Biomedical subjects

A Bartolini

Publications and source records attributed to A Bartolini.

At least 37 records · Page 2Linked to original sources

PubMed2000

Pro-cognitive activity induced in the rat by low doses of R-(+)-hyoscyamine.

In the passive-avoidance test R-(+)-hyoscyamine (10-100 microg kg(-1) i.p.) prevented amnesia induced by antimuscarinic treatment with AF-64A and benzhexol. The antiamnesic effect of R-(+)-hyoscyamine was comparable to that exerted by the cholinesterase inhibitor physostigmine (0.2 mg kg(-1) i.p) and the M(1) selective agonist AF-102B (10 mg kg(-1) i.p.). In the social learning test, R-(+)-hyoscyamine (10-100 microg kg(-1) i.p.) in adults rats, reduced the duration of active exploration of the familiar partner in the second session of the test similar to the nootropic drug piracetam (30 mg kg(-1) i.p.). These results demonstrated the ability of R-(+)-hyoscyamine to modulate memory functions and suggest that R-(+)-hyoscyamine could be useful in the treatment of cognitive deficits.

Amnesia↗

PubMed2000

Loss of muscarinic antinociception by antisense inhibition of M(1) receptors.

The effect on cholinergic analgesia of inactivation of the M(1) gene by an antisense oligodeoxyribonucleotide (aODN) was investigated in the mouse hot plate test. Mice received a single intracerebroventricular (i.c.v.) injection of anti-M(1) aODN (0.3, 1. 0 or 2.0 nmol per injection), degenerate ODN (dODN) or vehicle on days 1, 4 and 7. A dose-dependent inhibition of the antinociception induced by the muscarinic agonists oxotremorine (0.1 mg kg(-1) s.c.) and McN-A-343 (30 microg per mouse i.c.v.) and the cholinesterase inhibitor physostigmine (0.2 mg kg(-1) s.c.) was observed 24 h after the last i.c.v. injection of aODN. Time-course experiments revealed that, after the end of the aODN treatment, sensitivity to analgesic drugs progressively appeared reaching the normal range at 96 h. The anti-M(1) aODN was selective against muscarinic antinociception since the enhancement of pain threshold produced by morphine and baclofen were not affected by the above-mentioned treatment. dODN, used as control, did not affect muscarinic antinociception. Binding studies evidenced a selective reduction of M(1) receptor levels in the hippocampus of aODN-treated mice. Neither aODN, dODN nor vehicle produced any behavioural impairment of mice as revealed by the rota-rod and Animex experiments. These results indicate that activation of M(1) muscarinic receptor subtype is fundamental to induce central cholinergic analgesia in mice.

Animals↗

PubMed2000

Antinociception induced by amitriptyline and imipramine is mediated by alpha2A-adrenoceptors.

The involvement of alpha2-adrenoceptors in the antinociception induced by the tricyclic antidepressants amitriptyline and imipramine was investigated in mice by using the hot-plate and abdominal constriction tests. The antinociception produced by amitriptyline (15 mg/kg, i.p.) and imipramine (15 mg/kg, i.p.) was prevented by reserpine (2 mg/kg, i.p.) and yohimbine (3-10 mg/kg, i.p.) but not by naloxone (1 mg/kg, i.p.), atropine (5 mg/kg, i.p.), CGP 35348 (100 mg/kg, i.p.) and prazosin (1 mg/kg, i.p.). On the basis of the above data, it can be postulated that amitriptyline and imipramine exerted their antinociceptive effect by activation of alpha2-adrenoceptors. Administration of the alpha2A-adrenoceptor antagonist BRL 44408 (1 mg/kg, i.p.) prevented amitriptyline and imipramine antinociception, whereas the alpha2B/C-adrenoceptor antagonist ARC 239 (10 mg/kg, i.p.) was ineffective. These data indicate that the enhancement of the pain threshold produced by amitriptyline and imipramine is mediated by activation of alpha2A-adrenoceptors. Neither tricyclic antidepressants nor the antagonists used impaired mouse performance evaluated by the rota-rod and hole-board tests.

Amitriptyline↗

PubMed2000

Role of 5-HT1A receptors in a mouse passive avoidance paradigm.

The effect on memory processes of modulation of 5-HT1A receptor subtype was investigated in the mouse passive avoidance test. The administration of 5-HT1A-receptor antagonists NAN-190 (1-(2-methoxyphenyl)-4-[4-2-phthalimmido)butyl]piperazine) and WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide) produced a dose-dependent amnesic effect comparable to that obtained with the well-known amnesic agents scopolamine and dicyclomine. Pretreatment with the 5-HT1A-receptor agonists 8-OH-DPAT ((+/-)-8-hydroxy-dipropylaminotetralin) and 5-CT (5-carboxamidotryptamine) dose-dependently prevented the amnesia induced by 5-HT1A antagonists, scopolamine, dicyclomine and exposure to an hypoxic environment. The antiamnesic effect exerted by 5-HT1A-receptor agonists was comparable to that produced by the nootropic drug piracetam and cholinesterase inhibitor physostigmine. At effective doses, neither 5-HT1A-receptor agonists nor 5-HT1A-receptor antagonists produced any impairment of mouse motor coordination (rota-rod test), spontaneous motility (Animex apparatus) and inspection activity (hole board). These results indicate that modulation of 5-HT1A-receptors appears to play an important role in the regulation of cognitive processes.

Amnesia↗

PubMed1999

Tiagabine antinociception in rodents depends on GABA(B) receptor activation: parallel antinociception testing and medial thalamus GABA microdialysis.

The effects of a new antiepileptic drug, tiagabine, (R)-N-[4,4-di-(3-methylthien-2-yl)but-3-enyl] nipecotic acid hydrochloride, were studied in mice and rats in antinociceptive tests, using three kinds of noxious stimuli: mechanical (paw pressure), chemical (abdominal constriction) and thermal (hot plate). In vivo microdialysis was performed in parallel in awake, freely moving rats in order to evaluate possible alterations in extracellular gamma-aminobutyric acid (GABA) levels in a pain-modulating region, the medial thalamus. Systemic administration of tiagabine, 30 mg kg(-1) i.p., increased nearly twofold the extracellular GABA levels in rats and increased significantly the rat paw pressure nociceptive threshold in a time-correlated manner. Dose-related significant tiagabine-induced antinociception was also observed at the doses of 1 and 3 mg kg(-1) i.p. in the mouse hot plate and abdominal constriction tests. The tiagabine antinociception was completely antagonised by pretreatment with the selective GABA(B) receptor antagonist, CGP 35348, (3-aminopropyl-diethoxy-methyl-phosphinic acid) (2.5 microg/mouse or 25 microg/rat i.c.v.), but not by naloxone (1 mg kg(-1) s.c.), both administered 15 min before tiagabine. Thus, it is suggested that tiagabine causes antinociception due to raised endogenous GABA levels which in turn activate GABA(B) receptors.

Abdomen↗

PubMed1999

Antisense 'knockdowns' of M1 receptors induces transient anterograde amnesia in mice.

The effect on memory processes of inactivation of the M1 gene by an antisense oligodeoxyribonucleotide (aODN) was investigated in the mouse passive avoidance test. Mice received a single intracerebroventricular (i.c.v.) injection of M1 aODN (0.3, 1.0 or 2.0 nmol per injection), degenerated ODN (dODN) or vehicle on days 1, 4 and 7. An amnesic effect, comparable to that produced by antimuscarinic drugs, was observed 12, 24, 48 and 72 h after the last i.c.v. aODN injection, whereas dODN and vehicle, used as controls, did not produce any effect. Reduction in the entrance latency to the dark compartment induced by aODN disappeared 7 days after the end of aODN treatment, which indicates the absence of any irreversible damage or toxicity caused by aODN. Quantitative reverse transcription-polymerase chain reaction analysis demonstrated that a decrease in M1 mRNA levels occurred only in the aODN-treated group, being absent in all control groups. Furthermore, a reduction in M1 receptors was observed in the hippocampus of aODN-treated mice. Neither aODN, dODN nor vehicle produced any behavioral impairment of mice. These results indicate that the integrity and functionality of M1 receptors are fundamental in the modulation of memory processes.

Amnesia↗

PubMed1999

The role of potassium channels in antihistamine analgesia.

The effect of the administration of pertussis toxin as well as modulators of different subtypes of K+ channels on the antinociception induced by the H1-antihistamines pyrilamine, diphenhydramine and promethazine was evaluated in the mouse hot plate test. Pretreatment with pertussis toxin (0.25 microg/mouse i.c.v.) prevented pyrilamine, diphenhydramine and promethazine antinociception. The K(ATP) channel openers minoxidil and pinacidil potentiated the antinociception produced by the H1-antihistamines whereas the K(ATP) channel blocker gliquidone prevented the anti H1-induced analgesia. The Ca2+-gated K+ channel blocker apamin antagonized pyrilamine, diphenhydramine and promethazine analgesia. Pretreatment with an antisense oligonucleotide (aODN) to mKv1.1, a voltage-gated K+ channel, at the dose of 3.0 nmol/single i.c.v. injection, never modified the antinociception induced by the H1-antihistamines in comparison with degenerate oligonucleotide (dODN)-treated mice. At the highest effective doses, none of the drugs used modified animals' gross behaviour nor impaired motor coordination, as revealed by the rota rod test. The present data demonstrate that both K(ATP) and Ca2+-gated K+ channels, contrary to voltage-gated K+ channel Kv1.1, represent an important step in the transduction mechanism underlying central antinociception induced by H1-antihistamines.

Animals↗

PubMed1999

Hybridized and isosteric analogues of N1-acetyl-N4-dimethyl-piperazinium iodide (ADMP) and N1-phenyl-N4-dimethyl-piperazinium iodide (DMPP) with central nicotinic action.

A series of piperazine derivatives, obtained by hybridization of N1-acetyl-N4-dimethyl-piperazinium iodide (1, ADMP) and N1-phenyl-N4-dimethyl-piperazinium iodide (3, DMPP) or of the corresponding tertiary bases (2, 4) with arecoline (5) and arecolone (6) or by isosteric substitution of the phenyl ring of DMPP, has been synthesized. Hybridization afforded compounds that, both as tertiary bases and as iodomethylates, have no affinity for the nicotinic receptor. On the contrary, isosteric substitution gave compounds that maintain affinity for the receptor; among them, two tertiary bases (37, 38), show affinity in the nanomolar range for the nicotinic receptor. The pharmacological profile of these isomeric compounds is quite interesting as they present differences in their peripheral and central effects, suggesting that they interact with different subtypes of the nicotinic receptor.

Analgesics↗

PubMed1999

Role of potassium channels in the antinociception induced by agonists of alpha2-adrenoceptors.

1. The effect of the administration of pertussis toxin (PTX) as well as modulators of different subtypes of K+ channels on the antinociception induced by clonidine and guanabenz was evaluated in the mouse hot plate test. 2. Pretreatment with pertussis toxin (0.25 microg per mouse i.c.v.) 7 days before the hot-plate test, prevented the antinociception induced by both clonidine (0.08-0.2 mg kg(-1), s.c.) and guanabenz (0.1-0.5 mg kg(-1), s.c.). 3. The administration of the K(ATP) channel openers minoxidil (10 microg per mouse, i.c.v.), pinacidil (25 microg per mouse, i.c.v.) and diazoxide (100 mg kg(-1), p.o.) potentiated the antinociception produced by clonidine and guanabenz whereas the K(ATP) channel blocker gliquidone (6 microg per mouse, i.c.v.) prevented the alpha2 adrenoceptor agonist-induced analgesia. 4. Pretreatment with an antisense oligonucleotide (aODN) to mKv1.1, a voltage-gated K+ channel, at the dose of 2.0 nmol per single i.c.v. injection, prevented the antinociception induced by both clonidine and guanabenz in comparison with degenerate oligonucleotide (dODN)-treated mice. 5. The administration of the Ca2+-gated K+ channel blocker apamin (0.5-2.0 ng per mouse, i.c.v.) never modified clonidine and guanabenz analgesia. 6. At the highest effective doses, none of the drugs used modified animals' gross behaviour nor impaired motor coordination, as revealed by the rota-rod test. 7. The present data demonstrate that both K(ATP) and mKv1.1 K+ channels represent an important step in the transduction mechanism underlying central antinociception induced by activation of alpha2 adrenoceptors.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1999

Effect of potassium channel modulators in mouse forced swimming test.

1. The effect of intracerebroventricular (i.c.v.) administration of different potassium channel blockers (tetraethylammonium, apamin, charybdotoxin, gliquidone), potassium channel openers (pinacidil, minoxidil, cromakalim) and aODN to mKv1.1 on immobility time was evaluated in the mouse forced swimming test, an animal model of depression. 2. Tetraethylammonium (TEA; 5 microg per mouse i.c.v.), apamin (3 ng per mouse i.c.v.), charybdotoxin (1 microg per mouse i.c.v.) and gliquidone (6 microg per mouse i.c.v.) administered 20 min before the test produced anti-immobility comparable to that induced by the tricyclic antidepressants amitriptyline (15 mg kg(-1) s.c.) and imipramine (30 mg kg(-1) s.c.). 3. By contrast pinacidil (10-20 microg per mouse i.c.v.), minoxidil (10-20 microg per mouse i.c.v.) and cromakalim (20-30 microg per mouse i.c.v.) increased immobility time when administered in the same experimental conditions. 4. Repeated administration of an antisense oligonucleotide (aODN) to the mKv1.1 gene (1 and 3 nmol per single i.c.v. injection) produced a dose-dependent increase in immobility time of mice 72 h after the last injection. At day 7, the increasing effect produced by aODN disappeared. A degenerate mKv1.1 oligonucleotide (dODN), used as control, did not produce any effect in comparison with saline- and vector-treated mice. 5. At the highest effective dose, potassium channels modulators and the mKv1.1 aODN did not impair motor coordination, as revealed by the rota rod test, nor did they modify spontaneous motility as revealed by the Animex apparatus. 6. These results suggest that modulation of potassium channels plays an important role in the regulation of immobility time in the mouse forced swimming test.

Animals↗

PubMed1999

Binding profiles of a series of 2-arylpropionic acid esters on cloned human muscarinic receptor subtypes (m1-m5) and their relationship to nootropic activity.

The muscarinic binding profile of a series of 2-arylpropionic acid esters on cloned human muscarinic receptor subtypes (m1-m5) was determined to investigate whether there is a correlation between pharmacological activity and muscarinic receptor subtype selectivity. Among the tested compounds, 1, 7 and 9 showed the highest affinity for the m2 and m4 receptors. Compounds 1, 7 and 9 show good affinity for m4 receptors (pKi = 7.87; 7.73 and 7.10, respectively) and are able to discriminate 10-60 fold between m4/m1, m4/m3, and m4/m5 subtypes. Conversely, these compounds are able only to weakly discriminate between m4/m2. Compounds 1 (50-300 micrograms kg-1 i.p.) and 7 (1-10 micrograms kg-1 i.p.), injected 20 min before the training session, are able to prevent the amnesia induced by dicyclomine (2 mg kg-1 i.p.) in the mouse passive-avoidance test. Compounds 1 and 7, at the highest antiamnesic doses, do not modify motor coordination and spontaneous motility as evaluated by the rota-rod test and Animex apparatus experiments.

Animals↗

PubMed1999

Antinociceptive effect of R-(+)-hyoscyamine on the conjunctival reflex test in rabbits.

R-(+)-Hyoscyamine (1-10 microg/kg, s.c.) dose-dependently increased the local anesthetic effect of procaine (50 microg/ml) and lidocaine (50 microg/ml) in the conjunctival reflex test in the rabbit. This potentiating effect is completely prevented by the M1 antagonist dicyclomine (10 mg/kg, s.c.). The intensity of R-(+)-hyoscyamine antinociception was comparable to that induced by morphine (2 mg/kg, s.c.) and minaprine (15 mg/kg, s.c.), used as analgesic reference drugs. In the same experimental conditions, the S-(-)-enantiomer of atropine (0.1-10 microg/kg, s.c.), was completely ineffective. The present results confirm the ability of R-(+)-hyoscyamine to produce a paradoxical antinociceptive effect mediated by a cholinergic mechanism not only in rodents but also in the rabbit.

Adjuvants, Anesthesia↗

PubMed1998

Kv1.1 channel antisense attenuates learning and modulation of dentate polysialylated NCAM.

The distribution and modulation of neural cell adhesion molecule polysialylation state (NCAM PSA) and the consequence of antisense inactivation of the Kv1.1 potassium channel was investigated following avoidance learning in mice. PSA immunoreactivity was most notable on cells at the inner denate border and in cortical layer II. Task acquisition resulted in a significant 30% transient increase in the frequency of dentate polysialylated neurons at the 12 h post-training time. In contrast, animals pretreated with the Kv1.1 antisense oligonucleotide exhibited both attenuated recall avoidance latencies and polysialylated cell frequency. As Kv1.1 is enriched on the dendrites of these granule-like cells, the attenuated polysialylation response is considered secondary to NCAM-mediated events during their transient synapse production in the 6-8 h post-training period.

Animals↗

PubMed1998

Mono- and disubstituted-3,8-diazabicyclo[3.2.1]octane derivatives as analgesics structurally related to epibatidine: synthesis, activity, and modeling.

A series of 3,8-diazabicyclo[3.2.1]octanes substituted either at the 3 position (compounds 1) or at the 8 position (compounds 2) by a chlorinated heteroaryl ring were synthesized, as potential analogues of the potent natural analgesic epibatidine. When tested in the hot plate assay, the majority of the compounds showed significant effects, the most interesting being the 3-(6-chloro-3-pyridazinyl)-3,8-diazabicyclo[3.2.1]octane (1a). At a subcutaneous dose of 1 mg/kg, 1a induced a significant increase in the pain threshold, its action lasting for about 45 min. 1a also demonstrated good protection at a dose of 5 mg/kg in the mouse abdominal constriction test, while at 20 mg/kg it completely prevented the constrictions in the animals. Administration of naloxone (1 mg/kg i.p.) did not antagonize its antinociception while mecamylamine (2 mg/kg i.p.) did, thus suggesting the involvement of the nicotinic system in its action. Binding studies confirmed high affinity for the alpha 4 beta 2 nAChR subtype (Ki = 4.1 +/- 0.21 nM). nAChR functional activity studies on three different cell lines showed that 1a was devoid of any activity at the neuromuscular junction. Finally, due to the analogy in their pharmacological profile with that of epibatidine, compounds were compared from a structural and conformational point of view through theoretical calculations and high-field 1H NMR spectroscopy. Results indicate that all of them present one conformation similar to that of epibatidine.

Abdominal Muscles↗

PubMed1998

Effect of pertussis toxin on baclofen- and diphenhydramine-induced amnesia.

The effect of pretreatment with pertussis toxin at the doses of 0.25 and 0.50 microg per mouse ICV on the amnesic effect produced by baclofen (0.1 4 mg kg(-1) i.p.), diphenhydramine (15-30 mg kg(-1) i.p.) and scopolamine (0.5-5 mg kg(-1) i.p.) was investigated in the mouse passive avoidance test. Ten days after a single injection of pertussis toxin, baclofen (2 4 mg kg(-1) i.p.) amnesia was prevented. By contrast, pertussis toxin had no effect on diphenhydramine- and scopolamine-induced amnesia. Pretreatment with pertussis toxin at both doses used did not impair motor coordination of the mice, as revealed by the rota-rod test. The present results indicate that the activation of pertussis toxin-sensitive G-proteins represents an important transduction step in memory impairment induced by GABA(B) (gamma-aminobutyric acid B) agonists, but not by antihistaminic and antimuscarinic drugs.

Amnesia↗

PubMed1998

Evidence for hypernociception induction following histamine H1 receptor activation in rodents.

To characterize the mechanism of the analgesic action of H1 antihistaminics the effects of a new, highly selective agonist, 2-(3-trifluoromethylphenyl)histamine dihydrogenmaleate (FMPH), and of the better known H1 agonist, 2-thiazolylethylamine (2-TEA), were studied on pain threshold by means of three different kinds of tests for nociception (mouse hot plate and abdominal constriction, and rat paw pressure tests). Low doses of both substances (2.65 and 6.5 microg/animal i.c.v. for FMPH in the hot plate and paw pressure tests, and 0.3 microg/rat i.c.v. for 2-TEA in the paw pressure test) were slightly but significantly hypernociceptive. The selective H1 receptor antagonist, pyrilamine maleate (10-30 mg/kg s.c.), induced a dose-dependent antinociception in all three tests, and both FMPH and 2-TEA prevented its effect, but not that of morphine, thus indicating action on H1 receptors. The same low doses of FMPH were also able to enhance animals' spontaneous motility and curiosity. High doses of FMPH (13.23-132.3 microg/mouse i.c.v.) raised the pain threshold, but due to the severe motor impairment evidenced by the rota rod test, this cannot be considered as real antinociception. An increase in the pain threshold lacking any motor impairment was observed for tenfold higher doses of 2-TEA (3 and 10 microg/mouse i.c.v.). This may be due to action on H2 receptors, with the reported relative potency of 2-TEA for H1 and H2 receptors being about 12:1. It is therefore suggested that H1 receptor activation increases sensitivity to noxious stimuli.

Animals↗

PubMed1998

No development of tolerance to analgesia by repeated administration of H1 antagonists.

The effect produced by repeated administration of the H1-antihistaminics diphenhydramine, promethazine and pyrilamine on their ability to induce antinociception was evaluated in the mouse hot-plate and abdominal constriction tests. Contrary to morphine, baclofen and oxotremorine, the three H1 antagonists investigated did not promote the development of tolerance to the analgesic effect after 14 days of repeated treatment. H1 antagonists could, therefore, represent a promising pharmacological approach to the management of chronic pain.

Analgesia↗

PubMed1998

Influence of potassium channel modulators on cognitive processes in mice.

1. The effect of i.c.v. administration of different potassium channel openers (minoxidil, pinacidil, cromakalim) and potassium channel blockers (tetraethylammonium, apamin, charybdotoxin, gliquidone, glibenclamide) on memory processes was evaluated in the mouse passive avoidance test. 2. The administration of minoxidil (10 microg per mouse i.c.v.), pinacidil (5-25 microg per mouse i.c.v.) and cromakalim (10-25 microg per mouse i.c.v.) immediately after the training session produced an amnesic effect. 3. Tetraethylammonium (TEA; 1-5 microg per mouse i.c.v.), apamin (10 ng per mouse i.c.v.), charybdotoxin (1 microg per mouse i.c.v.), gliquidone (3 microg per mouse i.c.v.) and glibenclamide (1 microg per mouse i.c.v.), administered 20 min before the training session, prevented the potassium channel opener-induced amnesia. 4. At the highest effective doses, none of the drugs impaired motor coordination, as revealed by the rota rod test, or modified spontaneous motility and inspection activity, as revealed by the hole board test. 5. These results suggest that the modulation of potassium channels plays an important role in the regulation of memory processes. On this basis, the potassium channel blockers could be useful in the treatment of cognitive deficits.

Amnesia↗