Biomedical subjects

O Gandolfi

Publications and source records attributed to O Gandolfi.

At least 19 recordsLinked to original sources

PubMed1992

Spontaneous recovery of MPTP-damaged catecholamine systems in goldfish brain areas.

In goldfish, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administered for 3 consecutive days (10 mg/kg), produced a marked decrease in dopamine (DA) and noradrenaline (NA) levels in telencephalon, diencephalon and medulla oblongata, without affecting the serotonin (5-HT) content. Furthermore the neurotoxin decreased either [3H]DA high affinity uptake or K(+)-stimulated DA release from synaptosomal (P2) preparations, with concomitant up-regulation of D2 postsynaptic receptors as well. No significant changes of choline acetyltransferase and glutamic acid decarboxylase activity or [3H]glutamate uptake were observed. Moreover the pretreatment with deprenyl (1 mg/kg) or mazindol (10 mg/kg) but not with clorgyline (5 mg/kg) prevented catecholamine depletion. Added in vitro to synaptosomal preparations both MPTP and more potently MPP+, in a concentration-dependent manner, inhibited [3H]DA uptake. Time course study revealed that MPTP-induced alteration of neurochemical parameters in goldfish brain areas were almost completely reversed within 6 weeks, suggesting that catecholamine systems in goldfish brain show a remarkable power of recovery after MPTP lesion.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1992

Effect of chronic treatment with dizocilpine (MK-801) on the behavioral response to dopamine receptor agonists in the rat.

The D2 or D1 dopamine receptor blockers (-)-sulpiride or SCH 23390 antagonized, in a dose dependent manner, the hypermotility induced by the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (0.25 mg/kg IP). MK-801 induced hyperactivity was not detected when rats were observed on days 7, 14 or 21 of 21 daily injections of MK-801. This lack of hyperactivity was also noted 5 days after the last administration of the repeated treatment with MK-801. The hypermotility induced by the D2 dopamine receptor agonist LY 171555 (0.3 mg/kg IP) was reduced 5 days following repeated treatment (21 days) with MK-801, while no change in the behavioral responses to the selective D1 agonist, SKF 38393, or the mixed D1/D2 agent apomorphine was detected. The results, although suggesting the involvement of dopaminergic pathways in the behavioral effect of MK-801, are conflicting with regard to the underlying mechanisms and to the adaptive changes of dopaminergic system following repeated NMDA receptor blockade.

Animals↗

PubMed1992

The modulation of dopaminergic transmission in the striatum by MK-801 is independent of presynaptic mechanisms.

This paper reports biochemical and behavioural experiments, planned to obtain a deeper knowledge on the mechanisms of the facilitating action of dopaminergic transmission, induced by the NMDA-sensitive glutamate receptor antagonist, dizocilpine (MK-801). Single or repeated administrations of MK-801 (0.25 mg/kg, i.p., daily for 21 consecutive days) failed to change levels of either dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) in the striatum of the rat or the haloperidol-induced (0.125 mg/kg, i.p.) accumulation of DOPAC. Consistently, the NMDA antagonist, given at a dose which did not affect the spontaneous motility of the animal (0.125 mg/kg, i.p.), failed to potentiate the behavioural stimulatory effect, induced by the dopaminomimetic agents, methamphetamine or nomifensine. All these results, taken together, exclude a facilitating action of MK-801 on dopaminergic neurotransmission. The possibility that the stimulatory effect of MK-801 on dopaminergic neurones is indirect and independent of presynaptic mechanisms is discussed.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

NMDA antagonists interact with 5-HT-stimulated phosphatidylinositol metabolism and impair passive avoidance retention in the rat.

The NMDA receptor antagonists APV (5 micrograms/10 microliters/rat i.c.v.) or ketamine (12.5 mg/kg i.p.), administered 5 min before training, decreased the retention of a passive avoidance conditioning. In hippocampal or cortical slices of APV- and ketamine-treated rats, 5-HT-stimulated phosphoinositide metabolism was potentiated. It is suggested that excitatory amino acids could modulate the mechanism operative in signal transduction of serotonin; this interaction could play a role in memory retention.

2-Amino-5-phosphonovalerate↗

PubMed1990

Repeated treatment with (-)-sulpiride plus a low dose of SCH 23390 displays wider neuroleptic activity without inducing dopaminergic supersensitivity.

Combined treatment with (-)-sulpiride plus a low dose of the D1 receptor antagonist SCH 23390, unlike (-)-sulpiride given alone, blocked rat striatal dopaminergic transmission. Five days after the withdrawal of 21-day repeated administration of the combined treatment, no increase in apomorphine-induced stereotyped behaviour was observed. The results suggest that the combination of a D2 blocker and a low dose of a D1 blocker produces a wider spectrum of neuroleptic activity without an overt risk of inducing dopaminergic behavioural supersensitivity.

Animals↗

PubMed1989

Synergistic blockade of some dopamine-mediated behaviours by (-)-sulpiride and SCH 23390 in the rat.

Several studies have indicated that the D2 dopamine receptors mediate the antidopaminergic activity of the neuroleptics; nevertheless, the selective blocker (-)-sulpiride weakly inhibits dopamine-mediated behaviour. The present study investigated whether the concomitant injection of doses of the D1 antagonist SCH 23390, which by themselves are without effect, would enable (-)-sulpiride to express fully neuroleptic activity in the rat. The benzamide YM 09151-2 that strongly inhibits dopamine-mediated behaviour was also studied. Rats receiving different doses of (-)-sulpiride, YM 09151-2 and SCH 23390 given alone or in combination were tested for exploratory activity, apomorphine-induced stereotyped behaviour and hyperactivity elicited by the D2 agonist LY 171555. When given alone, (-)-sulpiride (10, 20 and 40 mg/kg IP) had no effect on exploratory activity and stereotypy. When (-)-sulpiride was administered in combination with an ineffective dose of SCH 23390 (5 micrograms/kg) both responses were significantly inhibited. The combined administration of subthreshold doses of (-)-sulpiride (2.5 mg/kg) and SCH 23390 (2.5 micrograms/kg) significantly inhibited hypermotility induced by LY 171555. Moreover, the combined administration of ineffective doses of YM 09151-2 with subthreshold doses of SCH 23390 strongly inhibited all the behavioural responses. The results indicate that SCH 23390 allowed (-)-sulpiride to exhibit a wider spectrum of neuroleptic activity and potentiated the antidopaminergic activity of YM 09151-2.

Animals↗

PubMed1989

Effects of repeated trazodone administrations on serotonergic neurotransmission: biochemical studies.

1. Repeated administrations of trazodone as well as imipramine or mianserin (10 mg/kg i.p. twice daily for 3 weeks) attenuated the norepinephrine (NE) stimulation of adenylate cyclase studied in brain minces. Therefore trazodone shares with "tricyclic" (imipramine) and "atypic" (mianserin) antidepressants the capability to modulate the beta-adrenergic function. 2. Daily treatments with imipramine or trazodone enhanced the Vmax of neural uptake of serotonin (5HT) in minces prepared from rat frontal cortex; in contrast mianserin failed to modify the [3H]-5HT uptake. 3. Repeated administrations of imipramine but not of trazodone or mianserin reduced the maximum number of [3H]-imipramine recognition sites which are located on serotonergic axon terminals. 4. Differently, only repeated administration of trazodone decreased Bmax values of [3H]-mianserin binding sites which are located on membranes innervated by serotonergic neurons. Moreover trazodone did not change the number or affinity of 5HT2 receptors either after single or repeated administrations; in contrast even a single administration with mianserin or repeated administrations with imipramine down-regulated [3H]-ketanserin specific binding in membranes prepared from the frontal cortex. 5. Our observations therefore suggest that trazodone, imipramine or mianserin exerts similar effects on the adenylate cyclase system, by acting on a interneuronal loop which links serotonergic and noradrenergic transmission function. However, its exact mechanism of action, in part resembling both tricyclic and atypic depressants, requires further examination.

Animals↗

PubMed1988

Lead neurotoxicity: a role for dopamine receptors.

Chronic lead exposure differentially affects dopamine receptor subtypes (D1 and D2). In particular dopamine D2 recognition sites in striatum are up-regulated while in nucleus accumbens they are down-regulated. These changes may be correlated to the observed alterations of dopamine terminal activity. Consistent with these biochemical changes behavioral studies indicate that lead-treated rats show more pronounced basal activity, attenuation of apomorphine (63 micrograms/kg s.c.) induced hypomotility and tendency to increased stereotyped response to apomorphine (300 micrograms/kg s.c.). On the contrary, both behavioral and biochemical markers of D1 receptors are unmodified by lead treatment. In fact, SKF 38393-induced grooming behavior, [3H]SCH 23390 binding and the dopamine stimulated adenylate cyclase activity are comparable in controls and lead-exposed rats.

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

PubMed1988

Single or repeated administrations of SCH 23390 fail to affect serotonergic neurotransmission.

In synaptic membrane preparations from the frontal cortex of rats treated with single or repeated administration of mianserin or methysergide (10 mg/kg i.p.) the number of 5-HT2 receptors was reduced. In contrast, single (0.1 mg/kg or 5 mg/kg i.p.) or repeated administration of SCH 23390 (0.05 mg/kg i.p. twice daily for 3 weeks) failed to change the kinetic characteristics of 5-HT2 receptors. Moreover, in several cerebral areas, 5-HT levels and turnover were not modified by any treatment. Although SCH 23390 has a high affinity for cerebral 5-HT2 receptors, and there are conflicting data on the antagonistic activity in the periphery, our data show that doses which selectively affect dopaminergic transmission are devoid of serotonergic effects.

Animals↗

PubMed1988

Behavioral and biochemical expression of D1-receptor supersensitivity following SCH 23390 repeated administrations.

In this study concomitant changes of behavioral and biochemical responses in rats repeatedly treated with SCH 23390 were evaluated. Apomorphine-induced stereotyped behavior was increased in D1-supersensitive rats, in contrast no change in the behavioral response to the pure D1-agonist SKF 38393 was detected. Parallel biochemical studies indicated that the enhancement in striatal dopamine (DA) metabolite concentration due to the administration of spiroperidol plus SKF 38393 was not potentiated in SCH 23390 repeatedly treated rats. The results show that the expression of D1-supersensitivity could depend on the stimulation of D2-receptors.

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

PubMed1988

Changes in behavioural responses to the combined administration of D1 and D2 dopamine agonists in normosensitive and D1 supersensitive rats.

The selective D1 receptor stimulant SKF 38393 dose-dependently increased grooming time in rats without affecting locomotor activity or eliciting stereotyped behaviour. The selective D2 receptor agonist LY 171555 induced a dose-dependent increase in rat motility, a marked decrease in grooming time and a low occurrence of stereotyped behaviour. Concurrent administration of the two selective agonists induced high-degree stereotyped responses and reductions in locomotor and grooming behaviours. Rats withdrawn from repeated treatment with the selective D1 receptor blocker SCH 23390 (0.05 mg/kg twice daily for 21 days; 7 days of washout) did not exhibit any change of locomotor and grooming responses to threshold doses of LY 171555 and SKF 38393 given alone or in combination. On the contrary, a significantly greater occurrence of high-degree stereotyped responses to the combination of the two selective agonists was observed. The data support the view that D1 and D2 receptors have a cooperative role in the generation of stereotypies and suggest that D1 receptor supersensitivity needs D2 stimulation to be revealed.

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

PubMed1988

Neuroleptic-induced reduction of quipazine-elicited head-twitches in rats: possible involvement of striatal dopaminergic supersensitivity.

Rats were treated with a single large dose of various neuroleptic compounds and, 5-7 days after, they were assayed for either behavioral sensitivity to apomorphine (hypermotility and stereotyped behavior) or head-twitch response to the mixed serotonin-dopamine agonist quipazine. The animals withdrawn from chlorpromazine, fluphenazine, haloperidol, metoclopramide and the D1 selective blocker SCH 23390, showed enhanced hypermotility and/or stereotyped responses to apomorphine and reduced head-twitch response to quipazine. The rats withdrawn from thioridazine, (-)-sulpiride and sultopride responded to apomorphine only with enhanced hypermotility while their response to quipazine was either unchanged or even increased. The results are discussed in terms of dopaminergic brain areas and/or receptor subtypes involved in the modulation of the head-twitch response to quipazine. We concluded that an enhancement of dopaminergic tone at the striatal level could be related to the reduced head-twitch response to quipazine.

Animals↗

PubMed1988

Molecular mechanisms in the action of minaprine.

1. Minaprine is a pyridazine derivative endowed with antidepressant activity, however biochemical studies following repeated administrations are still lacking. 2. Rats were administered with minaprine (10 mg/kg i.p.) twice daily for 3 weeks. 3. In minces from the frontal cortex of rats receiving minaprine the NE-induced cAMP accumulation is reduced suggesting that, similarly to other antidepressant treatments, minaprine attenuates the beta-adrenergic receptor function. 4. The selective lesion of the serotonergic axons abolished such attenuation. 5. In synaptic plasma membranes prepared from rats repeatedly treated with pargyline (at doses which block MAO tipo A and B) but not with minaprine, the number of 5HT1C and 5HT2 receptors was reduced. 6. Repeated administrations of minaprine but not of pargyline increased the Bmax values of [3H]-imipramine binding. In 5, 7-DHT lesioned rats minaprine failed to increase the number of the residual [3H]-imipramine recognition sites. 7. The authors conclude that the increase in the number of [3H]-imipramine recognition sites is unrelated to the IMAO activity of minaprine. 8. The presence of 5HT axons on which [3H]-imipramine recognition sites are located is an absolute requirement for the clinical efficacy of minaprine. 9. The action of minaprine in the regulation of the synthesis and/or of the release of an endogenous substance that is important in mediating brain beta-adrenergic function is discussed.

Adenylyl Cyclases↗

PubMed1987

Lesioning and recovery of the serotoninergic projections to the hippocampus.

The time course of the changes of the hippocampal 5-hydroxytryptamine (5-HT) system after a lesion of the dorsal afferents to this brain area was studied by measuring the content of 5-HT and of 5-hydroxyindoleacetic acid (5-HIAA) in the dorsal, medial and ventral hippocampus. Furthermore, the binding sites for [3H]5-HT, [3H]ketanserin, [3H]imipramine and [3H]mianserin and a 5-HT-mediated behavior (head-twitch responses) were studied in controls and in animals bearing such a lesion. The contents of 5-HT and of 5-HIAA are higher in the ventral than in the dorsal hippocampus. Seven days after the lesion the 5-HT content decreases by 78% in the dorsal and by 50% in the ventral hippocampus. However, 60 days later, a partial recovery, possibly due to a collateral sprouting, does occur. The ratios between 5-HIAA and 5-HT are also increased 10, 14 and 21 days after the lesion, suggesting an increased utilization of the amine by the remaining neuronal terminals. The Bmax of the recognition sites for [3H]5-HT and [3H]mianserin, but not those for [3H]ketanserin are increased 10 days after the lesion and this increase lasts at least 30 days. Finally, starting 10 days after surgery and lasting for 40 days, a 5-HT-mediated behavior (head-twitch responses) shows supersensitivity. These results suggest that important changes occur in the 5-HT innervation of the hippocampus after a mechanical lesion: among these we showed a slow collateral sprouting, an increased utilization of the amine and a supersensitivity of 5-HT receptors.

Animals↗

PubMed1987

Enhanced stereotyped response to apomorphine after chronic D-1 blockade with SCH 23390.

Rats were treated for 21 days with the selective D-1 blocker SCH 23390 (0.1 mg/kg SC). Threshold doses of apomorphine for hypermotility (0.15 mg/kg SC) and for stereotyped response (0.25 mg/kg SC) were given 7, 21, 35, and 77 days after discontinuation of the chronic treatment. The rats always showed enhanced stereotyped response to the higher dose of apomorphine but never any change in their motility response to the lower dose of dopamine agonist. This finding may represent a behavioral correlate of the reported supersensitivity of D-1 receptors induced by SCH 23390.

Animals↗

PubMed1986

Behavioral differentiation between pharmacokinetic and pharmacodynamic components of the interaction of antidepressants or neuroleptics with methamphetamine.

This study proposes a method capable of separating the pharmacodynamic from the pharmacokinetic component in the methamphetamine (MA) hyperactivity potentiation induced by antidepressants. Several antidepressants and neuroleptics, other centrally-acting drugs and the inhibitor of hepatic drug metabolism SKF 525-A were studied. The motility counts taken between 10 and 20 min after MA injection were considered as an index of pharmacodynamic interaction and the whole duration of the hyperactivity syndrome as an index of pharmacokinetic interaction. The duration of MA effect was prolonged by some of the drugs studied and left unchanged by the others regardless of their clinical classification. On the contrary, our evaluation of the intensity of MA effect produced a sharp differentiation between classical neuroleptics and typical antidepressants: the former antagonized and the latter potentiated MA peak intensity. Only the D-2 blocking neuroleptics sulpiride and tiapride potentiated MA intensity. Regarding the specificity of our model, none of the compounds known to be devoid of clinical antidepressant or antipsychotic activity interacted with MA in such a way as to be included in either category. As to the sensitivity of the test, two "false negatives" were obtained: the neuroleptic clozapine and the antidepressant mianserin. Such exceptions were discussed taking into account their peculiar mechanisms of action.

Animals↗

PubMed1986

Involvement of different dopamine receptors in rat diphasic motility response to apomorphine.

A critical dose of apomorphine (300 micrograms/kg SC) given immediately before placing rats into a novel environment produced a diphasic motility response (initial sedation followed by enhanced locomotion). Various neuroleptics having different clinical and/or pharmacological profiles were studied by using such a model. (-)-Sulpiride and sultopride preferentially antagonized apomorphine inhibition; haloperidol and tiapride antagonized both phases of apomorphine response at similar doses; chlorpromazine, fluphenazine, thioridazine, metoclopramide and SCH 23390 preferentially antagonized apomorphine stimulation. The results are discussed in terms of the dopamine receptor subtypes involved in the two phases of apomorphine effect. Apomorphine stimulation can be antagonized by D-1 as well as D-2 receptor blockade. A higher affinity for D-2 receptors seems a necessary requisite for the antagonism of apomorphine inhibition; moreover, the ability of neuroleptics to antagonize apomorphine inhibition seems to depend on the ratio of their presynaptic versus postsynaptic D-2 activity.

Animals↗

PubMed1985

Different effects of serotonin antagonists on 3H-mianserin and 3H-ketanserin recognition sites.

In minces prepared from the frontal cortex of rats treated with ketanserin (10 mg/kg i.p.) or mianserin (5 mg/kg i.p.) twice daily for 21 days, the Vmax of the adenylate cyclase stimulated by NE (100 microM) is attenuated, suggesting that ketanserin and mianserin share with a number of antidepressants the ability to attenuate the adenylate cyclase stimulation by NE. Ketanserin, given with the above mentioned dose schedule for 7 consecutive days, reduced the Bmax of 5HT2 recognition sites but failed to change either the Bmax or the apparent Kd of H-mianserin binding. A significant decrease in the Bmax of 5HT2 binding sites is elicited also by a single injection of mianserin (1). This drug also down-regulates its own binding when given twice daily for 3 weeks. From this and other information (2,3), it is concluded that ketanserin and mianserin bind to distinct recognition sites. The possibility that 5HT2 and mianserin recognition sites are functionally related and that serotonergic synapses are modulated by multiple chemical signals might be considered.

Animals↗