Roberto Andreatini

Depression in Parkinson's disease: a double-blind, randomized, placebo-controlled pilot study of omega-3 fatty-acid supplementation.

BACKGROUND Effect of fish oil supplementation in parkinsonian patients with depression measured by Montgomery-Asberg Rating Scale (MADRS), the Clinical Global Impressions Scale (CGI) and Beck Depression Inventory (BECK). METHOD Double-blind, placebo-controlled study analyzed depression in 31 patients with Parkinsons Disease and Major Depression (DSM-IV). The patients were double-blind separated in 2 groups that received fish oil (containing omega-3 fatty acids) or mineral oil capsules for 3 months; each group was separated in 2 new groups: one taking antidepressant medication and another one not taking it. RESULTS 29 patients completed the 12-week trial, 58% were female and the mean age was 64.4 years old. Patients supplemented with fish oil showed a significant decrease in MADRS and CGI-Depression scores, and there was no difference among groups in BDI. 14 patients (42%) met criteria for > or = 50% reduction in MADRS score, 7 patients (22%) met criteria for remission (final MADRS total score < or = 12), and 2 patients (6%) discontinued supplementation of fish oil. HPLC analysis of fatty-acid profile showed increase of omega-3 fatty acid in the erythrocyte membrane of patients taking fish oil. CONCLUSION These results reveal that PD patients taking fish oil, with or without antidepressants, presented improvement in depressive symptoms and indicate that the intake of omega-3 can be used with an antidepressant effect or as adjuvant therapy with some other medication. This is a first pilot study with parkinsonian patients and omega-3 supplementation and requires replication in a larger sample.

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 Parkinsons Disease amnesia and is discussed in terms of the importance of the nigrostriatal pathway to memory acquisition and storage processes.

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.

Dual monoamine modulation for the antidepressant-like effect of lamotrigine in the modified forced swimming test

Lamotrigine is an anticonvulsant drug that exhibits a clinical antidepressant effect. However, few studies have been conducted with lamotrigine in animal models of depression and its mechanism of antidepressant action is still unclear. The present study evaluates the effect of lamotrigine (5-20mg/kg, i.p.) in the modified forced swimming test and compare its behavior pattern in the test with those of paroxetine (20mg/kg, i.p.), nortriptyline (20mg/kg, i.p.) and dizolcipine-MK-801 (0.1mg/kg, i.p.). The effect of lamotrigine on locomotor activity and memory was also studied in order to exclude false-positive results. At low doses, lamotrigine (10mg/kg) decreased immobility and increased climbing scores, a similar pattern to nortriptyline. A higher lamotrigine dose (20mg/kg) also increased swimming scores. Lamotrigine neither changed locomotion in the open-field test nor impaired habituation. Paroxetine and dizolcipine decreased immobility and increased swimming. Dizolcipine also decreased climbing. However, although the effects of paroxetine and nortriptyline were seen without effect on locomotor activity, dizolcipine increased locomotor activity. The present study indicates that the antidepressant-like effect of lamotrigine is probably related to noradrenergic/serotonergic systems.

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.

Evaluation of the face validity of reserpine administration as an animal model of depression--Parkinson's disease association.

The aim of the present study was to develop an animal model for the study of depressive symptoms associated with Parkinsons disease (PD). Mice treated intraperitoneally with reserpine (RES), 2.0 and 1.0 mg/kg, or its vehicle (VEHIC) were submitted to the sucrose solution (2%) consumption test (a model employed to mimic the depressive symptoms found in PD) and to the spontaneous locomotor activity test (a model employed to mimic the motor impairment found in PD). All animals were submitted to both tests. Twenty-four hours after treatment, only RES 2.0-treated animals showed a significantly decreased preference for the sucrose solution (mean +/- S.E.M. RES 2.0 = 54.4 +/- 4.1%, RES 1.0 = 68.5 +/- 2.5%, VEHIC = 62.3 +/- 4.1%). There was no significant difference among groups in water, sucrose or total fluid consumption. Locomotor activity was significantly decreased by both RES doses (number of beam interruptions: RES 2.0 = 59.9 +/- 11.4, RES 1.0 = 82.2 +/- 9.7, VEHIC = 116.8 +/- 8.2). Thus, RES 2.0 administration to mice induced depressive (anhedonia) and motor (decreased locomotor activity) symptoms of depression-PD association. This suggests that the RES model shows an important aspect of face validity for the depressive state associated with PD, i.e., phenomenological similarities between the model and the situation being modeled.

Increased oxidative stress in prefrontal cortex and hippocampus is related to depressive-like behavior in streptozotocin-diabetic rats.

Depression is a common comorbid in diabetic patients. The pathophysiologic mechanisms that relate this comorbidity is not completely elucidated yet, although several lines of evidence point out that increased oxidative stress resulting from hyperglycemia may have a crucial role. Thus, the effect of prolonged treatment with insulin (INS), the antioxidant vitamin E (VIT E) or the antidepressant imipramine (IMI) was evaluated in animals submitted to forced swimming test. Oxidative stress parameters (lipid peroxidation product levels, reduced gluthatione levels and catalase and superoxide dismutase activities) were also evaluated in brain areas related to depression, prefrontal cortex (PFC) and hippocampus (HIP). Our data show that treatment of streptozotocin-induced diabetic (DBT) rats with INS (6 UI/day, s.c.) prevented the blood glucose increase, reduced the immobility time, an antidepressant-like behavior, and normalized the reduced weight gain. Although the VIT E treatment (300 mg/kg, p.o.) had not altered the blood glucose levels, this treatment was able to reduce the immobility time and to reestablish the reduced weight gain in DBT rats. Differently, treatment with IMI (15 mg/kg, i.p.) induced antidepressant-like behavior in normoglycemic besides DBT animals. While VIT E and IMI treatments restored only specific oxidative stress parameters, INS was able to prevent all changed parameters evaluated in both PFC and HIP from DBT animals. Therefore, our data provide further evidence of the importance of oxidative stress in PFC and HIP in the pathophysiology of depression related to diabetes.

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 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.

Anxiolytic-like effect of lavender essential oil inhalation in mice: participation of serotonergic but not GABAA/benzodiazepine neurotransmission.

ETHNOPHARMACOLOGICAL RELEVANCE Lavandula angustifolia (lavender) inhalation has been used in folk medicine for the treatment of anxiety, and clinical and animal studies have corroborated its anxiolytic effect, although its mechanism of action is still not fully understood. AIMS OF THE STUDY The objective of the present study was to determine whether the GABAA/benzodiazepine complex or serotonin neurotransmission mediates the anxiolytic-like effect of lavender essential oil. MATERIALS AND METHODS Male Swiss mice were subjected to the marble-burying test after being exposed to the aroma of lavender essential oil (1-5%), amyl acetate (5%; used as a behaviorally neutral odor), or distilled water for 15 min via inhalation. Additionally, the effect of 5% lavender essential oil was also evaluated in mice subjected to the elevated plus maze. GABAA/benzodiazepine mediation was evaluated by pretreating the mice with the GABAA receptor antagonist picrotoxin before the marble burying test and [(3)H]flunitrazepam binding to the benzodiazepine site on the GABAA receptor. Serotonergic mediation was studied by pretreating the mice with O-methyl-[3H]-N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY100635), a serotonin 5-HT1A receptor antagonist before the marble burying test. We also evaluated changes in the pharmacologically induced serotonin syndrome and the effects of combined administration of subeffective doses of lavender essential oil and the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). RESULTS Lavender essential oil (1-5%) decreased the number of marbles buried compared with the control and amyl acetate groups. In the elevated plus maze, 5% lavender essential oil inhalation increased the percentage of time spent on and number of entries into the open arms compared with controls. No effect was seen in the number of closed arm entries or number of beam interruptions in the automated activity chamber. Pretreatment with the GABAA receptor antagonist picrotoxin (0.5mg/kg) did not modify the behavioral effect of 5% lavender essential oil in the marble-burying test. Lavender essential oil also did not alter [(3)H]flunitrazepam binding to the benzodiazepine site on the GABAA receptor. Pretreatment with the serotonin 5-HT1A receptor antagonist WAY100635 (3mg/kg) blocked the anxiolytic-like effect of lavender essential oil and the 5-HT1A receptor agonist 8-OH-DPAT (3mg/kg). A combination of ineffective doses of 8-OH-DPAT (0.5mg/kg) and lavender essential oil (0.1%) reduced the number of marbles buried. Finally, 5% lavender essential oil attenuated the serotonin syndrome induced by 40 mg/kg fluoxetine plus 80 mg/kg 5-hydroxytryptophan. CONCLUSIONS These results indicate an important role for the serotonergic system in the anxiolytic-like effect of lavender essential oil.