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Biomedical subjects

S Consolo

Publications and source records attributed to S Consolo.

At least 73 records · Page 4Linked to original sources
PubMed1989

Galanin receptor and its ligands in the rat hippocampus.

Receptors for the 29-amino-acid peptide, galanin, in membranes from the rat ventral hippocampus were examined using chloramine-T-iodinated porcine galanin as ligand. The equilibrium binding of 125I-galanin showed the presence of a high-affinity binding site (Kd = 1.91 +/- 0.40 nM). The concentration of the high-affinity-binding sites was 107 +/- 15 fmol/mg membrane protein. The on rate constant was estimated to be 2.6 +/- 0.1 M-1 min-1 at 37 degrees C. The affinity of rat galanin (differing in three amino acid residues from the porcine protein) was equal to that of porcine galanin. The 125I--galanin-binding site is a trypsin-sensitive membrane protein, which is heat-denaturated at 60 degrees C within 5 min. The effect of GTP and its analogs and of pertussis-toxin-catalyzed ADP-ribosylation on the binding of 125I-galanin suggest that the galanin receptor is coupled to an inhibitory G protein (Gi protein). 127I-galanin was shown to be a ligand with affinity equal to that of galanin in displacing 125I-galanin. The 125I-galanin-binding site in the ventral hippocampus recognizes as a ligand the tryptic fragments 1-20 and 21-29 of rat galanin and the synthetic fragments 12-29, 18-29 and 21-29 of porcine galanin. None of these afforded full inhibition of the binding of fragment 1-29 of 125I-galanin at a concentration of 1 microM.

Animals↗
PubMed1989

Mode of action of tiaspirone on the central cholinergic system.

Tiaspirone, a potential antipsychotic drug, reduced the acetylcholine content of rat hemispheric brain regions (striatum 35%, hippocampus 20%, cortex 32% with no effect on N. accumbens) at an oral dose of 40 mg/kg. Choline content was uniformly raised in the same brain regions. A kinetic study showed that the drug is evenly distributed in the brain. Tiaspirone's effects on acetylcholine and choline in the striatum were not related in time. The fall off (30-240 min) of tiaspirone's effect on choline content paralleled the decline in striatal drug concentration (t1/2 = 240 min) whereas that on acetylcholine did not. No tolerance was observed to an acute challenge with tiaspirone on acetylcholine and choline in the striatum after 11 days' subchronic treatment. In vitro the drug had no effect on striatal choline acetyltransferase and acetylcholinesterase activities up to a concentration of 300 microM. The muscarinic agonist oxotremorine did not interfere with the acetylcholine decrease produced by the drug suggesting that muscarinic receptors are not essential for this effect. Tiaspirone, however, was found to be a competitive, reversible inhibitor of the sodium-dependent high-affinity choline uptake (SDHACU) by crude hippocampal and striatal synaptosomal preparations, giving IC50 values of respectively 3.69 microM and 1.14 microM. The compound did not alter SDHACU ex vivo despite the fact that it readily crosses the blood-brain barrier and achieves brain concentrations equivalent to its in vitro IC50 concentration. Tiaspirone antagonized the striatal acetylcholine increasing effect of apomorphine, a selective dopaminergic receptor agonist, supporting the idea that the drug affects the striatal cholinergic system by a primary action on dopamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1989

Cross-talk between different intracellular signalling pathways in the rat hippocampus.

The activation of alpha 1-adrenergic receptors in rat hippocampal slices enhances polyphosphoinositide (PPI) breakdown and cyclicAMP (cAMP) accumulation. The latter effect is antagonized by different protein kinase C (PKC) inhibitors and mimicked by a diacylglycerol (DAG) analogue, 1,2-diolein, which activates PKC, suggesting that cAMP synthesis is indirectly affected by alpha 1-adrenoceptors through the stimulated generation of DAG upon PPI hydrolysis. Furthermore the elevation of hippocampal cAMP decreases the ability of alpha 1-receptor agonists to enhance PPI breakdown. It is proposed that the observed effects are part of a complex cross-talk between PPI and AC signalling pathways operating in hippocampal neurons.

Animals↗
PubMed1989

N-terminal galanin-(1-16) fragment is an agonist at the hippocampal galanin receptor.

The galanin N-terminal fragment [galanin-(1-16)] has been prepared by solid-phase synthesis and by enzymic cleavage of galanin by endoproteinase Asp-N. This peptide fragment displaced 125I-labeled galanin in receptor autoradiography experiments on rat forebrain and spinal cord and in equilibrium binding experiments from high-affinity binding sites in the ventral hippocampus with an IC50 of approximately 3 nM. In tissue slices of the same brain area, galanin-(1-16), similarly to galanin, inhibited the muscarinic agonist-stimulated breakdown of inositol phospholipids. Upon intracerebroventricular administration, galanin-(1-16) (10 micrograms/15 microliters) also inhibited the scopolamine (0.3 mg/kg, s.c.)-evoked release of acetylcholine, as studied in vivo by microdialysis. Substitution of [L-Trp2] for [D-Trp2] resulted in a 500-fold loss in affinity as compared with galanin-(1-16). It is concluded that, in the ventral hippocampus, the N-terminal galanin fragment [galanin-(1-16)] is recognized by the galanin receptors controlling acetylcholine release and muscarinic agonist-stimulated inositol phospholipid breakdown as a high-affinity agonist and that amino acid residue [Trp2] plays an important role in the receptor-ligand interactions.

Animals↗
PubMed1988

Modulation of phospholipid methylation in rat striatum by the corticostriatal pathway.

Surgical undercutting of cortical afferents and subsequent interruption of excitatory input increased phospholipid (PL) methylation (30-40%) in rat striatal synaptosomes as early as 3 days after lesion. The increase was still present 60 days after lesion, was protein-dependent and lesion-specific. The role of the dopaminergic agents on PL methylation in decorticated rats was investigated. In contrast with sham-lesioned rats, in which dopamine stimulated PL methylation, dopamine did not further stimulate phosphatidylethanolamine N-methyltransferase (PEMT) activity in decorticated rats. In addition, dopamine antagonists reversed the increase in PL methylation in lesioned rats at concentrations that had no effect in blocking DA-stimulated PL methylation in sham-lesioned rats. The specific antagonist of N-methyl-D-aspartate receptors, 2-amino-5-phosphonovaleric acid, increased PL methylation in non-lesioned striata, mimicking the effect of decortication, while N-methyl-D-aspartic acid counteracted the decortication-induced increase in PEMT activity. These data suggest a modulatory role of the cortex on PEMT activity in rat striatum.

Animals↗
PubMed1988

Enhancement of opioid cataleptic response by cortical frontal deafferentation or intrastriatal injection of NMDA-receptor antagonists.

The cataleptic activity of morphine and methadone was markedly potentiated in frontally decorticated rats with no apparent changes in the onset or duration of action. Enhancement of the opioid cataleptic response was not due to changes in the availability of the drugs in the brain. The potentiation of methadone-induced catalepsy in decorticated rats was mimicked in naive rats by intrastriatal (i.s.) application of 2-amino-7-phosphonoheptanoic acid (AP7), a potent and selective antagonist of N-methyl-D-aspartate (NMDA) receptors. Therefore, degeneration of glutamatergic synapses following decortication could be responsible for the changes in behavioral effects caused by opioids. The failure of AP7 to elicit an effect after injection into the n. accumbens fits with the possibility of a selective involvement of the striatum in this phenomenon. That the striatum plays a critical role in the expression of opioid-induced catalepsy was substantiated by the findings that: (1) naloxone, an opioid antagonist, injected i.s., prevents the potentiation of catalepsy induced by methadone and morphine in decorticated animals, (2) oxotremorine, a muscarinic agonist, injected i.s., reverses the enhancement of opioid-catalepsy in decorticated rats, (3) earlier studies by others showed that ablation of the striatum had a facilitatory action on opioid-induced catalepsy. In conclusion, evidence is given that the corticostriatal pathway exerts an inhibitory effect upon narcotic-induced cataleptic behavior. The possibility that this effect is mediated through striatonigral GABAergic output is discussed. The data further suggest that the neuronal mechanisms through which the corticostriatal pathway mediates narcotic catalepsy is operative through activation of NMDA receptors within the striatum.

2-Amino-5-phosphonovalerate↗
PubMed1988

Serotonergic control of phenylephrine-induced cyclic 3,5'-adenosine monophosphate and inositol phosphates formation in rat hippocampus.

Chemical lesion of serotonergic afferents to the hippocampus resulted in a potentiation of phenylephrine (PHE) stimulation of cyclic AMP (cAMP) formation in rat hippocampal slices. The concentration-response curve of the alpha-1-agonist in lesioned rats was shifted markedly to the left with the peak increase occurring at a concentration 200 times lower (500 nM) than that required to raise cAMP to the same extent in slices of the sham-operated controls. Adenylate cyclase activity measured on crude homogenate preparations was increased by the lesion, too. The alpha-1 antagonist WB-4101 (dimethyloxyphenoxy-ethylamino-methyl benzo-1,4-dioxan) was the most potent inhibitor of PHE in lesioned rats with an IC50 of 125 nM, 110 times lower than that of prazosin (14 microM); yohimbine and propranolol, respectively, alpha-2 and beta-antagonists caused inhibition only at very high concentrations. Serotonin (10 microM) induced a marked rightward shift in the concentration response of PHE in lesioned rats, without any effect of its own on the cAMP level. PHE stimulated inositol phosphates accumulation in hippocampal slices in a concentration-dependent manner with an EC50 of 20 microM. Chemical lesion of the serotonergic median raphe nuclei caused a significant reduction of PHEs maximal effect on inositol phosphate accumulation by 50% with no change detectable in the EC50. The results imply that both second messenger responses to PHE stimulation are modulated by serotonin. Whether cAMP and phosphatidylinositol-4,5-bisphosphate generated second messengers act in a cooperative manner, or independently, is discussed.

5,7-Dihydroxytryptamine↗
PubMed1987

Striatal cholinergic function reflects differences in D-2 dopaminergic receptor activation.

The ergot derivatives, bromocriptine, lisuride and quinpirole (Ly-171555), activators of D-2 receptors, increased striatal acetylcholine (ACh) content by about 40% and induced a 30% inhibition of ACh evoked release from striatal slices, similar to the effects of the dopaminergic agonist apomorphine. These actions were a consequence of dopaminergic activation since they were antagonized by pretreatment with the neuroleptic agent, pimozide. In contrast, pretreatment with L-sulpiride (100 mg/kg), a specific antagonist for the D-2 dopaminergic receptor only, prevented the rise of ACh levels induced by apomorphine or quinpirole but did not interfere with the lisuride- or bromocriptine- induced ACh increases. Similarly, inhibition of the ACh evoked release produced by lisuride (3 microM) was prevented by pimozide (1 mg/kg) but not by pretreatment with L-sulpiride. Addition of L-sulpiride (5 microM) to the Krebs solution had no effect on the inhibition of ACh-evoked release induced by lisuride, but a lower concentration (1 microM) antagonized the inhibition induced by quinpirole. Lisuride and bromocriptine responses were both insensitive to sulpiride. These results are discussed in terms of different interaction with the dopaminergic D-2 receptors by the drugs studied.

Acetylcholine↗
PubMed1987

BM-5, a centrally active partial muscarinic agonist with low tremorogenic activity. In vivo and in vitro studies.

The acute and chronic effects of the centrally active oxotremorine analog, BM-5, [N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)-acetamide] were examined in rats and mice. In vivo studies in mice and rats indicated that this compound is a partial muscarinic agonist with large regional differences in its efficacy: BM-5 produced low tremor in doses which evoke full salivary response. The maximal tremor response to BM-5 was much smaller than that produced by oxotremorine, while the maximal salivary response to BM-5 was greater than that evoked by oxotremorine. The tremor response to BM-5 was bell-shaped, the peak dose being around 2 mg/kg. In contrast, the salivary response increased with increasing doses of BM-5. The apparent muscarinic antagonist properties of higher doses of BM-5 were specific to the striatum in which BM-5 (0.05-10 mg/kg) caused significant decreases in the level of acetylcholine while these levels were unaltered in the cerebral cortex, hippocampus, and brainstem. Pretreatment of rats with BM-5 (5 mg/kg) also prevented the increase in striatal acetylcholine induced by oxotremorine (0.75 mg/kg). Chronic treatment of mice with BM-5 (0.2-2 mg/kg) for 14 days also showed that BM-5 at higher doses, behaved as an antagonist, since it caused supersensitivity to oxotremorine on the tremor response. In addition, the number of receptor sites, as measured by binding of 3H-3-quinuclidinyl benzilate (3H-3-QNB), was increased in the striatum while no similar increase was observed in other brain areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1987

Galanin inhibits acetylcholine release in the ventral hippocampus of the rat: histochemical, autoradiographic, in vivo, and in vitro studies.

A high density of galanin binding sites was found by using 125I-labeled galanin, iodinated by chloramine-T, followed by autoradiography in the ventral, but not in the dorsal, hippocampus of the rat. Lesions of the fimbria and of the septum caused disappearance of a major population of these binding sites, suggesting that a large proportion of them is localized on cholinergic nerve terminals of septal afferents. As a functional correlate to these putative galanin receptor sites, it was shown, both in vivo and in vitro, that galanin, in a concentration-dependent manner, inhibited the evoked release of acetylcholine in the ventral, but not in the dorsal, hippocampus. Intracerebroventricularly applied galanin (10 micrograms/15 microliters) fully inhibited the scopolamine (0.5 mg/kg, s.c.)-stimulated release of acetylcholine in the ventral, but not in the dorsal, hippocampus, as measured by microdialysis technique. In vitro, galanin inhibited the 25 mM K+-evoked release of [3H]acetylcholine from slices of the ventral hippocampus, with an IC50 value of approximately 50 nM. These results are discussed with respect to the colocalization of galanin- and choline acetyltransferase-like immunoreactivity in septal somata projecting to the hippocampus.

Acetylcholine↗
PubMed1987

Determination of endogenous acetylcholine release in freely moving rats by transstriatal dialysis coupled to a radioenzymatic assay: effect of drugs.

The technique of intracerebral dialysis in combination with a sensitive and specific radioenzymatic method was used for recovery and quantification of endogenous extracellular acetylcholine from the striata of freely moving rats. A thin dialysis tube was inserted transversally through the caudate nuclei, and the tube was perfused with Ringer solution, pH 6.1, at a constant rate of 2 microliter min-1. The perfusates were collected at 10-min intervals. In the presence of 1 and 10 microM physostigmine, acetylcholine release was 4.5 +/- 0.02 and 7.3 +/- 0.3 pmol/10 min, respectively (not corrected for recovery). The latter concentration of the acetylcholinesterase inhibitor was used in all experiments. Under basal conditions, acetylcholine output was stable over at least 4 h. A depolarizing K+ concentration produced a sharp, reversible 87% increase in acetylcholine output. Both the basal and K+-stimulated release were Ca2+ dependent. The choline uptake inhibitor hemicholinium-3 (20 micrograms intracerebroventricularly) reduced striatal acetylcholine output to 35% of the basal value within 90 min. Scopolamine (0.34 mg/kg s.c.) provoked a sharp enhancement of acetylcholine release of approximately 63% over basal values, whereas oxotremorine (0.53 mg/kg i.p.) transiently reduced acetylcholine release by 54%. These results indicate the physiological and pharmacological suitability of transstriatal dialysis for monitoring endogenous acetylcholine release.

Acetylcholine↗
PubMed1987

D-1 receptor-linked mechanism modulates cholinergic neurotransmission in rat striatum.

SCH 23390, a D-1 dopaminergic antagonist, was examined for its effects on the cholinergic system in rat brain. The compound raised the content of acetylcholine selectively in striatum and not in other brain areas including the hippocampus, nucleus accumbens, hemispheric residuum and midbrain-hindbrain, mirroring the action of dopaminomimetic drugs. That the increase in acetylcholine content reflected a depression of striatal cholinergic neuronal activity was substantiated by the drug's ability to inhibit sodium-dependent high affinity choline uptake, to reduce the electrically evoked release of [3H]acetylcholine from striatal slices in vitro and to reduce acetylcholine release from striatum in freely moving rats in vivo. The increase in striatal acetylcholine was prevented by the D-1 dopaminergic agonist, SK 38393-A, but not by the D-2 agonist, LY 171555. Inhibition of dopamine synthesis by DL alpha-methyltyrosine methyl ester HCI or the selective degeneration of nigrostriatal dopaminergic terminals by the neurotoxin 6-hydroxydopamine HBr prevented the acetylcholine increasing effect of SCH 23390 completely, suggesting that presynaptic dopamine is important in the action of the dopaminergic antagonist. In agreement with these findings, SCH 23390 amplified the action of amphetamine, a dopamine releaser, on striatal cholinergic neurons. Furthermore, blockade of D-2 receptors by pimozide or sulpiride did not suppress the cholinergic effect of SCH 23390. When combined with a subthreshold dose of LY 171555, SCH 23390 did not potentiate the action of the D-2 dopaminergic agonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1986

In vivo and in vitro studies on the regulation of cholinergic neurotransmission in striatum, hippocampus and cortex of aged rats.

Young (3 months) and senescent (23 months) rats were challenged with oxotremorine both in vivo, to determine its effects on acetylcholine content in hemispheric regions, and in vitro, to assess its action on K+-evoked release of ACh from brain synaptosomes. The drug failed to inhibit KCl-induced [3H]ACh release from the P2 fraction of striatal and hippocampal homogenates of the senescent animals, whereas it was less efficient in increasing striatal ACh content. In contrast, oxotremorine was still able to stimulate an increase in ACh in the hippocampus and cerebral cortex of the aged rats to the same extent as it did in the young ones. The [3H]ACh output from striatal synaptosomes was lower in old rats with respect to young ones at low KCl depolarizing concentrations but was equal in the two groups at a high depolarizing concentration. In the hippocampus of the senescent rats, the release was significantly lower at each concentration of KCl used, resulting in a parallel downward-shift in the concentration-release plot. We also measured cholinergic muscarinic receptor binding in rat hemispheric regions using the radioligand [3H]dexetimide, a classical non-selective muscarinic receptor antagonist. It was found, in conformity with some of the literature, that receptor binding was decreased by about 32% in striatum of aged female rats as compared to younger rats. Changes were not observed in cortex and hippocampus. Analysis of the binding data indicated that the observed decrease in specific ligand binding was due to a decrease in the number of binding sites without a change in affinity. The results favor, once again, the cholinergic hypothesis for geriatric dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1986

Frontal decortication and adaptive changes in striatal cholinergic neurons in the rat.

Interruption of the corticostriatal pathway by undercutting the cortex resulted in a reduction of glutamate uptake by 55% and in a depression of acetylcholine (ACh) synthesis by 30% in striatum after two postlesion weeks without affecting the content of ACh and choline, the specific binding of [3H]dexetimide to muscarinic receptors, the activity of choline acetyltransferase and the levels of noradrenaline, serotonin, dopamine and 3,4-dihydroxyphenylacetic acid. The influence of this excitatory pathway on striatal cholinergic neuropharmacology was investigated. It was found that the effect of a number of agonists (R-apomorphine, bromocriptine, lisuride, quinpirole, JL-14389, 2-chloroadenosine, oxotremorine and methadone), capable of depressing cholinergic activity in the striatum through receptor-mediated responses--reflected as an increase in ACh content--is operative only when the corticostriatal pathway is intact. By contrast, antagonists capable of decreasing ACh content, i.e. the typical neuroleptics pimozide, haloperidol and the atypical ones clozapine, L-sulpiride, as well as the anti-muscarinic agent scopolamine, were not influenced by the lesion. The possibility that the lesion non-specifically damaged striatal cells on which the agonists, but not the antagonists acted was excluded by results showing, firstly, that the increase in striatal ACh elicited by the ACh precursor, choline, was not blocked by decortication, and secondly, that the degeneration of the corticostriatal neurons did not prevent the ACh-increasing effect of bromocriptine, a long-acting ergot alkaloid, when sufficient time was allowed for the drug to act. It was furthermore possible to restore the inhibitory action of apomorphine on cholinergic neurons either by short-term chemical lesion of the nigrostriatal dopaminergic input or by the administration of choline.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1986

Qualitative differences in the effects of adenosine analogs on the cholinergic systems of rat striatum and hippocampus.

The effect of the purinergic agonist, 2-chloroadenosine (2-CADO), on central cholinergic parameters was studied in the rat. The drug (20 micrograms, i.c.v.) increased acetylcholine (ACh) content (approximately 30%) and inhibited sodium dependent high affinity choline uptake (30%) in the hippocampus. In striatum, the increase of ACh content was less marked (approximately 15%) and was not associated with inhibition of choline uptake. In both areas, ACh accumulation was prevented by theophylline but not by atropine or oxotremorine pretreatments. Differences were noted in the purinergic control of cholinergic function in the hippocampus and striatum. In hippocampus, the selective degeneration of noradrenergic, serotonergic and glutamatergic afferent pathways or the destructions of intrinsic neurons did not prevent the rise in ACh content induced by 2-CADO. Differently, in striatum, the action of 2-CADO was potentiated both by raphe deafferentation and by inhibition of serotonin synthesis and was completely prevented by chronic unilateral decortication. The cholinergic effect of 2-CADO was unchanged after impairment of the noradrenergic or dopaminergic systems. In addition, the D- and L-isomers of phenylisopropyladenosine, which have different affinities for A1 purinergic receptors but equal affinity for the A2 purinergic subtype, differed in their ability to affect acetylcholine content in these two brain regions, suggesting that A1 purinergic receptor activation mediates the effect of 2-CADO in the hippocampus and A2 receptor activation mediates the drug's action in the striatum.

2-Chloroadenosine↗