 nM and 23.1 +/- 6.4 microM, both representing about 80% of oligomycin-dependent ATPase total activity. Resveratrol was effective as a protecting agent on the three models of oxidation. On lipid peroxidation of brain synaptosomes induced by the Fenton reaction, it was three times more potent than DUQH2. Its effectiveness in reducing 1,1-diphenyl-2-picryl hydrazyl radical (DPPH degrees) showed a stoichiometry of two, indicating that two hydrogen atoms of resveratrol were abstracted by the process. Resveratrol was also able to scavenge the superoxide anion (O2 degrees) generated from rat forebrain mitochondria in a concentration dependent manner. In conclusion, resveratrol can decrease complex III activity by competition with coenzyme Q. This property is especially interesting as this complex is the site where reactive oxygen substances (ROS) are generated. By decreasing the activity of complex III, resveratrol cannot only oppose the production of ROS but can also scavenge them.

Adenosine Triphosphatases↗

PubMed1998

Glucocorticoids decrease cytochrome c oxidase activity of isolated rat kidney mitochondria.

The importance of mitochondria is rising as a target in pathologic processes such as ischemia. We have investigated the effects of hydrocortisone, prednisolone, dexamethasone and triamcinolone on oxidative phosphorylation, Ca2+ fluxes, swelling and membrane potentials in isolated kidney mitochondria. The measurement of respiration state 3 showed a significant decrease in presence of glucocorticoids whereas the other respiration states were not modified. When mitochondria were uncoupled and either the complexes III and IV or the complex IV were stimulated, the O2 consumption was decreased by glucocorticoids. These results suggest the cytochrome c oxidase is a target of the glucocorticoid effect on the respiratory chain. Indeed, the other mitochondrial functions investigated were unchanged, ruling out a direct effect on Ca2+ fluxes or swelling. A regulation of cytochrome c oxidase activity by glucocorticoids will be of particular interest in pathology involving metabolic insult.

Animals↗

PubMed1998

Structure-property relationships of trimetazidine derivatives and model compounds as potential antioxidants.

Twenty-five compounds (trimetazidine derivatives and other compounds, mostly having a free phenolic group) were examined for their radical scavenging and antioxidant properties. Their reaction with DPPH (2,2-diphenyl-1-picrylhydrazyl) as a measure of radical scavenging capacity was assessed by two parameters, namely EC50 (the concentration of antioxidant decreasing DPPH by 50%), and log Z, a kinetic parameter proposed here and derived from initial second-order rate constants and antioxidant/DPPH ratios. Antioxidant activities were determined by the inhibition of lipid peroxidation and albumin oxidation. The most active compounds were derivatives having a trolox or hydroquinone moiety. Physicochemical and structural properties were determined by molecular modeling as lipophilicity (virtual log P calculations) and H-Surf (solvent-accessible surface of hydroxyl hydrogen) and by quantum mechanical calculations (deltaH(ox) = oxidation enthalpy; deltaH(abs) = enthalpy of hydrogen abstraction). QSAR models were derived to identify molecular mechanisms responsible for the reactivity toward the DPPH radical and for the inhibition of lipid peroxidation. A useful prediction of antioxidant capacity could be achieved from calculated molecular properties and the kinetic parameter developed here.

Antioxidants↗

PubMed1998

Evidence for the stabilisation of the high-affinity state of beta-adrenoceptors by an endogenous factor in rat brain.

Inhibition of binding of the labelled antagonist (-)[3H]CGP 12177 by the full agonist (-)isoproterenol results in shallow competition curves, characteristic of the presence of both high- and low-affinity states of beta-adrenoceptors (betaAR). When in excess, the GTP analog 5'-guanylylimidodiphosphate (GppNHp) is expected to convert all receptors in the high-affinity state to the low-affinity state. However, in the rat cortex and cerebellum synaptosomes, a proportion of the betaAR in the high-affinity state was GppNHp-insensitive. This apparent GppNHp-insensitivity decreased with decreasing temperature of incubation. Moreover, it was totally abolished by the gentle treatment of membranes with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). We propose that a protein factor interacts with the betaAR/Gs protein complex and that it induces the GppNHp-insensitivity. This factor would be released by CHAPS in a functional form because it may regenerate the GppNHp-insensitivity after concentration and reconstitution with CHAPS-treated membranes. It is likely that the factor acts as a stabiliser of betaAR in the high-affinity state.

Animals↗

PubMed1998

Tacrolimus decreases in vitro oxidative phosphorylation of mitochondria from rat forebrain.

The effects of tacrolimus (FK 506) on brain phosphorylation have been investigated in vitro using mitochondria isolated from rat brain. Respiratory control ratio (RCR), oxygen consumption, ATP synthesis and enzymatic activities of involved complexes have been measured to assess the mechanisms of action of tacrolimus. Our data show that this drug decreases RCR and ATP synthesis. This effect is quantitatively limited after a single application of the drug (14%), concentration-dependent and biphasic, the respective effect 50%-concentration (EC50) being 0.129 and 247 nM, each step corresponding to 50% of the total oxygen consumption inhibition. Tacrolimus acts mainly as an inhibitor of ubiquinol-cytochrome c reductase (complex III), competing at least partly with antimycin A or myxothiazol, the corresponding EC50 being 0.27 and 103 nM respectively. Tacrolimus inhibits also complex V i.e. ATPase activity (40%) and ATP synthase activity (30%) in a concentration-dependent manner, the relevant EC50 being 78 and 394 nM respectively. These data may be relevant for the protective effect of tacrolimus observed in ischemia-reperfusion, which may be due to its inhibition of both complex III, where Reactive Oxygen Species (ROS) are generated, and complex V, where ATP is depleted by ATPase activation. It may also be related to neurotoxicity occurring along chronic administration of tacrolimus in humans.

Adenosine Triphosphate↗

PubMed1997

A match between binding to beta-adrenoceptors and stimulation of adenylyl cyclase parameters of (-)isoproterenol and salbutamol on rat brain.

Inhibition experiments of (-)[3H]CGP 12177 binding by (-)isoproterenol and salbutamol were performed on synaptosomes prepared from rat brain cortex and cerebellum. Adenylyl cyclase (AC) stimulation experiments on slices of these structures were also performed, with measuring [14C]cAMP obtained from [14C]adenine. Studying beta 1- and beta 2-adrenoceptors (beta 2AR) separately, dissociation constants of (-)isoproterenol for the high- (KH) and low- (KL) affinity states are 8 and 206 nM, respectively, for beta 1AR, vs 20 and 900 nM for beta 2AR. With salbutamol, KH and KL for beta 2AR are 37 and 1250 nM, respectively, vs 430 and 8500 nM for beta 1AR. In any case, the proportion of high-affinity state (RH) of beta 2AR in the cerebellum (59% and 35% for (-)isoproterenol and salbutamol, respectively) is twice that of beta 1AR (30% and 18%). Surprisingly, the RH of cortex beta 2AR with (-)isoproterenol (30%) is significantly lower than in the cerebellum, but not with salbutamol (35%). To allow meaningful comparisons of potencies in stimulating [14C]cAMP production, we define the coupling efficiency (CE), applicable to specified beta AR subtype and agonist, and expressed as the maximal production of mol cAMP.mol-1 beta AR.min-1. The order of CE was always in favor of (-)isoproterenol vs salbutamol on cerebellum beta 2AR > on cortex beta 2AR > on cortex beta 1AR. This order indicates the partial agonism of salbutamol for both beta AR subtypes, and an intrinsic better coupling of beta 2AR vs beta 1AR in rat brain. Moreover, this order corresponds roughly to that of RH. Hence, CE is directly correlated with RH at least for these two agonists. EC50 for cAMP production for each subtype and agonist is in the same order than the respective KL, and might only reflect the rapid return of receptor to low-affinity state after the activation of Gs protein. In binding experiments on the whole beta AR in both areas, the pseudo-Hill coefficient did not reach 1 with 0.3 mM guanosine 5'-(beta, gamma-imido)triphosphate (GppNHp). This dysfunction of GppNHp in rat brain structures might be caused by a major difference in the regulation of coupling in the ternary complex as compared with peripheral tissues.

Adenylyl Cyclases↗

PubMed1997

Characterization of beta-adrenergic receptors of freshly isolated astrocytes and neurons from rat brain.

The binding and characteristics of rat brain beta-adrenergic receptors (beta-AR) isolated from astrocytes and neurons were investigated. Equilibrium binding experiments demonstrated that beta-AR were more concentrated on astrocytes than on neurons isolated from forebrain, cerebral cortex and cerebellum. Inhibition experiments revealed that beta 1-AR and beta 2-AR were present in the two cell types. Isoproterenol revealed two interchangeable states of high and low affinity binding to both beta 1- and beta 2-AR in neurons. The high affinity binding sites were sensitive to guanylylimidodiphosphate (GppNHp). Similar results were found with other beta-AR agonists but not with salbutamol and salmeterol which recognized both affinity states of the neuronal beta 2-AR but only the low affinity state of beta 1-AR. In astrocytes only the low affinity state of beta-AR was observed.

Adrenergic beta-Agonists↗

PubMed1997

Prednisolone and azathioprine worsen the cyclosporine A-induced oxidative phosphorylation decrease of kidney mitochondria.

We investigated the effects of cyclosporine A, prednisolone and azathioprine on respiration rates, Ca2+-induced swelling and Ca2+ fluxes of rat kidney mitochondria. The three drugs significantly decreased the succinate induced-respiration rates according to concentration-dependent processes. Each drug inhibited about 10% of the respiratory control ratio, with EC50 of 3.7 x 10(-7) M, 5.8 x 10(-9) M for cyclosporine A and azathioprine respectively. Prednisolone was the most effective (19.2%) acting by a two-step process with EC50 of 9.2 x 10(-12) M and 1.9 x 10(-8) M. The combination of the three drugs developed a higher significant decrease of respiratory control ratio than that of each drug but lower than the sum of their respective effects. Inhibitions of swelling and Ca2+ fluxes through mitochondrial membrane due to the combination were not different from those induced by cyclosporine A alone. The action mechanisms of cyclosporine A and prednisolone were total and partial Ca2+ dependent respectively. Azathioprine appears to act by a Ca2+-independent one. It is concluded that azathioprine and prednisolone may worsen cyclosporine A-induced renal mitochondrial alteration of oxidative phosphorylation.

Animals↗

PubMed1996

Desipramine treatment differently down-regulates beta-adrenoceptors of freshly isolated neurons and astrocytes.

Eight days' desipramine administration (16 mg/kg per day i.p.) to rats resulted in a significant decrease in the density of beta-adrenoceptors in neuronal and astroglial cells from rat forebrain and cerebellum without modification of their corresponding affinity. beta-Adrenoceptor subtypes, beta 1 and beta 2, which coexist in neurons and astrocytes, are differently distributed in the brain and differently modified by desipramine administration which down-regulates beta 1-adrenoceptor in forebrain neurons and astrocytes and beta 2-adrenoceptor in cerebellum neurons. This down-regulation affects the predominant subtype, beta 1 or beta 2, of the relevant structure. Astroglial and neuronal beta-adrenoceptors are differently coupled to G-proteins. Only neuronal cells contain the high-affinity conformational state of the beta-adrenoceptors which is sensitive to GTP. The percentage of neuronal receptors in the high-affinity state differs according to brain area. Desipramine treatment decreases the neuronal density of both cerebellar high- and low-affinity sites and only the forebrain high-affinity site. The desipramine effects are thus subtype-dependent and differ between the two brain areas selected.

Adrenergic Uptake Inhibitors↗

PubMed1996

Tobacco smoking induces expression of very-high-affinity nicotine binding sites on blood polymorphonuclear cells.

The targets of nicotine in the central nervous system (CNS) have been identified as nicotinic acetylcholine (ACh) receptors. Because of their localization in the brain, no data are available about their in vivo modifications. However, nonneuronal nicotine binding sites have been identified on peripheral blood cells. The present study was designed to evaluate the effects of tobacco smoking on granulocyte nicotine binding sites. Binding assays were performed on granulocyte membranes using (-)(3H)nicotine and were analyzed by the Scatchard method in nonsmokers (n=10), smokers (n=10), and ex-smokers (n=10). In nonsmokers, a single-affinity binding site was detected with Kd = 1.08 +/- 0.05 x 10 -9 M. In contrast, in smokers, two different classes of binding sites were identified: one with Kd1 = 2.80 +/- 0.81 x 10 -11 M and another with Kd2 = 3.92 +/- 0.58 x 10 -9 M, similar to the binding site in nonsmokers. Moreover, a twofold increase in nicotine binding-site density was observed in smokers. Ex-smokers recovered a single class of binding sites similar to those observed in nonsmokers when they had stopped smoking for more than 1 yr, whereas recent ex-smokers (1 to 8 mo) displayed a pattern similar to that in smokers, as demonstrated by the persistence of two classes of nicotine binding sites. Chronic nicotine exposure induces modifications of nicotine binding sites on granulocytes. It is noteworthy that the persistence of such alterations corresponds to the very high rate of relapse into smoking observed during the early stages of tobacco cessation. Consequently, monitoring of nicotine binding sites could constitute an interesting approach to understanding the pharmacologic mechanisms involved in tobacco dependence.

Adult↗

PubMed1996

Inhibition of rat cerebral mitochondrial respiration by cyclosporins A, D, and G and restoration with trimetazidine.

The aim of this work was to investigate possible inhibitory effects of Ca+ and different cyclosporins (Cs) on the rat brain mitochondrial respiratory control ratio (RCR) and whether or not these effects could be antagonized by trimetazidine (TMZ). The RCR was evaluated as the state 3/state 4 ratio of oxidative phosphorylation. CsA, D, and G inhibited about 10% of RCR in a concentration-dependent manner with EC50 of 57, 19 and 7 nM, respectively, whereas CsH did not modify RCR. TMZ was able to fully antagonize this inhibitory effect in a concentration-dependent manner with EC50 of 5,200, 180, and 1 nM, respectively. The Ca2+ added to the mitochondrial preparation decreased RCR in a concentration-dependent manner with a maximal effect of 46% obtained with 100 microM Ca2+. In the presence of TMZ (100 microM), the inhibitory effect of Ca2+ was partly reversed (9%). TMZ alone showed no inhibitory or stimulant effect on RCR. These results show that restoration of RCR by TMZ is due to a Ca(2+)-dependent mechanism, promoting Ca2+ efflux from the mitochondrial matrix. However, Ca2+ efflux is only partial in case of Ca2+ overload. These data suggest that TMZ may restore ATP synthesis in circumstances where neither Ca2+ overload, nor a prooxidant have generated a RCR decrease.

Analysis of Variance↗

PubMed1994

Isoproterenol interacts differently with beta-adrenoceptors in astrocytes and neurons isolated from the adult rat brain.

The interaction of isoproterenol with beta-adrenoceptors has been investigated in astroglial and neuronal cells isolated from adult rat cerebral cortices. Using the non-selective beta-adrenergic antagonist (3H)CGP-12177 as a ligand, binding experiments revealed that both types of cells exhibit beta-adrenoceptors. However the analysis of the isoproterenol displacement curve indicated that only neuronal cells contained the high affinity conformational state of the beta-adrenoceptor.

Animals↗

PubMed1994

Cyclic AMP and inositol phosphate accumulations in rat brain cortical slices following chronic citalopram or desipramine administration.

The influence of chronic administration of desipramine (16 mg/kg per day for 8 days) or citalopram (1 mg/kg per day for 8 days) on the serotonergic and noradrenergic stimulations of phosphoinositide hydrolysis and cyclic AMP formation was investigated in rat cerebral cortical slices. This was done by means of a prelabelling method allowing the simultaneous measurement of the accumulations of (3H) inositol phosphates ((3H)IP) and of (14C) cyclic AMP. Our results show that neither of the two drugs altered the inhibition of adenylate cyclase activity induced by serotonin1 (5-HT1) receptor agonists nor did they alter 5-HT1A and 5-HT1B receptor densities. Similarly they did not modify the stimulation of the inositol phosphate metabolism induced by 5-HT or norepinephrine (NE). Desipramine treatment decreased both beta-adrenoceptor-elicited cyclic AMP accumulation (-37%) and beta-adrenoceptor density (-29%), whereas citalopram was without effect. These results reinforce the idea that the ability of antidepressants to decrease the activity of the beta-adrenoceptor-adenylate cyclase complex is not common to all antidepressants, and provide no evidence for the involvement of 5-HT1A and/or 5-HT1B in the mechanism of action of these drugs.

Animals↗

PubMed1993

Nucleotides modulate the low affinity binding sites for [3H]glibenclamide in the rat brain.

Receptors for hypoglycemic sulfonylureas, such as glibenclamide, are commonly linked to the activity of ATP-sensitive K+ channels (K-ATP). High and low affinity binding sites for glibenclamide were described previously in numerous tissues. High affinity binding sites have been thought to be responsible of the modulation of K-ATP, but new evidences suggest that low affinity ones could also regulate these channels. In order to clarify the properties of the two binding sites, with respect to their interaction with K-ATP, we characterized biochemically and pharmacologically [3H]glibenclamide binding in the rat brain cortex. Competitive inhibition plots with [3H]glibenclamide performed on membranes of adult and neonatal rat brain cortex exhibited a biphasic pattern with similar binding parameters, indicating the presence of two similar binding sites in adult as well as in neonatal animals. Membranes of adult rat cortex treated with thiol groups modifying agents, N-ethylmaleimide or 1,4-dithiothreitol, increased the inhibition constant of glibenclamide for the low affinity binding sites (K(i)L) by about 4-fold. The divalent cations Mg++ and Ca++ also increased K(i)L by 3- to 6-fold and enhanced the low affinity binding capacity (BmaxL) by 55 and 103%, respectively, both cations increasing BmaxL by 144%. Among the numerous nucleotides studied, adenine and guanidine triphosphate nucleotides were the most potent to affect the low affinity binding sites. ATP, ADP, GTP and respective nonhydrolysable nucleotides increased K(i)L by 7- to 12-fold and decreased BmaxL by 10 to 30%. The effects of nucleotides were not Mg++ dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1992

Albumin binding and brain uptake of 6-fluoro-DL-tryptophan: competition with L-tryptophan.

We investigated potential competition between L-tryptophan (TRP) and 6-fluoro-DL-tryptophan (6-F-TRP) for binding to albumin and for passage through the blood-brain barrier (BBB). In experiments based on equilibrium dialysis, albumin (600 microM) bound about 80% of TRP and 50% of 6-F-TRP with affinity constants (Ka) of 3.7 +/- 0.04 x 10(4) and 0.62 +/- 0.01 x 10(4) M-1, respectively. Competitive inhibition was assessed as the decrease in the apparent Ka (K' a) of TRP in the presence of 6-F-TRP, with no modification of the N value. Competition between TRP, 6-F-TRP and L-valine (VAL) for passage across the BBB was demonstrated using two approaches. When administered concomitantly with TRP or 6-F-TRP to rats, VAL decreased brain uptake of TRP and 6-F-TRP and reversed their action on serotonin. In Oldendorf's model, 6-F-TRP and VAL decreased the brain uptake of TRP.

Animals↗

PubMed1992

Evaluation of central adrenergic receptor signal transmissions after an antidepressant administration to the rat.

The effects of several antidepressants, amitriptyline, citalopram, desipramine, fluoxetine, maprotiline, mianserin, nialamide, nomifensine, tranylcypromine and viloxazine, on the accumulation of cyclic AMP and inositol monophosphates were studied in rat cerebral cortical slices. The two enzymatic systems were stimulated either by adrenergic agonists or by forskolin. Cyclic AMP and inositol monophosphates (IPs) formed were determined by a double label method. In vitro all drugs, except inhibitors of monoamine oxidase, nialamide and tranylcypromine, inhibited alpha 1-agonist-mediated production but did not modify the cyclic AMP accumulation. Otherwise, chronic desipramine but not citalopram administration decreased the accumulation of cyclic AMP (-39%) elicited by beta-adrenoceptor agonists; no change was observed in inositol phosphate metabolism after administration of these two drugs. These data support previous investigations showing a decrease in cyclic AMP production after chronic treatment with norepinephrine uptake blockers but do not confirm the hypothesis of a modification of alpha 1-adrenoceptor-stimulated inositol phosphate metabolism.

Animals↗

PubMed1992

Serotonin enhances the beta-adrenergic response in rat brain cortical slices.

Serotonin increased the isoproterenol-induced cyclic AMP accumulation in rat brain cortical slices but did not itself stimulate the production of cyclic AMP in this area. This effect appeared to be inhibited by the 5-HT2 receptor antagonist, ritanserin. This potentiation was not observed in the hippocampus. These data reinforce the hypothesis of a coupling between the noradrenergic and serotonergic systems, which may be involved in the mechanism of action of antidepressant drugs.

Animals↗