Biomedical subjects

S Ferré

Publications and source records attributed to S Ferré.

At least 55 records · Page 3Linked to original sources

PubMed1997

Adenosine A2A agonists: a potential new type of atypical antipsychotic.

The systemic intraperitoneal (i.p.) administration of the adenosine A2A agonist CGS 21680 was found to dose-dependently antagonize spontaneous and amphetamine-induced (1 mg/kg i.p.) motor activity with similar ED50 values (about 0.2 mg/kg). The ratios between the ED50 values for induction of catalepsy and for antagonizing amphetamine-induced motor activity for CGS 21680, haloperidol, and clozapine were 12, 2, and > 30, respectively. Furthermore, CGS 21680 was comparably much stronger than haloperidol or clozapine at antagonizing the motor activity induced by phencyclidine (2 mg/kg subcutaneously) than motor activity induced by amphetamine (1 mg/kg i.p.). In conclusion, the present results show a clear "atypical" antipsychotic profile of the adenosine A2A agonist CGS 21680 in animal models.

Adenosine↗

PubMed1997

GABA-dopamine receptor-receptor interactions in neostriatal membranes of the rat.

Recent evidence has shown in membrane preparations that the binding of one ligand to its receptor is able to modify the binding parameters of a second receptor (receptor-receptor interactions), allowing the modulation of incoming signals onto a neuron. To further understand the gamma-amino-butyric acid (GABA)-dopamine (DA) interactions in the neostriatum we have carried out experiments to explore whether an activation of the GABA(A) receptor could affect the binding characteristics of the D2 DA receptor in membrane preparations of the rat neostriatum. The results show the GABA (30-100 nM) significantly increases the dissociation constant of the high affinity (KH) D2 DA binding site (labelled with the selective D2 DA receptor antagonist [3H]raclopride and that such an effect is fully counteracted by the GABA(A) receptor antagonist bicuculline (1 microM). It is suggested that such putative GABA(A)/D2 receptor-receptor interactions may take place in the somato-dendritic membrane of the striato-pallidal GABA neurons and that it may modulate the inhibitory effects of DA on these neurons, mediated via D2 receptors.

Animals↗

PubMed1996

Motor depressant effects of systemically administered polyamines in mice: involvement of central NMDA receptors.

The systemic administration of polyamines (s.c.) produced a dose-dependent motor depression. With high doses the depressant effect was long-lasting and the animals showed signs of toxicity. ED50 values for spermine, spermidine and putrescine were 38, 90 and 251 mg/kg respectively. The motor depression induced by the systemic administration of N-methyl-D-aspartate (NMDA; 25 mg/kg i.p.) was used as a model for studying the interactions between polyamines and the NMDA receptor. Results indicate that (1) the motor effects elicited by NMDA are very similar to those induced by polyamines at ED50 doses; (2) polyamines, even at non-active doses, potentiate the motor depressant effect induced by NMDA; (3) the NMDA receptor antagonist, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,1 0-imine (MK-801; 0.5 mg/kg i.p.), abolishes the depressant effect elicited by NMDA and by polyamines, even at toxic doses; (4) amphetamine (1.5 mg/kg i.p.) does not counteract the motor depressant effects of NMDA or polyamines. On the other hand, the adenosine receptor antagonist, theophylline (30 mg/kg i.p.), counteracts NMDA- but not polyamine-induced motor depression. The concentration of polyamines in the brain is modified after their systemic administration at high doses and at the ED50 dose of putrescine. In conclusion, the data suggest that the NMDA receptor could be a target mediating the motor effect elicited by polyamines. They also show that the quantitative analysis of the motor effects elicited by non-convulsant doses of NMDA might be a powerful tool for studying in vivo the interaction between neurotransmission systems involved in the regulation of motor activity.

Amphetamine↗

PubMed1996

Adenosine A2A receptors modulate the binding characteristics of dopamine D2 receptors in stably cotransfected fibroblast cells.

In membrane preparations from rat striatum, where adenosine A2A and dopamine D2 receptors are coexpressed, stimulation of adenosine A2A receptors was found to decrease the affinity of dopamine D2 receptors for dopamine agonists. We now demonstrate the existence of this antagonistic interaction in a fibroblast cell line (Ltk-) stably transfected with the human dopamine D2 (long-form) receptor and the dog adenosine A2A receptor cDNAs (A2A-D2 cells). In A2A-D2 cells, but not in control cells only containing dopamine D2 receptors (D2 cells), the selective adenosine A2A agonist 2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethyl-carboxamido adenosine (CGS 21680) induced a 2-3-fold decrease in the affinity of dopamine D2 receptors for dopamine, as shown in competition experiments with dopamine versus the selective dopamine D2 antagonist [3H]raclopride. By contrast, activation of the constitutively expressed adenosine A2B receptors with 5'-N-ethyl-carboxamidoadenosine (NECA) did not modify dopamine D2 receptor binding. In A2A-D2 cells CGS 21680 failed to induce or induced only a small increase in adenosine-3',5'-cyclic-monophosphate (cAMP) accumulation. In D2 cells NECA- or forskolin-induced adenylyl cyclase activation was not associated with any change in dopamine D2 receptor binding. These results indicate that adenylyl cyclase activation is not involved in the adenosine A2A receptor-mediated modulation of the binding characteristics of the dopamine D2 (long-form) receptor.

Animals↗

PubMed1996

Adenosine A1 receptor blockade selectively potentiates the motor effects induced by dopamine D1 receptor stimulation in rodents.

An antagonistic interaction between adenosine A1 and dopamine D1 receptors has previously been found in the basal ganglia. However, direct evidence for a selective adenosine A1 antagonist-induced potentiation of dopamine D1-mediated motor activation is lacking. The systemic administration of the adenosine A1 antagonist 8-cyclopentyl-1,3-dimethylxanthine significantly potentiated the motor activating properties of the systemically administered dopamine D1 agonist SKF 38393 in both reserpinized mice and unilaterally 6-hydroxy-dopamine-lesioned rats. However, 8-cyclopentyl-1, 3-dimethylxanthine did not modify the motor effects of the dopamine D2 agonist quinpirole. The present work shows that an antagonistic interaction between adenosine A1 and dopamine D1 receptors may be involved in the motor activating effects of adenosine antagonists, like caffeine.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1996

Reserpine potentiates NMDA-induced c-fos mRNA expression in the mouse brain.

The systemic administration of a non-convulsant dose of N-methyl-D-aspartate (NMDA; 75 mg/kg i.p.), which was associated with motor activation, induced a regional c-fos mRNA expression in the mouse brain. The NMDA-induced c-fos mRNA expression was predominant in the dentate gyrus and in the medial mammillary nucleus and less pronounced in other hippocampal areas, cortical areas, bed nucleus of the stria terminalis and posterior amygdaloid nuclei. It is suggested that the hippocampus and/or the extended amygdala might be involved in the previously hypothesized dopamine-independent NMDA-mediated motor activation mechanism. No increase in c-fos mRNA expression was observed 21 h after reserpine treatment (5 mg/kg s.c.). However, reserpinization induced a significant potentiation of the NMDA-induced c-fos mRNA expression. These results show the existence of a strong and selective amine-dependent modulation of NMDA neurotransmission in the brain.

Animals↗

PubMed1996

Stimulation of adenosine A1 receptors prevents the EEG arousal due to dopamine D1 receptor activation in rabbits.

The influence of adenosine A1 (N6-cyclopentyladenosine, CPA) and A2 (2-[4-(2-carboxylethyl)phenethylamino]-5'-N-ethylcarboxamido -adenosine hydrochloride, CGS 21680) receptor agonists on SKF 38393-induced electroencephalographic (EEG) arousal was studied in rabbits. While CPA (0.1 mg/kg i.v.) significantly prevented the EEG effects of SKF 38393, CGS 21680 (0.2 mg/kg i.v.) did not affect them. These results demonstrate that adenosine A1 receptors can modulate dopamine D1 receptor-induced EEG arousal and show, for the first time, that adenosine-dopamine interactions are involved in brain functions other than motor activity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1995

Dopamine-independent and adenosine-dependent mechanisms involved in the effects of N-methyl-D-aspartate on motor activity in mice.

The involvement of dopamine and adenosine mechanisms in the motor effects of systemically administered N-methyl-D-aspartate (NMDA) was studied in non-reserpinized and in reserpinized mice. In non-reserpinized mice NMDA induced motor depression (with 8, 25 and 75 mg/kg i.p.) during the first hour and motor activation (with 25 and 75 mg/kg i.p.) during the second hour after its administration. The non-selective adenosine antagonist, theophylline (3, 10 and 30 mg/kg i.p) induced motor activation during both 1-h periods of observation. NMDA-induced motor depression in non-reserpinized mice was antagonized by theophylline. Higher doses of theophylline were needed to counteract the motor depressant effect induced by higher doses of NMDA. The motor activation induced by NMDA and theophylline in non-reserpinized mice was not additive and theophylline did not enhance the motor activation induced by high doses of NMDA. Both NMDA (25 and 75 mg/kg i.p.) and theophylline (10 and 30 mg/kg) induced motor activation in reserpinized mice and, when coadministered, NMDA counteracted the effect of theophylline. NMDA (8 and 25 mg/kg i.p.) antagonized and theophylline (3, 10 and 30 mg/kg i.p.) potentiated the motor activation induced by the non-selective dopamine agonist, apomorphine (0.1 mg/kg s.c.), in reserpinized mice. In reserpinized mice, the non-selective dopamine antagonist, haloperidol (0.5 mg/kg s.c.) antagonized the motor activation induced by apomorphine (0.1 mg/kg s.c.) and the induced by theophylline (10 mg/kg i.p.) and did not modify NMDA-induced motor activation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed1995

Clozapine decreases serotonin extracellular levels in the nucleus accumbens by a dopamine receptor-independent mechanism.

By using brain microdialysis, clear differences in the effects of the systemic administration of clozapine and haloperidol on the extracellular concentration of dopamine (DA) and serotonin (5-HT) were found in the nucleus accumbens of freely moving rats. Haloperidol (0.5 mg/kg s.c.) significantly increased DA (ca. 40%) but did not modify 5-HT extracellular concentration, while clozapine (5 mg/kg s.c.) significantly decreased 5-HT (ca. 40%) but did not change DA concentration. Locally infused, clozapine (10(-5) M) significantly increased DA (75%) and reduced 5-HT extracellular concentration (50%). The reduction of 5-HT cannot be explained by a clozapine-induced blockade of DA receptors, because the local infusion (10(-5) M) of the DA D2-like antagonist raclopride and the DA D1-like antagonist SCH 23390 significantly increased DA (ca. 300% and 200%, respectively) but did not modify 5-HT extracellular concentration. Conversely, the DA D2-like agonist quinpirole and the DA D1-like agonist SKF-38393 significantly decreased (ca. 60% in both cases) DA extracellular concentration without affecting that of 5-HT. The present results indicate that clozapine displays a powerful anti-serotoninergic effect by inhibiting 5-HT release in the nucleus accumbens, an effect probably derived from the reduction of firing activity at the dorsal raphe and by local mechanisms that may involve some 5-HT receptor subtype(s).

Animals↗

PubMed1995

A brief appraisal on some aspects of the receptor-receptor interaction.

Receptor-receptor interaction is being recognized as a key cellular mechanism responsible for the integration of signals between different transmission lines at the membrane level. Receptor-receptor interaction extends the classical concept of integration of depolarization and hyperpolarization effects to the integration of chemical events at membrane level. In the present paper only some hypotheses on the possible mechanistic aspects of the interactions between the membrane receptors will be discussed. Furthermore, possible functional consequences of receptor-receptor interaction will be explored. The limitations of the present experimental approaches to the study of receptor-receptor interaction will also be analysed.

Animals↗

PubMed1994

Postsynaptic antagonistic interaction between adenosine A1 and dopamine D1 receptors.

Behavioural and biochemical evidence for the existence of a powerful specific postsynaptic interaction between adenosine A1 and dopamine D1 receptors in the mammalian brain was found. Behavioural data showed that A1 receptor stimulation induced a decrease in the D1-induced motor activation in reserpinized mice and a decrease in the D1-dependent oral dyskinesia in rabbits. Biochemical data suggested that A1 receptor stimulation could produce a GTP-independent uncoupling of the rat striatal D1 receptor to the G protein. The A1-D1 receptor-receptor interaction might represent an important additional mechanism of action responsible for the motor depressant effects of adenosine agonists and for the motor stimulant effects of adenosine antagonists, like the methylxanthines caffeine and theophylline.

Animals↗

PubMed1994

PEC-60 increases dopamine but not GABA release in the dorsolateral neostriatum of the halothane anaesthetized rat. An in vivo microdialysis study.

The effect of striatal perfusion with the intestinal peptide PEC-60 on endogenous dopamine (DA) and gamma-aminobutyric acid (GABA) release in the dorsolateral striatum and GABA release in the globus pallidus was monitored using in vivo microdialysis in the halothane anaesthetized rat. The results show that PEC-60 (100 nM) increases DA release in the dorsolateral striatum without influencing GABA release in the dorsolateral striatum or in the globus pallidus. In addition, PEC-60 failed to influence the extracellular striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. The PEC-60 induced increase in striatal DA was abolished by the addition of tetrodotoxin (1 microM) to the perfusion medium. These data suggest that PEC-60 plays a role in modulating striatal DA release but not DA metabolism and that this effect is primarily targeted on the presynaptic DA terminals of the nigrostriatal DA pathway rather than on the postsynaptic striatopallidal GABA projection neurons in the dorsolateral striatum.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Motor activation in short- and long-term reserpinized mice: role of N-methyl-D-aspartate, dopamine D1 and dopamine D2 receptors.

The effects of dopamine D1 and dopamine D2 receptor agonists and of subconvulsant doses of N-methyl-D-aspartate (NMDA) and the non-competitive NMDA receptor antagonist, dizocilpine (MK-801), alone and in combination, on the motor activity of short- and long-term reserpinized mice (mice pretreated with 5 mg/kg reserpine 4 h or 20 h before, respectively) were analyzed. With short-term reserpinization, the dopamine D2 receptor agonist, quinpirole (1.5 mg/kg), but not the dopamine D1 receptor agonist, SKF-38393 (15 mg/kg), increased motor activity. The effect of quinpirole in short-term reserpinized mice was potentiated by the simultaneous administration of SKF-38393 (15 mg/kg) and was counteracted by the previous administration of the dopamine D2 receptor antagonist, raclopride (1 mg/kg), or by the simultaneous administration of NMDA (25 mg/kg) or MK-801 (0.5 mg/kg). Neither NMDA (25-100 mg/kg) nor MK-801 (0.5-3 mg/kg) induced motor activation in short-term reserpinized mice. With long-term reserpinization, either quinpirole (1.5 mg/kg) or SKF-38393 (15 mg/kg) increased motor activity. The effect of quinpirole in long-term reserpinized mice was not potentiated by the concurrent administration of SKF-38393 (15 mg/kg), was inhibited by the simultaneous administration of MK-801 (0.5 mg/kg) and was not modified by NMDA (25 mg/kg). The effect of SKF-38393 (15 mg/kg) in long-term reserpinized mice was inhibited by the concomitant administration of MK-801 (0.5 mg/kg) and was slightly antagonized by NMDA (25 mg/kg). NMDA induced motor activation in long-term reserpinized mice at doses which were similar to those causing motor activation in non-reserpinized mice (75 and 100 mg/kg), while MK-801 induced motor activation at a dose which was associated with motor depression in non-reserpinized mice (2 mg/kg). The NMDA-induced motor activation in long-term reserpinized mice was counteracted by the previous administration of a low dose of MK-801 (0.5 mg/kg) and was still present when a stronger dopamine-depleting pretreatment was used. These results are interpreted on the basis of changes in sensitivity of the direct striatal efferent pathway after long-term reserpinization.

Animals↗

PubMed1994

Chronic haloperidol treatment leads to an increase in the intramembrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatum.

Stimulation of adenosine A2 receptors (with the selective adenosine A2 agonist CGS 21680) in rat striatal membrane preparations, produces a decrease in both the affinity of D2 receptors and the transduction of the signal from the D2 receptor to the G protein. This intramembrane A2-D2 interaction might be responsible for the behavioural depressant effects of adenosine agonists and for the behavioural stimulant effects of adenosine antagonists such as caffeine and theophylline. Dopamine denervation induces an increase in the intramembrane A2-D2 interaction, which may underlie the observed higher sensitivity to the behavioural effects induced by adenosine antagonists found in these animals. The present study was designed to examine if chronic treatment with haloperidol, which also produces dopamine receptor supersensitivity, is also associated with an increase in the intramembrane A2-D2 interaction in the neostriatum and with a higher sensitivity to the behavioural effects induced by adenosine antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed1994

Unilateral neonatal intracerebroventricular 6-hydroxydopamine administration in rats: II. Effects on extracellular monoamine, acetylcholine and adenosine levels monitored with in vivo microdialysis.

6-hydroxydopamine (6-OHDA, 100 micrograms in 5 microliters) was injected into the right ventricle of 3-day-old Sprague-Dawley rats in order to produce a unilateral dopamine (DA) lesion. At adult stage, the rats were implanted with microdialysis probes into the left and right striata. On the injected side, basal extracellular levels of DA were reduced by > 65%, as compared to the contralateral side or to the levels found in vehicle-injected rats. Extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were reduced by > 95%, while acetylcholine (ACh) was decreased by > 50%. d-Amphetamine (2 mg/kg SC) produced a 10-fold increase in extracellular DA levels in the striatum contralateral to the 6-OHDA-injected side, while on the ipsilateral side. DA levels were not affected by d-amphetamine. d-Amphetamine produced an increase (> 2 fold) in extracellular ACh levels, on both ipsilateral and contralateral sides. Choline and adenosine levels were unaffected by any of the experimental conditions. Thus, neonatal unilateral ICV administration of 6-OHDA produced an ipsilateral decrease in striatal extracellular DA, DOPAC and HVA levels, compared to the contralateral side. A reduction of extracellular ACh levels was also observed on the 6-OHDA-injected side. The DA releasing effect of d-amphetamine was abolished on the 6-OHDA-injected side, but not that on ACh levels, indicating that striatal DA and ACh d-amphetamine-induced release are produced by independent mechanisms in the neonatally unilateral 6-OHDA-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1994

Antagonistic interaction between adenosine A2A receptors and dopamine D2 receptors in the ventral striopallidal system. Implications for the treatment of schizophrenia.

Recent studies have shown the existence of a specific antagonistic interaction between adenosine A2a receptors and dopamine D2 receptors in the brain. This A2a-D2 interaction seems to be essential for the behavioural effects of adenosine agonists and antagonists, like caffeine. In the present study quantitative receptor autoradiography and brain microdialysis were combined to demonstrate a powerful antagonistic A2a-D2 interaction in the ventral striopallidal system. In the presence of the A2a agonist (2-p-carboxyethyl)phenylamino-5'-N carboxamidoadenosine, dopamine exhibited a lower efficacy in displacing the radiolabelled D2 receptor antagonist [125I]iodosulpiride from the rat ventral striatum, specially in the nucleus accumbens. A tonic dopaminergic modulation of the striopallidal neurons from the ventral striopallidal system was demonstrated by a dual-probe approach, by infusing selective dopamine agonists and antagonists in the nucleus and by measuring dopamine extracellular levels in the nucleus accumbens and GABA extracellular levels in the nucleus accumbens and in the ipsilateral ventral pallidum. The infusion of (2-p-carboxyethyl)phenylamino-5'-N-carboxamidoadenosine in the nucleus accumbens induced the same postsynaptic changes as the D2 antagonist raclopride, i.e. an increase in pallidal GABA extracellular levels, without changing those levels in the nucleus accumbens. Furthermore, the coinfusion in the nucleus accumbens of low concentrations of (2-p-carboxyethyl) phenylamino-5'-N-carboxamido-adenosine and raclopride, which were ineffective when administered alone, induced a significant increase in pallidal gamma-aminobutyric acids extracellular levels. These results suggest that A2a agonists, alone or in combination with D2 antagonists, could be advantageous antischizophrenic drugs, as blockage of D2 receptors in the ventral striopallidal system appears to be associated with the antipsychotic activity of neuroleptics but not with their extrapyramidal motor-side effects.

Adenosine↗

PubMed1994

Dopaminergic regulation of the serotonergic raphe-striatal pathway: microdialysis studies in freely moving rats.

Morphological evidence demonstrates the existence of dopaminergic afferent pathways and dopamine (DA)-containing neurons in the dorsal raphe nucleus (DRN). In a recent report, a DA D2-like receptor-mediated regulation of serotonin (5-HT) extracellular concentration in DRN has been found. Given the existence of somatodendritic 5-HT1A autoreceptors in the DRN, changes of the extracellular concentration of 5-HT in the vicinity of cell bodies and dendrites may be relevant for the control of the activity of ascending serotonergic pathways. In the present brain microdialysis study we have used a chromatographic method (HPLC) enabling the simultaneous measurement of DA, 5-HT, and their main metabolites dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA). The presence of a neuronal pool of DA within the DRN was revealed by the local infusion of amphetamine (10 microM), which significantly increased the extracellular concentration of both amines. The local striatal infusion (10 microM) of the selective DA D1-like agonist SKF-38393, the selective DA D2-like agonist quinpirole (LY 171,555), or the nonselective DA agonist apomorphine markedly decreased DA and DOPAC extracellular concentrations and failed to modify 5-HT or 5-HIAA in the striatum, indicating the lack of terminal (striatal) control of 5-HT release by dopaminergic transmission. In contrast, the systemic administration of apomorphine (2.8 mumol/kg, s.c.) significantly increased the extracellular concentration of 5-HT in the DRN and decreased it in the striatum. The reduction of striatal 5-HT extracellular concentration was prevented by the previous administration of the selective 5-HT1A receptor antagonist WAY 100135 (17.6 mumol/kg, s.c.), which by itself did not change extracellular 5-HT in striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Opposing actions of an adenosine A2 receptor agonist and a GTP analogue on the regulation of dopamine D2 receptors in rat neostriatal membranes.

We have previously found, in rat striatal membrane preparations, that stimulation of adenosine A2 receptors (with the selective adenosine A2 receptor agonist CGS 21680) increases the high- and low-affinity dissociation constants and increases the proportion of high-affinity dopamine D2 receptor binding sites labelled with the selective dopamine D2 receptor antagonist [3H]raclopride. As guanine nucleotides and divalent cations (such as Mg2+) are known to regulate the proportion of high-affinity D2 receptor binding sites in opposing ways, interaction experiments with CGS 21680, the GTP analogue Gpp(NH)p and MgCl2 were performed. Our results suggest that these three factors exert significant, though independent, effects on the proportion of high affinity D2 receptors, and that A2 receptors regulate both the affinity of D2 receptors and the transduction of the signal from the D2 receptor to the G-protein.

Adenosine↗