Anxiolytic-like effect of chronic treatment with Erythrina velutina extract in the elevated plus-maze test.

INTRODUCTION: In Brazil, Erythrina velutina (Fabaceae) is widely used as a tranquilizer and/or sedative, and its extract exerts an anxiolytic-like effect profile in animal models, although these results may be caused by its sedative or amnesic effects. AIMS, MATERIALS AND METHODS: Thus, this study evaluated the effect of acute and chronic (23-26 days) administrations of the hydroalcoholic extract of the stem bark of Erythrina velutina (orally) in mice submitted to the following tests: elevated plus-maze, forced swim, spontaneous locomotor activity, and habituation to active chamber. Chlordiazepoxide and imipramine were used as standard drugs. RESULTS: In the elevated plus-maze test, chronic, but not acute, Erythrina velutina (100mg/kg) administration increased the percentage of open arm entries, an effect also seen in both acute and chronic treatments with chlordiazepoxide (7.5mg/kg). In the forced swim test, only imipramine (25mg/kg) decreased immobility time. Impairment of habituation was seen only with acute imipramine administration and with the lowest doses of Erythrina velutina extract tested in acute (10mg/kg) and chronic (50mg/kg) administrations. CONCLUSIONS: These results suggest that chronic administration of the hydroalcoholic extract of the stem bark of Erythrina velutina exerts an anxiolytic-like effect on mice, and it could serve as a new approach for the treatment anxiety, although it may have an amnesic effect at low doses.

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.

Repeated paroxetine treatment reverses anhedonia induced in rats by chronic mild stress or dexamethasone.

The present study was designed to assess the effect of dexamethasone, a synthetic glucocorticoid receptor agonist, in the sucrose preference test in rats. Rats treated acutely with dexamethasone (5-10 mg/kg) showed a significant decrease in sucrose preference (anhedonia) in comparison to vehicle treated rats, although 1 mg/kg dexamethasone did not alter the sucrose preference. Daily paroxetine treatment (10 g/kg, i.p., 14 days) reversed the anhedonic effect of acute dexamethasone (5 mg/kg), while causing no increased sucrose preference in rats that received dexamethasone vehicle. The paroxetine vehicle treated rats showed anhedonia even 14 days after acute dexamethasone administration. Paroxetine (10 mk/kg, i.p. for 28 days) also reversed anhedonia induced by chronic mild stress (8 weeks). In conclusion, acute dexamethasone induced an enduring anhedonic state that was reversed by repeated paroxetine treatment. Thus, the present study adds new data to the evidence supporting an important role for glucocorticoid in depression.

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.

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.

Effect of valepotriates on the behavior of rats in the elevated plus-maze during diazepam withdrawal.

The effect of a mixture of valepotriates on the elevated plus-maze performance of diazepam withdrawn rats was evaluated. The rats were chronically (28 days) treated with diazepam (doses increased up to 5.0 mg/kg) and then treated with control solution for 3 days to induce a withdrawal syndrome. Chronically vehicle-treated rats were used as control. The abstinent animals treated with vehicle showed a significant decrease in the percentage of time spent in the open arms when compared with the control animals. Diazepam and valerian 12.0 mg/kg reversed this anxiogenic effect. Valerian 6.0 mg/kg did not show any difference in relation to the others group.

The effect of oxcarbazepine on behavioural despair and learned helplessness.

The effect of oxcarbazepine was evaluated in two tests of depression (forced swimming and learned helplessness) and in the open-field test. Acute (three times over 24 h) oxcarbazepine 80 mg/kg (but not 40 mg/kg) decreased immobility time in the forced swimming test. In the learned helplessness test, 4 days of treatment with oxcarbazepine 80 mg/kg reversed the deficits induced by foot-shock in rats submitted to the two-way active avoidance test. Oxcarbazepine 80 mg/kg did not modify the behaviour of rats in the open-field test, an indication that, at this dose, oxcarbazepine did not show a locomotor stimulatory effect. Thus, the data of the present study suggest that oxcarbazepine has a potential antidepressive effect.

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.

Animal models: trait or state measure? The test-retest reliability of the elevated plus-maze and behavioral despair.

1. The use of animal models in certain types of psychobiological studies (for instance, the relationship between anxiety and depression) requires that the behavior measured is stable over time. 2. The test-retest reliability of the elevated plus-maze indexes of anxiety and the immobility time in the behavioral despair were evaluated. 3. The behavior of two groups of drug naive mice was measured on two occasions on the same test, 1 week apart, on the elevated plus-maze or on the behavioral despair and then the intraclass correlation coefficient and kappa were calculated. 4. These behaviors showed a very low intraclass correlation coefficient (0.02 - 0.05) and low kappa (-0.08 - 0.21) in the test-retest design, which suggest a poor reliability of these measures. 5. These results suggest that the behavioral parameters of the elevated plus-maze and the behavioral despair are not stable and therefore they are possibly more related to state than trait characteristics. Therefore they appear to be not appropriate to evaluate trait characteristics which are supposed to be stable over time without treatment.

The effect of corticosterone in rats submitted to the elevated plus-maze and to to pentylenetetrazol-induced convulsions.

1. In order to examine the effects of corticosterone in the anxiety response, the effect of acute, subchronic and chronic corticosterone (CORT) administration were studied using two animal models to study anxiolytic effects of drugs: the elevated plus-maze and the blockade of pentylenetetrazol (PTZ)-induced clonic convulsion. 2. The results obtained with the plus-maze showed an increase in the percentage of open arm entries and time spent in the open arms after acute treatment with the CORT. These results may be interpreted as an anxiolytic effect of corticosterone. Three days of vehicle treatment followed by an acute CORT administration, produced results that should also indicate anxiolytic effect of the corticosteroid. No effect was seen after 14 days of vehicle treatment followed by an acute CORT injection. Subchronic or chronic CORT treatment did not produce results different from controls. CORT treatment did not affect the PTZ-induced clonic convulsion. 3. In conclusion these results suggest that the acute anxiolytic effect observed in the elevated plus-maze did not occur after repeated CORT administration or mild stressors. Moreover they also suggest that the anxiolytic effect did not involve GABA mechanisms.

The video-recorded Stroop Color-Word Test as a new model of experimentally-induced anxiety.

1. The use of the Stroop Color-Word Test as a model of experimentally induced anxiety was evaluated. 2. First, the authors examined the influence of trait anxiety and the type of instructions on the anxiety state level. Subjects with high trait anxiety (above 50 on State-Trait Anxiety Scale--STAI) showed a significant increase in anxiety state only with limited time (2 minutes) and error signal (with a ringing bell) procedures. This increase was blocked by diazepam (DZP) 5.0 mg p.o. both on pre- and post-test measures, but it was not changed by placebo administration. 3. The public performance simulation (with a video-camera) was effective to raise the anxiety state on normal volunteers with mean trait anxiety (between 30 and 50 on STAI). This raise was prevented with diazepam 5.0 mg p.o. but it was not prevented with placebo administration. 4. As a whole, these data suggest that the Video-recorded Stroop Color-Word Test is an effective anxiety provoking test, able to detect the effect of standard anxiolytic drug and stressed the importance of trait anxiety level and the instructions on tests that induced anxiety experimentally.

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.

Alcohol dependence criteria in DSM-III-R: presence of symptoms according to degree of severity.

According to DSM-III-R a positive diagnosis of alcohol dependence requires the presence of at least three of nine symptoms of a core dependence syndrome. In this study the presence of the nine symptoms according to degree of the severity of dependence is examined in 99 patients (mild, n = 23; moderate, n = 26; and severe, n = 50). It is shown that although the cut-off point for a positive diagnosis of dependence is the presence of "any three" out of nine DSM-III-R criteria, specific symptoms ("excessive drinking", "desire or efforts to control drinking", and "drinking despite major problems") have a high probability of occurrence across the dependence severity range (mild, moderate or severe). Conversely, other symptoms appear prominently only in the more severe cases ("much time devoted to alcohol", "important activities given up", and "drinking to relieve withdrawal"). The results suggest that in the DSM-III-R criteria for alcohol dependence some symptoms are more frequently associated with the diagnosis, while other symptoms are associated with severity of the alcohol dependence disorder.

Prolonged treatment with carbamazepine increases the stimulatory effects of ethanol in mice.

Carbamazepine (CBZ) has been used in the treatment of alcohol withdrawal (AW). However, cases of induction of euphoric feelings when mixed with alcohol have been reported. We verified whether CBZ could potentiate ethanol stimulatory effects in animals. Two groups of mice were injected with saline (group I) or 2 g/kg ethanol (group II) IP, for 20 days. On the next day, each group was divided into two subgroups that received either a single dose of CBZ (10 mg/kg) or vehicle IP, followed, 30 min later, by saline or ethanol injection. Locomotor activity was measured. Acute CBZ did not change locomotor activity of ethanol-treated mice. Treatment with CBZ or vehicle continued for 6 days. Finally, on the 28th day, 30 min after the last CBZ or vehicle injection, an ethanol challenge was given to group II and a saline injection to group I. The results showed a significant potentiation of ethanol stimulatory effects by chronic CBZ treatment. Data indicated that CBZ should be cautiously administered to alcohol-dependent patients.

Evidence against the involvement of ACTH/CRF release or corticosteroid receptors in the anxiolytic effect of corticosterone.

The present study was designed to evaluate the role of ACTH and/or CRF release and corticosteroid receptors (glucocorticoid and mineralocorticoid) in the anxiolytic effect of corticosterone (CORT). Costicosteroid receptor mediation was evaluated using a dose-response analysis of the effect of CORT and by the action of dexamethasone (DEX), which binds to glucocorticoid receptors but not to mineralocorticoid receptors. DEX administration also permits indirect evaluation of the effect of ACTH/CRF release on the anxiolytic effect of CORT. Male Wistar rats (3 months old) weighing 250-350 g were treated sc with vehicle (N = 38), CORT 1.25 (N = 18), 2.5 (N = 13) and 5.0 (N = 24) mg/kg, or DEX 5.0 (N = 19) and 10.0 (N = 17) mg/kg and tested in the elevated plus-maze 2 h later. The group that received the highest dose of CORT (5.0 mg/kg) showed a significant increase in percent open arm entries (38 +/- 2.6, mean +/- SEM) as well as in percent time spent in open arms (27 +/- 4.0) when compared with the vehicle-treated rats (24.3 +/- 2.8 and 12.4 +/- 1.9, respectively; both P < 0.05). There were no other significant differences among groups in the two parameters tested or in total arm entries. These data corroborate previous findings of the anxiolytic effect of CORT and suggest that inhibition of ACTH/CRF release and corticosteroid receptors do not play a major role in the anxiolytic effect of CORT.

The relationship between anxiety and depression in animal models: a study using the forced swimming test and elevated plus-maze.

The present study evaluated the correlation between the behavior of mice in the forced swimming test (FST) and in the elevated plus-maze (PM). The effect of the order of the experiments, i.e., the influence of the first test (FST or PM) on mouse behavior in the second test (PM or FST, respectively) was compared to handled animals (HAND). The execution of FST one week before the plus-maze (FST-PM, N = 10), in comparison to mice that were only handled (HAND-PM, N = 10) in week 1, decreased % open entries (HAND-PM: 33.6 +/- 2.9; FST-PM: 20.0 +/- 3.9; mean +/- SEM; P<0.02) and % open time (HAND-PM: 18.9 +/- 3.3; FST-PM: 9.0 +/- 1.9; P<0.03), suggesting an anxiogenic effect. No significant effect was seen in the number of closed arm entries (FST-PM: 9.5 (7.0-11.0); HAND-PM: 10.0 (4.0-14.5), median (interquartile range); U = 46.5; P>0.10). A prior test in the plus-maze (PM-FST) did not change % immobility time in the FST when compared to the HAND-FST group (HAND-FST: 57.7 +/- 3.9; PM-FST: 65.7 +/- 3.2; mean +/- SEM; P>0.10). Since these data suggest that there is an order effect, the correlation was evaluated separately with each test sequence: FST-PM (N = 20) and PM-FST (N = 18). There was no significant correlation between % immobility time in the FST and plus-maze indexes (% time and entries in open arms) in any test sequence (r: -0.07 to 0.18). These data suggest that mouse behavior in the elevated plus-maze is not related to behavior in the forced swimming test and that a forced swimming test before the plus-maze has an anxiogenic effect even after a one-week interval.

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.

The brain decade in debate: II. Panic or anxiety? From animal models to a neurobiological basis.

This article is a transcription of an electronic symposium sponsored by the Brazilian Society of Neuroscience and Behavior (SBNeC). Invited researchers from the European Union, North America and Brazil discussed two issues on anxiety, namely whether panic is a very intense anxiety or something else, and what aspects of clinical anxiety are reproduced by animal models. Concerning the first issue, most participants agreed that generalized anxiety and panic disorder are different on the basis of clinical manifestations, drug response and animal models. Also, underlying brain structures, neurotransmitter modulation and hormonal changes seem to involve important differences. It is also common knowledge that existing animal models generate different types of fear/anxiety. A challenge for future research is to establish a good correlation between animal models and nosological classification.

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.