Monosialoganglioside increased the in vivo affinity of D2 receptors for apomorphine in supersensitive rats.
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Animals↗
Biomedical subjects
R Frussa-Filho
Publications and source records attributed to R Frussa-Filho.
Effects of haloperidol and GM1 ganglioside treatment on striatal D2 receptor binding and dopamine turnover.
Previous studies have shown that whereas exogenous GM1 ganglioside co-administration leads to an increase of haloperidol-induced behavioral supersensitivity, GM1 significantly attenuates the behavioral parameters of dopaminergic supersensitivity when administered after abrupt haloperidol withdrawal. In the present study, the effects of GM1 and haloperidol co-administration (5 mg/kg GM1 i.p. and 1 mg/kg haloperidol i.p., twice daily, for 30 days) as well as the effects of a 3 day treatment with GM1 were investigated in rats withdrawn from haloperidol administration by measuring striatal D2 dopamine receptor binding and dopamine turnover. The results showed that under these two experimental conditions GM1 modified neither the haloperidol-induced striatal D2 dopamine receptor up regulation nor the decrease in dopamine turnover produced by haloperidol withdrawal. These results suggest that the effects of GM1 on behavioral supersensitivity are not related to modifications in dopamine receptor number or affinity and in the synaptic availability of this catecholamine.
Animals↗
Repeated monosialoganglioside administration attenuates behavioral sensitization to amphetamine.
The effects of repeated monosialoganglioside (GM1) administration on amphetamine-induced behavioral sensitization were studied using locomotion frequency of mice observed in an open-field as an experimental parameter. GM1 (30 mg/kg, once a day for 7 days) did not modify mouse behavior per se but decreased the hyperlocomotion of mice repeatedly treated with amphetamine (3.0 mg/kg, once a day for 7 days, 30 min after GM1 injection). GM1 acutely administered 30 min before amphetamine did not modify the increase in locomotion frequency induced by acute amphetamine administration. These results agree with previous reports that gangliosides treatment may affect synaptic-plasticity, modifying the induction of the adaptive changes following drug-treatment.
Animals↗
Effect of haloperidol on the development of the solid Ehrlich tumor in mice.
We determined the effect of 13 days of treatment with 2.0 mg/kg haloperidol (s.c) on the development of the Ehrlich solid carcinoma, after inoculation of 1.5 x 10(6) Ehrlich ascites tumor cells into the left footpad of mice. The footpad thickness of haloperidol treated animals was significantly smaller than control from day two after tumor inoculation, to the end of the experiment. Histopathological examination showed that haloperidol treated mice apparently presented less necrotic areas within the tumor mass as well as less invasion of subepithelial connective tissue and other adjacent structures. In particular, in comparison with the control group, no nerve bundles were invaded by neoplastic cells in experimental mice. The possible mechanism underlying these results is discussed in light of the specific pharmacological properties of this neuroleptics drug.
Analysis of Variance↗
Effects of buspirone on dopaminergic supersensitivity.
The effects of buspirone treatment on dopaminergic supersensitivity induced by long-term haloperidol administration were studied; both spontaneous activity (locomotion and rearing frequencies) of rats observed in an open-field and apomorphine-induced stereotypy were used as experimental parameters. Buspirone per se (3.0 mg/kg, twice daily, for 30 days) did not produce dopaminergic supersensitivity. When buspirone was given in combination to haloperidol (2.0 mg/kg, once daily, for 30 days), it decreased the neuroleptic withdrawal symptoms as detected in open-field behavior but not in apomorphine-induced stereotypy. Although single administration of buspirone per se decreased both open-field and apomorphine-induced stereotypy behavior, buspirone single administration did not modify the acute effects of haloperidol on these two behavioral models. Taken together with previous behavioral results showing that buspirone reverses haloperidol-induced catalepsy, the present data suggest that buspirone co-administration may lead to important clinical advantages concerning different extrapyramidal side effects of neuroleptic treatment.
Animals↗
Effects of monosialoganglioside on a new model of tardive dyskinesia.
1- The effects of monosialoganglioside GM1 were studied on a new model of tardive dyskinesia, i.e., the frequency of spontaneous tongue protrusions in rats repeatedly treated with reserpine. 2- Rats were co-treated with vehicle (VEH) or reserpine (RES) (0.1 mg/kg, s.c., every other day) and saline (SAL) or GM1 (5 mg/kg, i.p., every day) for 30 days and observed for tongue protrusions on days 10, 20 and 30. 3- During each test day animals of the RES + SAL group exhibited an increase in tongue protrusions relative to rats of the VEH + SAL group. However, rats of the RES + GM1 group showed an increased frequency of tongue protrusions only on day 10, when compared to animals of the VEH + SAL group. There were no significant differences in tongue protrusion frequency between the VEH + GM1 and the VEH + SAL groups. 4- These results differ from previous studies which reported a facilitatory effect of GM1 co-administration on conventional behavioral animal models of tardive dyskinesia. The possibility is raised that GM1 attenuates the reserpine-induced increase in tongue protrusions through its protective effect on glutamate/oxidative stress neurotoxicity.
Animals↗
Behavioural subsensitivity induced by long-term administration of a low dose of haloperidol to rats.
This study examines the effects on open-field and stereotyped behaviour of rats of abrupt withdrawal from repeated treatment with a low (0.03 mg kg-1) dose of haloperidol. Single administration of this low dose of haloperidol significantly increased open-field locomotion without modifying apomorphine (0.5 or 2.0 mg kg-1)-induced stereotyped behaviour. Forty-eight hours after abrupt withdrawal from 0.03 mg kg-1 haloperidol (twice daily for 15 days) a significant decrease in locomotion frequency was observed, but no change was observed in apomorphine-induced stereotypy. Our results suggest that dopamine autoreceptor supersensitivity might be evaluated in a behavioural situation of absence of postsynaptic dopamine receptor supersensitivity.
Administration, Oral↗
Effects of long-term ganglioside GM1 administration on a new discriminative avoidance test in normal adult mice.
The beneficial effects of monosialoganglioside GM1 (GM1) on learning and memory have been detected mostly in animals presenting genetic, lesion-induced or age-related memory deficits. The present study was carried out to investigate the effects of GM1 on the discriminative avoidance behavior of normal adult mice. EPM-M1 male mice were treated daily IP with 50 mg/kg GM1 or saline for 14 days. The discriminative avoidance conditioning was performed on day 15 in a modified elevated plus-maze. In one of the enclosed arms, the animals received aversive stimulation (light and noise). Tests were performed on days 20, 25 and 30 (tests 1, 2 and 3). The time the animals spent in each of the enclosed arms was recorded. In tests 1 and 2, GM1-treated mice spent less time in the aversive arm in comparison to the non-aversive enclosed arm. On the other hand, control animals spent a shorter time in a aversive arm only in test 1. The results suggest that the beneficial effects of GM1 on learning and memory can be observed in normal animals as well.
Animals↗
Monosialoganglioside attenuates the excitatory and behavioural sensitization effects of ethanol.
The effects of long-term monosialoganglioside GM1 treatment on the acute excitatory effects of ethanol and behavioural sensitization to this effect were studied, using locomotion frequency of mice observed in an open field as an experimental parameter. GM1 (30 mg/kg, once a day, for 21 days) did not modify mouse behaviour but decreased both the acute excitatory (1.8 g/kg) and the behavioural sensitization effects of ethanol (1.8 g/kg, once a day for 21 days, 30 min after GM1 injections). GM1 administered acutely 30 min or 24 h before ethanol did not modify the ethanol-induced increase in locomotion frequency. These results agree with previous reports in which ganglioside treatment modified both dopaminergic plasticity and other behavioural and biochemical effects of ethanol.
Animals↗
Effects of microgram doses of haloperidol on open-field behavior in mice.
This study was designed to evaluate the effects of low doses of haloperidol on the open-field behavior of mice. A three-phase effect of haloperidol on the motor activity of mice was observed (depression, no effect, depression). This three-phase action was clear-cut in three experimental approaches (amphetamine-induced hyperactivity, and apomorphine- and bromocriptine-induced hypoactivity). A differential action of haloperidol on dopamine receptors mediating motor stimulation and motor depression was proposed. The present data indicate that considerably more attention should be paid to the novel behavioral and biochemical actions of neuroleptic drugs in the microgram dose range.
Amphetamine↗
Antinociceptive effect of purine nucleotides.
The antinociceptive effect of purine nucleotides administered systematically (sc) was determined using the formalin and writhing tests in adult male albino mice. The mechanisms underlying nucleotide-induced antinociception were investigated by preinjecting the animals (sc) with specific antagonists for opioid (naloxone, 1 mg/kg), purinergic P1 (caffeine, 5, 10, of 30 mg/kg); theophylline, 10 mg/kg) or purinergic P2 receptors (suramin, 100 mg/kg; Coomassie blue, 30-300 mg/kg; quinidine, 10 mg/kg). Adenosine, adenosine monophosphate (AMP), diphosphate (ADP) and triphosphate (ATP) caused a reduction in the number of writhes and in the time of licking the formalin-injected paw. Naloxone had no effect on adenosine- or adenine nucleotide-induced antinociception. Caffeine (30 mg/kg) and theophylline (10 mg/kg) reversed the antinociceptive action of adenosine and adenine nucleotide derivatives in both tests. P2 antagonists did not reverse adenine nucleotide-induced antinociception. These results suggest that antinociceptive effect of adenine nucleotides is mediated by adenosine.
Analgesics↗
Effects of monosialoganglioside on dopaminergic supersensitivity.
The effects of monosialoganglioside (GMl) treatment on dopaminergic supersensitivity induced by long-term haloperidol administration were studied; both general activity of rats observed in an open-field and apomorphine-induced stereotyped behavior were used as experimental parameters. GMl per se (5.0 mg/kg, twice daily, for 30 days) did not modify rat behavior, but when given in combination with haloperidol (1.0 mg/kg, twice daily, for 30 days) it increased neuroleptic withdrawal symptoms as detected in both models. When GMl (5.0 mg/kg, twice daily) was administered after abrupt withdrawal from haloperidol (1.0 mg/kg, twice daily, for 30 days), it attenuated the increases in both general activity of rats observed in the open-field and apomorphine-induced stereotyped behavior. These results suggest that GMl may affect synaptic plasticity, facilitating the induction of the adaptative changes in receptor function (up and down-regulation), following long-term haloperidol treatment and withdrawal.
Animals↗
Effect of withdrawal from long-term nifedipine administration on open-field habituation in the rat.
The effects of withdrawal from long-term administration of nifedipine (2.5 mg/kg, ip, twice daily for 30 days) on open-field habituation were evaluated in 3-month old male Wistar rats (13-14 animals per group). Habituation was evaluated by the ratio between locomotion or rearing frequencies obtained in the second and the first open-field session for each animal. Nifedipine treatment did not modify the locomotion ratio (with a mean +/- SEM ratio of 0.66 +/- 0.12 for control and 0.45 +/- 0.08 for nifedipine-treated group) nor the rearing ratio (with a mean +/- SEM ratio of 0.51 +/- 0.12 for control and 0.62 +/- 0.18 for nifedipine-treated group). The possible factors underlying the discrepancy between the present results and the commonly reported positive effects of calcium channel blockers on memory are discussed.
Animals↗
Effects of single and long-term administration of nifedipine on nociception and stereotyped behavior of rats.
In the present investigation, nociception and stereotyped behavior were evaluated in 3-month old male Wistar rats after a single nifedipine dose (2.5 and 5.0 mg/kg, ip, 1 h before testing, 6-7 rats per group for stereotypy studies and 15 animals per group for nociception experiments) or after long-term nifedipine treatment (2.5 mg/kg, ip, twice daily for 30 days, with testing performed 72 or 96 h after the last injection, 7 rats per group for stereotypy studies and 14-16 animals per group for nociception experiments). Stereotypy was induced with 2.5 mg/kg amphetamine, ip, and nociception was measured by the tail-immersion test. Administration of a single nifedipine dose did not modify nociception or amphetamine-induced stereotypy (with a mean +/- SEM tail-withdrawal latency of 4.5 +/- 0.5 s for control, 4.4 +/- 0.3 s for 2.5 mg/kg nifedipine and 4.7 +/- 0.7 s for 5.0 mg/kg nifedipine and with mean +/- SEM sum of stereotypy scores of 32.5 +/- 1.6 for control, 29.1 +/- 1.0 for 2.5 mg/kg nifedipine and 29.1 +/- 1.6 for 5.0 mg/kg nifedipine). Withdrawal from long-term nifedipine treatment did not affect stereotyped behavior (with mean +/- SEM sum of stereotypy scores of 28.7 +/- 1.6 for control and 30.7 +/- 1.3 for nifedipine-treated rats) but significantly increased tail-withdrawal latencies (with a mean +/- SEM tail-withdrawal latency of 4.1 +/- 0.3 s for control and 6.4 +/- 0.6 s for nifedipine-treated rats). Therefore, long-term nifedipine treatment induced plastic modifications in nociception but not in stereotyped behavior.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of single and long-term administration of nifedipine on dopamine-related behaviors.
The effects of single (2.5 and 5.0 mg/kg) and long-term (2.5 mg/kg, twice daily, for 30 days) ip administration of nifedipine on open-field and apomorphine-induced stereotyped behavior were evaluated in young male Wistar rats (12-16 animals per group for the open-field studies and 7 animals per group for the stereotypy experiments). Administration of a single dose of nifedipine produced no changes in ambulation or rearing frequencies or in immobility duration in the open-field compared to controls. Similarly, treatment with a single dose of nifedipine did not modify apomorphine-induced stereotypy. Withdrawal from long-term nifedipine administration caused a significant increase only in rearing frequency 24 h after the last drug injection (with a mean +/- SEM frequency of 23.2 +/- 2.8 for the nifedipine group and of 14.7 +/- 2.0 for control rats, after 6-min observation). This enhancement of rearing frequency was no longer observed 48 h after abrupt nifedipine withdrawal (means +/- SEM: 15.0 +/- 2.2 and 19.6 +/- 2.7 for nifedipine-treated and control rats, respectively). The other open-field behavioral parameters and apomorphine-induced stereotypy (which was observed 96 h after nifedipine withdrawal) were not affected by long-term nifedipine treatment; for example, the sum of stereotypy scores (mean +/- SEM) was 26.9 +/- 3.0 for nifedipine-treated rats and 25.5 +/- 2.2 for vehicle-treated animals. The possible mechanisms underlying these results are discussed in light of the changes in dopaminergic neurotransmission induced by dihydropyridine calcium channel blockers.
Animals↗
Evaluation of memory in an elevated T maze: a comparison between spontaneously hypertensive, Wistar-Kyoto and Wistar EPM-1 rats.
Four-month old male spontaneously hypertensive (SHR), Wistar-Kyoto (WKY) and Wistar EPM-1 (EPM-1) rats (14-15 animals per group) were tested in an elevated T maze to evaluate memory. Blood pressures of SHR were hyper at the time of experiment (200-235 mmHg). The elevated T maze used consisted of an open arm at right angles with two enclosed arms elevated 50 cm above the ground. Memory was quantified by the escape latency ratio (the ratio of the time it took for the rat to move from the open arm to one of the enclosed arms in the second session to that in the first session) and by the inhibitory avoidance latency (time from being placed at the end of an enclosed arm to move to the open arm, in a 3rd session). No significant differences in escape latency ratios were observed among SHR, WKY and EPM-1 rats. Conversely, SHR presented a significant reduction in inhibitory avoidance latency as compared to those of WKY and EPM-1 rats (mean +/- SEM latency: 65.9 +/- 18.4 s for SHR, 129.9 +/- 21.8 s for WKY animals and 181.2 +/- 11.2 s for EPM-1 rats). These data were discussed in light of the known lowered reaction to aversive environments exhibited by SHR, as compared to WKY and EPM-1 rats.
Animals↗
Effects of a single administration of buspirone on catalepsy, yawning and stereotypy in rats.
In the present study, the effects of a single administration of buspirone (0.1, 0.3, 1.0, and 3.0 mg/kg sc-30 min before testing) on three dopamine-related behaviors were evaluated in 4-month old male Wistar rats (7-10 animals per group). Buspirone decreased haloperidol (2.0 mg/kg ip)-induced catalepsy in a dose-dependent manner (from 7.30 to 5.09 1n of s compared to the untreated control group). Apomorphine (0.06 mg/kg sc)-induced yawning was also dose-dependently reduced (from 26.7 to 0.9 yawns in 30 min) and so was apomorphine (1.0 mg/kg sc)-induced stereotypy (from 32.9 to 5.9, sum of scores). The present results indicate that buspirone presents unique pharmacological effects related to dopaminergic transmission not only in biochemical but also in behavioral terms.
Analysis of Variance↗
Comparison of anxiety measured in the elevated plus-maze, open-field and social interaction tests between spontaneously hypertensive rats and Wistar EPM-1 rats.
On the basis of open-field and plus-maze results it has been proposed that spontaneously hypertensive (SHR) rats are less emotionally reactive than their normotensive controls, Wistar-Kyoto (WKY). However, the proposed "anxiolytic characteristics" of SHR rats may be questioned in view of the significant hypoactivity presented by WKY rats. In the present study, the behavioral response of spontaneously hypertensive (SHR) and equally active normotensive Wistar EPM-1 (EPM-1) rats (4-month old males, 10-13 animals per group) were evaluated in the open-field, social interaction and elevated plus-maze tests. In the open-field study, no differences were observed for total locomotion frequency and immobility duration, but SHR rats presented a higher central square locomotion frequency (23.8 +/- 2.1 vs 10.3 +/- 1.6) as compared to EPM-1. SHR rats also exhibited a greater duration of social interaction when compared to EPM-1 rats (mean +/- SEM values were 113.9 +/- 8.7 s for SHR vs 72.7 +/- 8.6 s for EPM-1 rats after 8-min observation). In the elevated plus-maze test, SHR rats presented an increased percent of entries (52.8 +/- 3.3 vs 28.3 +/- 4.5) and time in the open arms (65.6 +/- 6.0 vs 11.1 +/- 1.9) as compared to EPM-1 rats, although the total number of arm entries (9.2 +/- 0.9 vs 9.7 +/- 1.0) was unchanged. These results suggest that the "anxiolytic behavior" of SHR rats in relation to normotensive controls is not related to differences in motility levels.
Animals↗