The nonsteroidal antiinflammatory drug piroxicam reverses the onset of depressive-like behavior in 6-OHDA animal model of Parkinson's disease.

Depression is one of the most common psychiatric symptoms in patients with Parkinson's disease (PD). Some authors have reported that depression is characterized by activation of the inflammatory response. Animal models of PD also present with depressive-like behavior, such as increased immobility time in the modified forced swim test and anhedonia-like behavior in the sucrose preference test. Considering the potential neuroprotective effect of nonsteroidal antiinflammatory drugs in neurodegenerative diseases, the objective of the present study was to investigate the effects of piroxicam on depressive-like behavior in male Wistar rats lesioned with 6-hydroxydopamine (6-OHDA) in the substantia nigra (SN). Antidepressant-like effects were observed after prolonged administration of piroxicam for 21days. In the forced swim test, the 6-OHDA+saline group exhibited significant reductions in swimming time and increased immobility time compared with the sham+saline. In the sucrose preference test, the 6-OHDA+piroxicam group exhibited no reduction of sucrose preference compared with the sham+saline, with significant effects of treatment and time and a significant treatment×time interaction. 5-Hydroxytryptamine (5-HT) levels significantly decreased in the hippocampus in the 6-OHDA+saline group and not changed in the 6-OHDA+piroxicam group when compared with the sham+saline on day 21. In conclusion, 21-day treatment with piroxicam reversed the onset of depressive-like behavior and prevented the reduction of hippocampal 5-HT levels.

Myricitrin, a nitric oxide and protein kinase C inhibitor, exerts antipsychotic-like effects in animal models.

Myricitrin is a nitric oxide (NO) and protein kinase C (PKC) inhibitor that has central nervous system activity, including anxiolytic-like action. Nitric oxide inhibitors blocked the behavioral effects of apomorphine, suggesting an antipsychotic-like effect. Furthermore, PKC inhibition reduced psychotic symptoms in acute mania patients and blocked amphetamine-induced hyperlocomotion, suggesting a potential antipsychotic-like effect. The present study evaluated the effects of myricitrin in animal models that assess antipsychotic-like effects (apomorphine-induced stereotypy and climbing and the paw test) and extrapyramidal side effects (catalepsy test and paw test). Olanzapine was used as a positive control. 7-Nitroindazole (7-NI), a NOS inhibitor, and l-arginine, a NO precursor, were used to evaluate nitrergic modulation, and tamoxifen was used to test the effect of PKC inhibition. In mice, myricitrin dose-dependently and olanzapine blocked the stereotypy and climbing induced by apomorphine at doses that did not induce catalepsy. 7-Nitroindazole also blocked apomorphine-induced stereotypy and climbing, which were reversed by l-arginine pretreatment. l-arginine only attenuated the effects of myricitrin on apomorphine's effects. Tamoxifen also blocked apomorphine-induced stereotypy and climbing. In the paw test in rats, myricitrin and olanzapine increased hindlimb retraction time at doses that did not affect forelimb reaction time, whereas haloperidol affected both parameters at the same dose. Myricitrin did not induce catalepsy in the bar test. Tamoxifen did not affect hindlimb retraction time or forelimb retraction time, whereas 7-NI significantly increased hindlimb reaction time. Thus, myricitrin exhibited an antipsychotic-like profile at doses that did not induce catalepsy, and this effect may be related to nitrergic action.

Nicotine induces sensitization of turning behavior in 6-hydroxydopamine lesioned rats.

Nicotinic drugs have been proposed as putative drugs to treat Parkinson's disease (PD). In this study, we investigated whether nicotine can sensitize parkinsonian animals to the effect of dopaminergic drugs. Testing this hypothesis is important because nicotine has been shown to present neuroprotective and acute symptomatic effects on PD, but few studies have addressed the question of whether it may induce long-lasting effects on dopamine neurotransmission. We tested this hypothesis in the 6-hydroxydopamine (6-OHDA) rat model of PD. A pretreatment of these rats with 0.1-1.0 mg/kg nicotine induced a dose-dependent sensitization of the turning behavior when the animals were challenged with the dopamine receptor agonist apomorphine 24 h later. In agreement with previous studies, while apomorphine induced contraversive turns, nicotine, as well as amphetamine, induced ipsiversive turns in the 6-OHDA rats. This result suggests that, like amphetamine, nicotine induces turning behavior by promoting release of dopamine in the non-lesioned striatum of the rats. However, it is unlikely that the release of dopamine may also explain the nicotine-induced sensitization of turning behavior. First, the dopamine amount that could be released in the lesioned hemi-striatum by the nicotine pretreatment was minimum-less than 3%, as detected by HPLC-EC. Second, a pretreatment with amphetamine did not induce this behavioral sensitization. A pretreatment with apomorphine-induced sensitization, but it was minimal when compared to that induced by nicotine. Therefore, it is unlikely that the sensitization of the turning behavior induced by nicotine was consequent of the release of dopamine. However, the expression of such sensitization seems to depend on the activation of dopaminergic receptors, since it was seen when the nicotine-sensitized animals were challenged with apomorphine, but not with a second nicotine challenge. These findings are relevant for PD drug therapy since they suggest that the doses of dopaminergic drugs used to treat PD could be reduced if a nicotinic drug were co-administered.

Veratrine blocks the lamotrigine-induced swimming increase and immobility decrease in the modified forced swimming test.

Lamotrigine exhibits an anti-immobility effect in the modified forced swimming test, increasing swimming and climbing, behaviors that are related to serotonergic and noradrenergic effects, respectively. However, these effects could be secondary to lamotrigine blockade of Na(+) sensitive channel. Thus, this study investigated the influence of veratrine (0.1 mg/kg, ip, 10 min before each lamotrigine administration), an Na(+) channel activator, in the effect of lamotrigine (20 mg/kg, ip, 24, 5, 1 h before the test session) in the modified forced swimming test. Veratrine pre-treatment blocked lamotrigine-induced immobility decrease and swimming increase but it did not change the effect of lamotrigine on climbing. These results suggest that the serotonergic effect of lamotrigine in the modified forced swimming test is dependent on Na(+) voltage sensitive channel blockade, whereas its noradrenergic effect is not.

Monosialoganglioside (GM1) attenuates the behavioural effects of long-term haloperidol administration in supersensitive rats.

In the present study we investigated the effects of co-administration of GM(1) (15.0 mg/kg, twice daily, for 30 days) and haloperidol (1.0 mg/kg, twice daily, for 30 days), as well as the effects of a 5-day treatment with this dose of GM(1) after withdrawal from haloperidol in rats. The animals were evaluated in the open-field test and apomorphine-induced stereotyped behaviour. The results show that GM(1) was able to attenuate dopaminergic supersensitivity evaluated by the locomotion frequency at 24 and 48 h after the withdrawal from haloperidol. On the other hand, rearing frequency was changed neither by haloperidol nor by GM(1.) In haloperidol-treated rats immobility time differs from 30 min observation session in comparison with the following sessions after the withdrawal from neuroleptic. Apomorphine-induced stereotyped behaviour produced a significant increase in scores of haloperidol-withdrawn rats. GM(1) did not modify the haloperidol effects and did not change the dopamine receptor affinity to apomorphine 100 h from abrupt neuroleptic withdrawal.

Reliability and clinical utility of a Portuguese version of the Abnormal Involuntary Movements Scale (AIMS) for tardive dyskinesia in Brazilian patients.

The objective of the present study was to evaluate the reliability and clinical utility of a Portuguese version of the Abnormal Involuntary Movements Scale (AIMS). Videotaped interviews with 16 psychiatric inpatients treated with antipsychotic drugs for at least 5 years were evaluated. Reliability was assessed by the intraclass correlation coefficient (ICC) between three raters, two with and one without clinical training in psychopathology. Clinical utility was assessed by the difference between the scores of patients with (N = 11) and without (N = 5) tardive dyskinesia (TD). Patients with TD exhibited a higher severity of global evaluation by the AIMS (sum of scores: 4.2 +/- 0.9 vs 0.4 +/- 0.2; score on item 8: 2.3 +/- 0.3 vs 0.4 +/- 0.2, TD vs controls). The ICC for the global evaluation was fair between the two skilled raters (0.58-0.62) and poor between these raters and the rater without clinical experience (0.05-0.29). Thus, we concluded that the Portuguese version of the AIMS shows an acceptable inter-rater reliability, but only between clinically skilled raters, and that it is clinically useful.

Reliability and clinical utility of a Portuguese version of the Abnormal Involuntary Movements Scale (AIMS) for tardive dyskinesia in Brazilian patients

The objective of the present study was to evaluate the reliability and clinical utility of a Portuguese version of the Abnormal Involuntary Movements Scale (AIMS). Videotaped interviews with 16 psychiatric inpatients treated with antipsychotic drugs for at least 5 years were evaluated. Reliability was assessed by the intraclass correlation coefficient (ICC) between three raters, two with and one without clinical training in psychopathology. Clinical utility was assessed by the difference between the scores of patients with (N = 11) and without (N = 5) tardive dyskinesia (TD). Patients with TD exhibited a higher severity of global evaluation by the AIMS (sum of scores: 4.2 ± 0.9 vs 0.4 ± 0.2; score on item 8: 2.3 ± 0.3 vs 0.4 ± 0.2, TD vs controls). The ICC for the global evaluation was fair between the two skilled raters (0.58-0.62) and poor between these raters and the rater without clinical experience (0.05-0.29). Thus, we concluded that the Portuguese version of the AIMS shows an acceptable inter-rater reliability, but only between clinically skilled raters, and that it is clinically useful

Memory disruption in rats with nigral lesions induced by MPTP: a model for early Parkinson's disease amnesia.

Intra-nigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) caused a lesion in the substantia nigra, compact part (SNc) and a specific loss of dopamine and its metabolites in the striatum of rats. The animals were then tested in the two-way active avoidance task. MPTP-treated animals presented lower learning scores in the training and test sessions, an effect that was not caused by motor impairment or by a decreased sensitivity to footshock since their reaction time to the footshock (unconditioned stimulus - UCS) was not reduced. These lower scores were also not attributable to lower acoustic sensitivity or to a slowing in the association of the sound cue (conditioned stimulus - CS) with the UCS since the reaction time to the CS in the active avoidance response did not differ between MPTP-treated and control groups. Therefore, these results are more properly attributable to an impairment of the memory acquisition and retention processes. In addition, this study is presented as a model of early Parkinson's Disease amnesia and is discussed in terms of the importance of the nigrostriatal pathway to memory acquisition and storage processes.

Phosphatidylserine reverses reserpine-induced amnesia.

The effects of phosphatidylserine (PS) were studied in rats treated with reserpine (1 mg/kg) immediately after training in the passive avoidance task. In experiment I, phosphatidylserine (25 mg/kg) was administered 30 min before or immediately after training. Acute pre- or post-treatment with phosphatidylserine was effective in reversing the amnestic effect of reserpine in test trials performed 24 h and 1 week after training. Experiment II was performed to determine if the long-term pretreatment with phosphatidylserine (25 mg/kg) for 7 days is able to protect the rats against the amnestic effects of reserpine in this task. The data show that phosphatidylserine reverses the impairment induced by reserpine in trials performed 24 h and 1 week after training. These results indicate that the memory deficits associated with catecholamine depletion caused by reserpine can be attenuated by acute pre- or post-training or by long-term pretreatment with this phospholipid.

The antidepressive-like effect of oxcarbazepine: possible role of dopaminergic neurotransmission.

It has been previously shown that oxcarbazepine (OXCBZ), a keto-analogue of carbamazepine, exhibits an antidepressive-like effect profile in the learned helplessness and forced swimming test (FST). Since carbamazepine possesses dopaminergic effect, the present study was carried out to evaluate the extent to which the antidepressive effect of OXCBZ might be mediated by dopaminergic system. Thus, the effects of OXCBZ in haloperidol-induced catalepsy and apomorphine-induced stereotypy were studied. The anti-immobility effect of OXCBZ in the FST was also evaluated in haloperidol pre-treated rats. OXCBZ (40 and 80 mg/kg, i.p.) dose-dependently reduced the catalepsy induced by haloperidol (2.0 mg/kg, i.p.). Moreover, OXCBZ (80 mg/kg, but not 20 or 40 mg/kg, i.p.) increased the intensity of apomorphine-induced stereotypy (0.6 mg/kg, s.c.). Finally, it was observed that the combination of OXCBZ (80 mg/kg, i. p.) and haloperidol (0.5 mg/kg, i.p.) antagonized the anti-immobility effect of OXCBZ and further increased the immobility time when compared to haloperidol alone. Haloperidol alone (0.5 or 1. 0 mg/kg) did not change the immobility time. Thus, these results suggest that OXCBZ could enhance dopaminergic neurotransmission, which might mediate its antidepressive-like effect.

The effect of caffeine in animal models of learning and memory.

In the present investigation we studied the effect of caffeine on memory task inhibitory avoidance and habituation to a new environment. Caffeine impaired retention scores in mice submitted to inhibitory avoidance and habituation when administered 30 min before training at the doses of 10-30 mg/kg. These effects cannot be explained by state-dependency since the administration of caffeine 30 min before the test session did not reverse the effect of pre-training caffeine administration, but can more probably be explained by an impairment in the acquisition or by interference with attentional processes. On the other hand, caffeine improved the inhibitory avoidance (but not habituation) retention scores when administered immediately after the training or 30 min before the test session at the doses of 1-30 mg/kg or 3-10 mg/kg, respectively. These results suggest that caffeine differentially affects the different stages of memory processing and that this effect depends on particularities of the memory task under study.

Kinetic analysis of GM1 effects on haloperidol-induced dopaminergic supersensitivity.

The relative affinity of metoclopramide as indicated by K(B) values was calculated in control and in haloperidol-withdrawn rats treated or not with monosialoganglioside-1 (GM1) by using dose-response curves constructed for apomorphine-induced stereotyped behavior. Haloperidol withdrawal decreased K(B) data--that is, increased the D2-receptor affinity for metoclopramide. GM1 treatment per se did not modify K(B) values but, when given in combination with haloperidol, GM1 induced a decrease in K(B) values. No differences were found in K(B) data when GM1 was administered after withdrawal from haloperidol.

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.

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.

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.

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.

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.

Effect of ganglioside (GM1) on memory in senescent rats.

Monosialoganglioside GM1 (GM1) has been found to alleviate genetic and lesion-induced memory deficits. The purpose of this study was to investigate the effects of 7-day treatment with GM1 (50 mg/kg IP) on acquisition and retention performance of senescent rats in a passive avoidance situation. Saline-treated old rats showed a decreased performance in acquisition and retention tests as compared to saline-treated adult rats. GM1 improved both acquisition and retention performance of old animals, and there was no significant difference between GM1-treated old rats and saline-treated adult rats. These data suggest that GM1 treatment can improve memory deficits in intact senescent animals.

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.

Anxiety-induced antinociception in the mouse.

It has been suggested that exposure to the elevated plus-maze (EPM) apparatus induces antinociceptive effects in mice as measured by the tail-flick assay, which are not blocked by the opiate antagonist naltrexone. The present study performed on 3-month old male EPM-M1 albino mice (12-14 animals per group) was designed to assess a) if exposure limited to the open or to the enclosed arm of the EPM would alter this effect; b) whether or not pharmacologically induced anxiety (1.0 mg/kg pentylenetetrazole, PTZ) would also reduce nociception; c) if exposure to the EPM would alter visceral pain, as measured by the abdominal contortion test. The simultaneous exposure to both the open and enclosed arms of the EPM, but not the exposure limited to each type of arm, led to statistically significant increases in tail withdrawal latencies (TWL). Indeed, 10 min after exposure to both arms, TWL values (mean +/- SEM) were 10.31 +/- 0.87 s as compared to a baseline value of 5.46 +/- 0.53 s. The acute administration of PTZ significantly increased TWL. Conversely, EPM-induced antinociception was not detected by the abdominal contortion test. These results confirm the existence of EPM-induced antinociceptive effects demonstrated by others and show that they may be influenced by multiple determinants.