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Biomedical subjects

F Borsini

Publications and source records attributed to F Borsini.

At least 37 records · Page 2Linked to original sources
PubMed1997

BIMG 80, a novel potential antipsychotic drug: evidence for multireceptor actions and preferential release of dopamine in prefrontal cortex.

In radioligand binding studies, BIMG 80, a new putative antipsychotic, displayed good affinity at certain serotonin (5-HT1A, 5-HT2A, 5-HT6), dopamine (D1, D2L, D4), and noradrenergic (alpha1) receptors. The effect of acute subcutaneous BIMG 80, clozapine, haloperidol, risperidone, amperozide, olanzapine, and Seroquel was then investigated on dopamine release in medial prefrontal cortex, nucleus accumbens, and striatum in freely moving rats using the microdialysis technique. Four different neurochemical profiles resulted from the studies: (a) Systemic administration of BIMG 80, clozapine, and amperozide produced greater percent increases in dopamine efflux in medial prefrontal cortex than in the striatum or the nucleus accumbens. (b) Haloperidol induced a similar increase in dopamine concentrations in the striatum and nucleus accumbens with no effect in the medial prefrontal cortex. (c) Risperidone and olanzapine stimulated dopamine release to a similar extent in all brain regions investigated. (d) Seroquel failed to change significantly dopamine output both in the medial prefrontal cortex and in the striatum. Because an increase in dopamine release in the medial prefrontal cortex may be predictive of effectiveness in treating negative symptoms and in the striatum may be predictive of induction of extrapyramidal side effects, BIMG 80 appears to be a potential antipsychotic compound active on negative symptoms of schizophrenia with a low incidence of extrapyramidal side effects.

Animals↗
PubMed1996

Effects of desipramine and maprotiline on the coeruleus-cortical noradrenergic system in anaesthetized rats.

Desipramine (1-3000 micrograms/kg i.v.) and maprotiline (1-10,000 micrograms/kg i.v.), two selective noradrenaline uptake blockers, inhibited the firing rate of noradrenergic locus coeruleus neurons and induced excitation of the prefronto-cortical neurons. The selective destruction of ascending noradrenergic pathways by intracerebroventricular injection of 6-hydroxydopamine antagonized the excitatory effect of desipramine and maprotiline on the prefronto-cortical neurons. These results suggest that desipramine and maprotiline dose dependently stimulate the electrical activity of prefronto-cortical neurons, probably by acting on noradrenergic cells of the locus coeruleus.

Animals↗
PubMed1996

Itasetron (DAU 6215) prevents age-related memory deficits in the rat in a multiple choice avoidance task.

The effects of itasetron (endo-N-8-methyl-8-azabicyclo-[3.2.1.]-octo-3-yl) -2,3-dihydro-2-oxo-1 H-benzimidazole-1-carboxamide hydrochloride), a 5-HT3 receptor antagonist, on discrete memory abilities of the aged rat were assessed by using the multiple choice avoidance behavioral task. Chronic treatment with itasetron (i.p., 10 micrograms/kg, b.i.d., for three consecutive weeks), but not with vehicle, significantly improved retention abilities of the aged rats in this memory test. These results further support the important role of this 5-HT3 receptor antagonist in counteracting age-related memory degeneration in rodents.

Age Factors↗
PubMed1996

Pharmacological characterization of AMPA-induced biting behaviour in mice.

The spinal cord dorsal horn contains neural mechanisms which can greatly facilitate pain. It is well established that excitatory amino acids, aspartate and glutamate, are involved in the spinal transmission of nociceptive information and in the development of hyperalgesia. In the present study, intrathecal (i.t.) administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), a structural analog of L-glutamate, produced a dose-dependent behavioural syndrome characterized by caudally directed biting in mice. We demonstrated that peripheral pre-administration of the AMPA receptor antagonists 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX, 10-100 mg/kg s.c.) and 1-(4-aminophenyl)-3-methylcarbamoyl-4-methyl-3,4-dihydro-7, 8-methylene-dioxy-5H-2,3-benzo-diazepine-HCl (GYKI 53655, 3-10 mg/kg s.c.), and also of the NMDA receptor antagonist 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine maleate (MK 801, 0.3-1 mg/kg s.c.) reversed this effect. These findings suggest that the hyperalgesia induced by the i.t. injection of AMPA in mice involves the activation of both NMDA and non-NMDA excitatory amino acid receptor sites.

Animals↗
PubMed1995

BIMT 17, a 5-HT2A receptor antagonist and 5-HT1A receptor full agonist in rat cerebral cortex.

In the search for antidepressant agents with a rapid onset of action, we have found that compound BIMT 17 (1-[2-[4-(3-trifluoromethylphenyl)piperazin-1- yl]ethyl]benzimidazol-[1H]-2-one) shows a good affinity for cerebral cortical 5-HT1A (pKi = 7.72) and 5-HT2A (pKi = 6.90) receptors, with no appreciable affinity for the other 5-HT receptor subtypes, including 5-HT2C. BIMT 17 reduced forskolin-stimulated cAMP accumulation in the cerebral cortex (pEC50 = 6.09) and in the hippocampus (pEC50 = 6.50), and antagonized 5-HT-induced phosphatidylinositol turnover (pKi = 6.96) in the cerebral cortex. The effect on cAMP accumulation was blocked by the 5-HT1A receptor antagonist tertatolol. Buspirone, 8-OH-DPAT and S 14671 (1-[2-(2-thenoylamino)ethyl]- 4[1-(7-methoxynaphtyl)]-piperazine), claimed to be 5-HT1A receptor agonists, did not reduce forskolin-stimulated cAMP formation in the cerebral cortex. On the basis of these data, it was concluded that BIMT 17 was the only compound that behaved as a full agonist with respect to the cAMP response in the cortex, while exerting concurrent agonism at 5-HT1A receptors and antagonism at 5-HT2A receptors. These characteristics might explain the peculiar behavior of BIMT 17 in mimicking the inhibitory action of 5-HT on the basal firing rate of the cortical neurons (see accompanying paper).

Animals↗
PubMed1995

BIMT 17, a 5-HT1A receptor agonist/5-HT2A receptor antagonist, directly activates postsynaptic 5-HT inhibitory responses in the rat cerebral cortex.

BIMT 17 (1-[2-[4-(3-trifluoromethyl phenyl) piperazin-1-yl] ethyl] benzimidazol- [1H]-2-one), a 5-HT1A receptor agonist/5-HT2A receptor antagonist (see Borsini et al., accompanying paper), in a dose range of 1-10 mg/kg i.v., dose-dependently inhibited the electrical activity of rat medial prefronto-cortical neurons, whereas buspirone, in a dose range of 0.1-1000 micrograms/kg, increased it. 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and 1-[2-(2-thenoylamino)ethyl]-4-[1-(7-methoxynaphthyl)] piperazine (S 14671) presented biphasic patterns of response; they increased electrical activity at doses in the range of 0.1-10 micrograms/kg and 0.1-3 micrograms/kg i.v. respectively, and reduced it at high doses, 30-300 micrograms/kg and 10-30 micrograms/kg i.v., respectively. The inhibitory effect of BIMT 17 on the firing rate of neurons in the frontal cortex was antagonized by the 5-HT1A antagonists tertatolol and WAY 100135, and was still present after destruction of serotonin (5-HT) containing neuronal endings by the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 150 micrograms/rat, given intraventricularly), which reduced the cortical 5-HT content by 85%. This destruction of 5-HT neurons, while suppressing the ability of 8-OH-DPAT to inhibit the firing rate at high doses, did not change the excitatory action of this compound at low doses. The addition of ritanserin, a 5-HT2A receptor antagonist, potentiated both the excitatory and inhibitory effects of 8-OH-DPAT on neuronal electrical activity. Direct microiontophoretic application (100 nA/20 s) of 5-HT and BIMT 17, but not that of 8-OH-DPAT, onto medial prefronto-cortical neurons, decreased the firing rate of these neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Role of the serotonergic system in the forced swimming test.

The effect of manipulations aimed at modifying the function of the 5-HT system has been reviewed. 5-HT uptake inhibitors are devoid of any activity in rats and induce an anti-immobility effect in mice. The so-called 5-HT1A agonists reduce the immobility time with some differences in mice and rats, mice being less sensitive. None of the procedure aimed at reducing 5-HT function reduced immobility time. Therefore, the 5-HT system does not play a tonic role in animals performing the forced swimming test. The involvement of possible brain regions mediating the anti-immobility effects of 5-HT mimetic drugs has been discussed.

Animals↗
PubMed1995

Effect of the 5-hydroxytryptamine3 receptor antagonist itasetron (DAU 6215) on (+)-N-allylnormetazocine-induced dopamine release in the nucleus accumbens and in the corpus striatum of the rat: an in vivo microdialysis study.

The in vivo brain microdialysis technique has been used to study the ability of itasetron, [DAU 6215, (3-alpha-tropanyl)1H-benzimidazolone-3-carboxamide hydrochloride], a novel 5-hydroxytryptamine3 (5-HT3)-receptor antagonist, to antagonize the effect of the sigma-agonist (+)-N-Allylnormetazocine (SKF 10,047) in inducing the release of dopamine from mesolimbic and nigrostriatal dopaminergic neurons, in comparison with haloperidol and clozapine. SKF 10,047 caused a dose-dependent increase in the release of endogenous dopamine preferentially from the nucleus accumbens septi with respect to the corpus striatum of the rat, the time to peak being 60 min from its administration. Itasetron (1-30 micrograms/kg s.c. given 45 min before SKF 10,047 5 mg/kg s.c.) dose dependently antagonized the SKF 10,047 response in the nucleus accumbens septi and not in the corpus striatum, without inducing by itself changes of basal DA output in either area at these doses. Another selective 5-HT3 receptor antagonist, ondansetron, at the dose of 10 micrograms/kg s.c., like itasetron, blocked the SKF 10,047-induced release of dopamine. At the dose of 100 micrograms/kg s.c., both itasetron and ondansetron failed to modify the effect of SKF 10,047 and increased DA release per se in the nucleus accumbens septi.

Animals↗
PubMed1994

Repeated treatment with fluoxetine decreases the number of spontaneously active cells per track in frontal cortex.

Repeated (10 mg/kg i.p. x 14 days, once daily), but not acute (10 and 40 mg/kg i.p., 30 min), treatment with fluoxetine decreased the number of active neurons in the frontal cortex 30 min (-55%) or 24 h (-62%) after the last drug injection. This result supports the view that repeated, but not acute, treatment with fluoxetine decreases the function of the frontal cortex.

Action Potentials↗
PubMed1994

Localization and gene expression of serotonin 1A (5HT1A) receptors in human brain postmortem.

We investigated the binding parameters, i.e. the maximum binding capacity (Bmax) and the dissociation constant (Kd), of [3H]8-hydroxy-2-(di-N-propylamino)tetralin ([3H]8-OH-DPAT) labeling the serotonin receptor of the 1A type (5HT1A), and the distribution of the mRNA encoding it in some human brain areas obtained from autoptic samples. The results showed that the Bmax was significantly higher in the hippocampus than in the prefrontal cortex and the striatum, while the Kd had the inverse, although not significant, pattern. The expression study revealed that 5HT1A mRNA distribution in the hippocampus and prefrontal cortex was consistent with the data of the [3H]8-OH-DPAT binding. A different result was obtained in the striatum where no 5HT1A mRNA expression was detected, despite the measurement of specific [3H]8-OH-DPAT binding. These findings underline the different nature of [3H]8-OH-DPAT binding sites in different brain areas and the need for further studies on 5HT receptor gene expression in human brain.

Aged↗
PubMed1994

The inhibitory effect of 8-OH-DPAT on the firing activity of dorsal raphe serotoninergic neurons in rats is attenuated by lesion of the frontal cortex.

The dose-response inhibitory effect of 8-OH-DPAT on the firing rate of dorsal raphe serotoninergic neurons was shifted 10-fold to the right after acute fronto-cortical deafferentation. This finding suggests that the inhibitory effect of 8-OH-DPAT on the dorsal raphe firing rate might be mediated indirectly by the frontal cortex.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Effect of DAU 6215, a novel 5-HT3 receptor antagonist, on scopolamine-induced amnesia in the rat in a spatial learning task.

The effects of different doses (1, 10, 30, and 100 micrograms/kg, IP) of a new 5-hydroxytryptamine3 (5-HT3) receptor antagonist, 3-alpha-tropanyl)1H-benzimidazolone-3-carboxamide chloride (DAU 6215), on memory and performance deficits induced by SC 0.2 mg/kg scopolamine were assessed in the Morris water maze task. No effect was observed on the performance of rats treated with DAU 6215 alone. The doses of 10 and 30 micrograms/kg DAU 6215 attenuated these scopolamine-induced behavioral deficits.

Amnesia↗
PubMed1993

Effect of fluoxetine on the spontaneous electrical activity of fronto-cortical neurons.

The effect of fluoxetine on spontaneous extracellular activity of fronto-cortical neurons of chloral hydrate-anesthetized rats was investigated. Fluoxetine significantly increased the basal firing rate of cortical neurons in a dose-dependent manner (0.1-1000 micrograms kg-1 i.v.), with a maximum excitatory effect of 53% at 1000 micrograms kg-1. Selective destruction of ascending serotoninergic pathways induced by intracerebroventricular injections of 150 micrograms 5,7-dihydroxytryptamine, in desipramine-pretreated rats, antagonized the excitatory effect of fluoxetine. The present results suggest that fluoxetine significantly increases the electrical activity of the fronto-cortical neurons acting on serotoninergic uptake mechanisms localized at the level of raphe nuclei.

5,7-Dihydroxytryptamine↗
PubMed1993

Mesulergine antagonism towards the fluoxetine anti-immobility effect in the forced swimming test in mice.

The anti-immobility effect of fluoxetine (40 mg kg-1) in the forced swimming test in mice was antagonized by the 5-HT1c/2 antagonist mesulergine (7.5 mg kg-1) and the dopamine D2 antagonist (+/-)-sulpiride (12.5 mg kg-1) but not by the 5-HT2/1C antagonist ritanserine (2 mg kg-1), the 5-HT1A/1B antagonist (-)-propranolol (20 mg kg-1) or the 5-HT3 antagonist DAU 6215 (0.1 mg kg-1). All compounds were administered intraperitoneally (i.p.) 6 min before fluoxetine, given i.p. 30 min before testing. The anti-immobility effect of fluoxetine was also prevented by pretreatment with p-chlorophenylalanine (300 mg kg-1 twice daily for 3 days) which produced an 80% reduction of 5-HT in brain. The results suggest that fluoxetine reduces immobility time in mice forced to swim, by acting indirectly through a mesulergine-sensitive site, probably the 5-HT1C receptor.

Animals↗
PubMed1993

DAU 6215, a novel 5-HT3-receptor antagonist, selectively antagonizes scopolamine-induced deficit in a passive-avoidance task, but not scopolamine-induced hypermotility in rats.

This study examined the effects of DAU 6215, a selective 5-HT3-receptor antagonist, on either impairment of a passive-avoidance task or hypermotility, both caused by scopolamine in rats. In the first experiment, scopolamine (0.75 mg kg-1, i.p.) disrupted acquisition of a one-trial 'step through' passive-avoidance response. Pretreatment with DAU 6215 (1, 10, 30 and 100 micrograms kg-1, i.p.) antagonized this deficit induced by scopolamine, with a bell-shaped dose-response curve. Scopolamine (0.75 mg kg-1, i.p.) produced a significant increase in locomotor activity which was unaffected by pretreatment with DAU 6215 (10 and 30 micrograms kg-1, i.p.). The present results further support the suggestion that 5-HT3-receptor antagonists may prevent the memory disturbance caused by a reduction in central cholinergic function in the rat. The inefficacy shown by DAU 6215 on hyperactivity induced by scopolamine appears to rule out the possibility of a pharmacokinetic interference between DAU 6215 and scopolamine.

Animals↗
PubMed1992

Chronic treatment with DAU 6215, a new 5-HT3 receptor antagonist, causes a selective decrease in the number of spontaneously active dopaminergic neurons in the rat ventral tegmental area.

Electrophysiological techniques were used to study the effects of the new compound, DAU 6215 ((3-alpha-tropanyl) 1H-benzimidazolone-3-carboxamide chloride), a selective 5-HT3 receptor antagonist, on the activity of dopamine (DA)-containing neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Acute i.v. injections of DAU 6215 did not cause any change in the basal firing rate of DA neurons in the SNc or in the VTA. Pretreatment with DAU 6215 did not modify the inhibitory effect of apomorphine on the firing rate of midbrain DA neurons. Acute s.c. administration of DAU 6215 caused a significant increase in the number of spontaneously active DA neurons in the VTA but not in the SNc. This effect was similar to that of acute clozapine, whereas acute haloperidol caused a significant increase of spontaneously active DA neurons in both the SNc and the VTA. Repeated consecutive s.c. administration of DAU 6215 and clozapine for 21 days produced a significant decrease in the number of spontaneously active DA neurons in the VTA but not in the SNc. Chronic haloperidol (21 days) decreased the number of DA cells both in the SNc and VTA. The effect of chronic DAU 6215 on the activity of VTA DA neurons was reversed by apomorphine, suggesting that these neurons were probably under a state of depolarization block. These findings indicate that DAU 6215 may have potential antipsychotic activity, probably associated with a low incidence of extrapyramidal side-effects.

Animals↗
PubMed1992

Effect of haloperidol and clozapine on (+)SKF 10,047-induced dopamine release: role of 5-HT3 receptors.

(+)SKF 10,047 preferentially increased dopamine release in the nucleus accumbens compared to the striatum. Dopamine output was evaluated in the same freely moving rats by trans-cerebral dialysis. Clozapine and DAU 6215, a 5HT3 antagonist, which itself did not modify dopamine release in both areas, selectively antagonized (+)SKF 10,047-induced dopamine release in the nucleus accumbens. Haloperidol by itself increased dopamine release in both areas and these effects were additive with those induced by (+)SKF 10,047.

Animals↗