Adele Lucchelli
University of Pavia
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Featured researches published by Adele Lucchelli.
British Journal of Pharmacology | 2000
Gianluigi D'Agostino; Maria Laura Bolognesi; Adele Lucchelli; Davide Vicini; B. Balestra; Valeria Spelta; Carlo Melchiorre; M. Tonini
Experiments were carried out in human detrusor strips to characterize muscarinic receptor subtypes involved in the prejunctional regulation of acetylcholine (ACh) release from cholinergic nerve terminals, and in the postjunctional smooth muscle contractile response. In detrusor strips preincubated with [3H]‐choline, electrical field stimulation (600 pulses) delivered in six trains at 10 Hz produced a tritium outflow and a contractile response. In the presence of 10 μM paraoxon (to prevent ACh degradation) the tritium outflow was characterized by HPLC analysis as [3H]‐ACh (76%) and [3H]‐choline (24%). Electrically‐evoked [3H]‐ACh release was abolished by tetrodotoxin (TTX: 300 nM) and unaffected by hexamethonium (10 μM), indicating a postganglionic event. It was reduced by physostigmine (100 nM) and the muscarinic receptor agonist, muscarone (10 nM–1 μM), and enhanced by atropine (0.1–100 nM). These findings indicate the presence of a muscarinic negative feedback mechanism controlling ACh release. The effects of various subtype‐preferring muscarinic receptor antagonists were evaluated on [3H]‐ACh release and muscle contraction. The rank potency (−log EC50) orders at pre‐ and postjunctional level were: atropine 4‐diphenyl‐acetoxy‐N‐piperidine (4‐DAMP)>mamba toxin 3 (MT‐3)>tripitramine>para‐fluorohexahydrosiladiphenidol (pF‐HHSiD)methoctraminepirenzepine>tripinamide, and atropine4‐DAMP>pF‐HHSiD>>pirenzepine=tripitramine>tripinamide>methoctramine>>MT‐3, respectively. The comparison of pre‐ and post‐junctional potencies and the relationship analysis with the affinity constants at human cloned muscarinic receptor subtypes indicates that the muscarinic autoreceptor inhibiting ACh release in human detrusor is an M4 receptor, while the receptor involved in muscular contraction belongs to the M3 subtype.
Cellular and Molecular Life Sciences | 2009
Cristina Lanni; Stefano Govoni; Adele Lucchelli; Cinzia Boselli
Clinical depression is viewed as a physical and psychic disease process having a neuropathological basis, although a clear understanding of its ethiopathology is still missing. The observation that depressive symptoms are influenced by pharmacological manipulation of monoamines led to the hypothesis that depression results from reduced availability or functional deficiency of monoaminergic transmitters in some cerebral regions. However, there are limitations to current monoamine theories related to mood disorders. Recently, a growing body of experimental data has showed that other classes of endogenous compounds, such as neuropeptides and amino acids, may play a significant role in the pathophysiology of affective disorders. With the development of neuroscience, neuronal networks and intracellular pathways have been identified and characterized, describing the existence of the interaction between monoamines and receptors in turn able to modulate the expression of intracellular proteins and neurotrophic factors, suggesting that depression/antidepressants may be intermingled with neurogenesis/neurodegenerative processes.
British Journal of Pharmacology | 1995
Adele Lucchelli; Maria Grazia Santagostino-Barbone; Annalisa Barbieri; Stefano M. Candura; M. Tonini
1 A combined study of receptor binding in central neuronal cell membranes and functional responses in isolated segments of guinea‐pig small intestine allowed characterization of the interaction of four antidepressant drugs with central and peripheral 5‐HT3 and 5‐HT4 receptors. 2 Clomipramine, paroxetine and fluoxetine inhibited [3H]‐DAU 6215 binding to 5‐HT3 recognition sites in NG 108‐15 cells with IC50 values in the range 1.3–4 μm. Litoxetine had an IC50 of 0.3 μm. The specific binding of [3H]‐GR 113808 to 5‐HT4 recognition sites in pig striatal membranes was inhibited by all four antidepressants with negligible potency (IC50 values ≥ 20 μm). 3 In whole ileal segments, concentration‐response curves to 5‐HT were biphasic, with the high‐ and low‐potency phases involving 5‐HT4 and 5‐HT3 receptors, respectively. Curves to 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT: a 5‐HT3 receptor agonist) and 5‐methoxytryptamine (5‐MeOT: a 5‐HT4 receptor agonist) were monophasic. All antidepressants were used at concentrations lacking anticholinoceptor properties, as demonstrated in both electrically stimulated longitudinal muscle‐myenteric plexus preparations (LMMPs) and in unstimulated LMMPs following addition of acetylcholine (100 nm). 4 Fluoxetine (0.1–1 μm) and litoxetine (0.3–3 μm) antagonized both the high‐ and low‐potency phases of the 5‐HT curve. Schild analysis for the low‐potency phase yielded pA2 estimates of 6.6 ± 0.3 (Schild slope of 1.1) and of 6.6 ± 0.1 (Schild slope of 1.1), respectively. At higher concentrations (3 μm), fluoxetine markedly inhibited the 5‐HT response maximum. Clomipramine (10–300 nm) inhibited, by a mechanism independent of concentration, both phases of the 5‐HT curve with a reduction of the maximum response. Paroxetine (1 μm) was ineffective on the high‐potency phase, but caused a rightward shift of the low‐potency phase (pKB: 6.1 ± 0.01). 5 Responses to 2‐methyl‐5‐HT were inhibited by 1 μm fluoxetine (pKB: 5.4 ± 0.02). Like clomipramine (30 and 100 nm), litoxetine (1 and 3 μm) produced rightward displacements of 2‐methyl‐5‐HT‐induced contractions, which were virtually independent of antidepressant concentration (pKB values: 6.0 ± 0.02 and 5.5 ± 0.01, respectively). At higher concentrations, fluoxetine (3 μm) and clomipramine (300 nm) markedly reduced the 2‐methyl‐5‐HT response maximum. Paroxetine (1 μm) was ineffective. 6 Responses to 5‐MeOT were shifted to the right by fluoxetine (0.1–1 μm) and litoxetine (1 and 3 μm) in a concentration‐dependent manner. At higher concentrations, fluoxetine (3 μm) markedly reduced the 5‐MeOT response maximum, an effect also observed with 100 and 300 nm clomipramine. Paroxetine (1 μm) was ineffective. 7 In unstimulated LMMPs, the excitatory effects evoked by 5‐HT, 2‐methyl‐5‐HT and 5‐MeOT and the antagonism produced by 300 nm clomipramine were comparable to those obtained in whole ileal segments. This suggests that 5‐HT contained in the mucosa of whole preparations does not interfere with agonist‐induced contractile responses and with the inhibitory effect of antidepressant drugs. 8 In conclusion, our results show that clomipramine, fluoxetine, paroxetine and litoxetine possess low to moderate potency/affinity at both central and peripheral (enteric) 5‐HT3 receptors. In contrast, all four antidepressants are virtually ineffective at central 5‐HT4 receptors. Inhibition of 5‐HT4 receptor‐mediated ileal contractions by fluoxetine, litoxetine and clomipramine may result from allosteric antagonism or, more likely, from post‐receptor blockade of second messenger generation. The interaction of antidepressants with central and peripheral 5‐HT3 and 5‐HT4 receptors may be relevant for both potential therapeutic action and adverse effects at gastrointestinal level.
British Journal of Pharmacology | 1995
Eliana Messori; C.A. Rizzi; Stefano M. Candura; Adele Lucchelli; B. Balestra; M. Tonini
1 In isolated detrusor strips from the guinea‐pig urinary bladder, contractile responses to electrical field stimulation were mostly mediated by neurally released acetylcholine (ACh) and adenosine 5′‐triphosphate (ATP). 2 5‐Hydroxytryptamine (5‐HT) produced a concentration‐dependent increase in the amplitude of stimulated detrusor strip contractions. The 5‐HT concentration‐response curve showed a biphasic profile: the high potency phase was obtained at sub‐micromolar concentrations (10–300 nM), while the low potency phase in the range 1–30 μm. The maximum response of the first phase was 30% of the total 5‐HT response. 3 Like 5‐HT, the 5‐HT3 receptor agonist, 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT: 0.3–100 μm), the 5‐HT2 receptor agonist, (±)‐l‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI: 30 nM‐3 μm) and the 5‐HT4 receptor agonist, 5‐methoxytryptamine (5‐MeOT: 0.1–30 μm) potentiated, though with lower potency, detrusor contractions. The resulting concentration‐response curves were monophasic in nature. 2‐Methyl‐5‐HT had a maximum effect comparable to that of 5‐HT. By contrast, the maximal effects of DOI and 5‐MeOT were only 20% and 30% of that elicited by 30 μm 5‐HT, respectively. 4 The 5‐HT3 receptor antagonist, granisetron (0.3 μm) had no effect on the high potency phase, but caused a rightward parallel shift of the low potency phase of the 5‐HT curve (pKB = 7.3). Granisetron (0.3 μm) antagonized with comparable affinity (pKB= 7.1) 5‐HT‐induced responses after pharmacological isolation of 5‐HT3 receptors with the 5‐HT1/5‐HT2 receptor antagonist, methiothepin (0.3 μm) and the 5‐HT4 receptor antagonist, GR 125487 (30 nM). Granisetron (0.1, 0.3 and 1 μm) competitively antagonized the potentiating effect of 2‐methyl‐5‐HT with an estimated pA2 of 7.3. 5 Methiothepin (0.3 μm) and the 5‐HT2A receptor antagonist, ketanserin (0.3 μm) produced a slight inhibition of the first phase of the 5‐HT curve. In the presence of ketanserin, an equimolar concentration of methiothepin was ineffective in further reducing the effect of 5‐HT. Similarly, the 5‐HT4 receptor antagonist, GR 125487 (30 nM) slightly inhibited the first phase of the 5‐HT curve. Conversely, this phase was suppressed when detrusor strips were coincubated with ketanserin (or methiothepin) and GR 125487. 6 In a separate set of experiments, the interactions of 5‐HT with either the purinergic or cholinergic components of excitatory neuromuscular transmission were investigated. In the presence of hyoscine (1 μm), 5‐HT was mostly effective at sub‐micromolar concentrations, while in the presence of the P2‐purinoceptor antagonist, suramin (300 μm), 5‐HT‐induced potentiation was mainly obtained with micromolar concentrations. 7 Thus, in electrically stimulated detrusor strips from guinea‐pig, 5‐HT potentiated excitatory neuromuscular transmission by activating at least three separate neural 5‐HT receptors. These include the 5‐HT2A and 5‐HT4 receptors, which mediate the 5‐HT high potency phase mainly by activation of purinergic transmission. On the other hand, the potentiating effect caused by micromolar concentrations of 5‐HT mostly involves cholinergic transmission and is mediated by the 5‐HT3 receptors.
Naunyn-schmiedebergs Archives of Pharmacology | 1986
Grana E; Adele Lucchelli; Franco Zonta; Maria Grazia Santagostino-Barbone; Gianluigi D'Agostino
SummaryThis study was undertaken to determine the potenties of seven muscarinic agonists (methylfurtrethonium, dioxolane, oxathiolane, carbachol, muscarine, muscarone and oxotremorine) on the postjunctional muscarinic receptors of seven isolated preparations (guinea pig taenia-coli, ileum, jejunum, trachea and atria and rat jejunum and urinary bladder).The results indicate that the rank order of sensitivity of the preparations varies independently of the potency of the agonist used and it is almost the same for all the compounds with the exception of oxotremorine.Muscarone was the most potent compound in all the tissues. Intergroup comparisons in each preparation and the evaluation of the equieffective molar ratios relative to muscarone revealed that carbachol possesses a certain degree of cardioselectivity and oxathiolane, on the other hand, is much less active on the cardiac tissue than on the others.Oxotremorine is a peculiar compound endowed with cardioselectivity.
Naunyn-schmiedebergs Archives of Pharmacology | 1998
Annalisa Barbieri; Maria Grazia Santagostino-Barbone; Franco Zonta; Adele Lucchelli
The α-adrenoceptors that mediate contractions in strips of splenic artery from the pig were characterized by the use of selective agonists and subtype-selective antagonists. Noradrenaline, the α1-selective agonist phenylephrine and the α1-/α2-agonist oxymetazoline caused the preparations to contract with potency (pD2) values of 6.94, 6.14 and 7.27, respectively. Compared to noradrenaline, phenylephrine and oxymetazoline induced 93% and 78% of noradrenaline maximum effect. Conversely, the two α2-selective agonists clonidine and B-HT 920 induced only 31% and 13% of noradrenaline maximum effect. B-HT 920 only marginally contracted the tissue even when it was precontracted with phenylephrine. The α2-selective antagonist yohimbine antagonized oxymetazoline- and phenyleprine-induced contractions with affinity (pA2) values (6.80 and 6.74, respectively) consistent with α1-adrenoceptor interaction. This suggests that the pig splenic artery possesses only functional α1-adrenoceptors. The α1-adrenoceptor antagonists of varying subtype selectivities like WB-4101, 5-methylurapidil, benoxathian and BMY 7378 competitively antagonized phenylephrine-induced contractions with affinity values of 9.46, 8.26, 9.06 and 6.91, respectively. These values correlated highly with published affinity values for functional α1A-adrenoceptors (r=0.92) and α1a-clones (r=0.94) and less well with affinity values for functional α1B-adrenoceptors (r=0.84) and α1b-clones (r=0.87). Conversely, correlation with functional α1D-adrenoceptors (r=0.26) and α1d-clones (r=0.33) was poor. In addition the α1D-selective antagonist BMY 7378 had a low affinity value compared to that reported for α1D-adrenoceptors. Therefore, based on correlation studies, the plot that resembled the line of equal values most closely was that for the α1A-subtype. The α1A-selective antagonist RS-17053 antagonized phenylephrine-induced contractions in an apparently non-competitive manner and gave an apparent pA2 value of 7.06 which is similar to the “low” affinity values reported in other α1A-containing tissues. Exposure to the irreversible α1B/D-antagonist chloroethylclonidine slightly decreased maximum response to phenylephrine without significantly affecting its potency value, indicating that the phenylephrine response is substantially chloroethylclonidine-insensitive.It is concluded that splenic artery strips from the pig contract in response to phenylephrine through activation of α1-adrenoceptors which display the pharmacological profile of the α1A-subtype for which the recently reported α1A-selective antagonist RS-17053 shows low affinity. Evidence for contribution of the α1B-subtype in the overall contractile response is elusive while no evidence was obtained for the involvement of the α1D-subtype. The contribution of functional α2-adrenoceptors to the contractile response was ruled out.
British Journal of Pharmacology | 1994
Adele Lucchelli; Maria Grazia Santagostino-Barbone; Annalisa Barbieri; M. Tonini
1 Experiments were carried out to characterize the receptors mediating the indirect excitatory response to 5‐hydroxytryptamine (5‐HT) in the guinea‐pig isolated trachea. 2 5‐HT caused concentration‐dependent contractions of tracheal strips, and the resulting concentration‐response curve was biphasic in nature. The first phase was obtained with agonist concentrations in the range of 0.01–3 nm and achieved a maximum which was 30% of the total 5‐HT response, while the second phase was in the range 10 nm–1 μm. 3 Atropine (0.1 μm) and tetrodotoxin (TTX: 0.3 μm) significantly reduced both phases of the 5‐HT curve. Morphine (10 μm), which can act to inhibit neuronal acetylcholine release, abolished the first phase and reduced the second phase. This suggests that the first phase is mainly neurogenic (cholinergic) in nature, while the second phase is in part neurogenic and in part due to direct activation of the effector cells. 4 The 5‐HT2A receptor antagonist, ketanserin (0.01, 0.1 μm) markedly depressed the first phase and shifted the second phase to the right in a parallel manner, with some depression of the 5‐HT response maximum. The less selective (5‐HT1/5‐HT2A) antagonist, methiothepin (0.1 μm) mimicked the action of ketanserin, albeit with less potency. Concomitant administration of ketanserin and methiothepin (each at 0.1 μm) produced an antagonism similar to that caused by ketanserin (0.1 μm) alone. 5 The 5‐HT3 receptor antagonists, ondansetron (0.1 μm) and granisetron (0.01 μm) slightly but significantly inhibited the first phase of the 5‐HT curve without altering the second phase. SDZ 205,557 (0.3 μm), a 5‐HT4 receptor antagonist, was ineffective. 6 Our results suggest that neural 5‐HT2A and, to a lesser extent, 5‐HT3 receptor subtypes mediate the first phase of the 5‐HT curve in the guinea‐pig trachea. The second phase is mediated by 5‐HT2A receptors, which are probably located at both the neural and muscular level. No evidence for the participation of 5‐HT1 receptors in the 5‐HT response has been obtained.
Naunyn-schmiedebergs Archives of Pharmacology | 1987
Grana E; Adele Lucchelli; Franco Zonta; Cinzia Boselli
SummaryThis study was undertaken to determine dissociation constants (KA) and relative efficacies (er) of seven muscarinic agonists (methylfurtrethonium; dioxolane, oxathiolane, carbachol, muscarine, muscarone and oxotremorine) in three isolated tissues (guinea-pig ileum and atria and rat urinary bladder).The rank order of affinities (-log KA) of the various compounds varied depending on the tissue used. er values for the different agonists did not differ significantly from each other in any of the three tissues, except that the er of muscarine in the guinea-pig ileum was higher than those of the other compounds and that of oxotremorine in the rat urinary bladder was lower than those of the other agonists.Comparisons among tissues show that KA and er values were the same in different tissues for some compounds (muscarone, muscarine and methylfurtrethonium), while significant differences were found for the other compounds. This suggests the existence of a discrete receptor population recognized by some but not all agonists.For oxotremorine er as well as -log KA, is greater in atria than in smooth muscle: these factors combine to determine the cardioselectivity of this compound which can now ascribed to receptor selectivity.
Canadian Journal of Physiology and Pharmacology | 2007
Cinzia Boselli; M. Santagostino Barbone; Adele Lucchelli
Substance P (SP) is possibly involved in the pathophysiology of depression and anxiety. We investigated interactions between antidepressants on SP-induced effects and their potential calcium-blocking activity in the isolated guinea pig ileum. All the antidepressants tested, except pargyline, moclobemide, mianserin, and reboxetine, were able to inhibit in a concentration-dependent manner the contraction induced by 100 nmol/L SP. Clomipramine, fluoxetine, maprotiline, and amitriptyline (all at 3 mumol/L) flattened the concentration-response curves to SP, resulting in a reduction of up to 59%, 63%, 32%, and 23%, respectively, of the maximum contractile effect. All the antidepressants tested (3 mumol/L), except pargyline, moclobemide, and mianserin, produced a rightward parallel shift of the concentration-response curve to CaCl2. The L-type selective calcium blocker nifedipine and the T-type selective mibefradil showed similar behaviour against both agonists used, SP and CaCl2. The relative order of potency was nifedipine (pA2, 7.6 +/- 0.1) > clomipramine (pA2, 7.0 +/- 0.1) > fluoxetine (pKB, 6.5 +/- 0.1) = mibefradil (pKB, 6.6 +/- 0.1) > amitriptyline (pKB, 6.3 +/- 0.1) = maprotiline (pKB, 6.2 +/- 0.1) > fluvoxamine (pKB, 5.9 +/- 0.1). The data reported in the present study suggest that the antidepressants tested did not behave as competitive antagonists versus NK1-receptor subtypes, but their inhibitory action seems to be related to their calcium-blocking properties.
Pharmacological Research | 1990
Adele Lucchelli; Cinzia Boselli; Grana E
The possible involvement of specific dopamine receptors in the relaxing effect of dopamine in the guinea-pig isolated jejunum has been investigated. The relaxing effect of dopamine does not show the tachyphylaxis phenomenon and it is present in preparations from guinea-pigs pretreated with reserpine. These results indicate that dopamine has a direct action. Comparison of the effect of dopamine with those of other dopamine receptor agonists, i.e. apomorphine, bromocriptine and the DA1 selective fenoldopam, were made to calculate potency ratios. Since apomorphine, bromocriptine and fenoldopam were shown to relax the guinea-pig jejunum, partly behaving as indirectly acting agents, comparisons were made on reserpine-pretreated guinea-pigs. It has been found that apomorphine is 2.5 times, fenoldopam 3 times and bromocriptine 20 times more active than dopamine in relaxing the guinea-pig jejunum. The order of potency is different from that found in other dopamine receptors containing tissues. The effects of the dopamine receptor blockers, haloperidol and cis-alpha-flupenthixol and the DA1 selective blocker SCH 23390 on the relaxing effect of dopamine were also studied. The relaxing effect of dopamine was not reduced by haloperidol, cis-alpha-flupenthixol and SCH 23390. It is concluded that specific postjunctional dopamine receptors are not involved in the relaxing action of dopamine. Since dopamine is known to interact with alpha- and beta-adrenoceptors in a variety of tissues, the effects of the alpha-adrenoceptor blocker phentolamine and the beta-adrenoceptor blocker propranolol on the relaxing effect of dopamine were also studied. Noradrenaline has been used to check the responsiveness of the tissue. Phentolamine did not block the responses to dopamine and propranolol was able only to partially reduce responses to dopamine, at concentrations higher than those at which it antagonized noradrenaline. Mechanisms other than dopamine, alpha- or beta-receptor activation should be involved in the relaxing effect of dopamine in the guinea-pig jejunum.