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1.
Artigo em Inglês | MEDLINE | ID: mdl-31447094

RESUMO

Rats emit ultrasonic vocalizations (USVs) about 22 kHz and 50 kHz sound frequency to communicate the presence of negative or positive emotional states, respectively. The calling behavior may be influenced by several factors, including environmental factors. Likewise, pain behavior can be modulated according to the social context, and also can be transferred to conspecifics through direct observation and/or social interaction. Herein we investigated if acute pain induction was related to changes in emission of aversive and appetitive calls and how different social contexts affected the nociceptive behavior and USVs. Our results demonstrated that orofacial formalin injection in rats induced aversive calls in addition to the nociceptive behavior, and both are reduced by systemic treatment with morphine (2.5 mg/kg). Exposure of formalin-injected rats to cagemates had no effect on the nociceptive behavior or calls emitted by the demonstrator, but the observer showed emotional contagion of pain. In contrast, exposure of formalin-injected rats to non-cagemates decreased the nociceptive behavior of the demonstrator, without affecting the calls emission. The emotional contagion was not detected in non-cagemates or in cagemates separated by a visual barrier. In conclusion, we suggest that familiarity and the visual contact contributes to emotional contagion of pain. USV analysis may represent an additional measure in the evaluation of the emotional aspect of orofacial pain, and for the study of pain modulation.

2.
Pharmacol Rep ; 71(4): 556-564, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31132685

RESUMO

BACKGROUND: Peroxisome proliferator-activated receptor γ (PPAR-γ) agonists have received much attention in research because of their neuroprotective and anti-inflammatory effects that reduce cell death and halt the progression of neurodegeneration. Thus, this study observed the pioglitazone effects on the main inflammatory markers after 6-hydroxydopamine (6-OHDA) lesion. METHODS: The effects of a 5-day administration of the PPAR-γ agonist pioglitazone (30 mg/kg) in male Wistar rats that received bilateral intranigral infusions of 6-OHDA. After surgery, the rats were evaluated in the open-field test on days 1,7,14, and 21. Immediately after the behavioral tests on day 21, the rats were euthanized, and the substantia nigra was removed to analyze the expression of nuclear factor κB (NF-κB) and IκB by western blot. To immunohistochemical, animals were intracardially perfused, with brain removal that was frozen and sectioned, being selected slices of the SNc region to detect tyrosine hydroxylase (TH) immunoreactivity, microglia activation (Iba-1) and NF-κB translocation in the nucleus. RESULTS: Pioglitazone protected rats against hypolocomotion and 6-OHDA-induced dopaminergic neurodegeneration on day 7. Decreases in the microglial activation and the NF-κB expression were observed, and the p65 activation was inhibited. CONCLUSIONS: These results suggest that pioglitazone may be a potential adjuvant for the treatment of Parkinson`s disease because of its effects on pathological markers of the progression of neurodegeneration.

3.
Phytother Res ; 33(4): 901-909, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30714232

RESUMO

Citrus fragrances have been used in aromatherapy for the treatment of anxiety, and the essential oil of Citrus sinensis (sweet orange) has shown promising results, although its mechanism of action was not known. The objective of this study was to evaluate the involvement of nitric oxide (NO) neurotransmission in the anxiolytic-like effect of C. sinensis essential oil. Swiss male mice were submitted to 15 min of C. sinensis essential oil inhalation (1%, 2.5%, 5%, and 10%) and tested in the marble-burying test, neophobia-induced hypophagia, and light/dark test. Locomotor activity was evaluated in an automated locomotor activity box. The coadministration of C. sinensis essential oil with L-arginine (200 mg/kg, i.p.), an NO precursor, was used for the behavioral evaluation of nitrergic system mediation. Additionally, the NO synthase activity was measured by nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) analysis in the cerebral cortex. C. sinensis essential oil exerted anxiolytic-like effect at dose that did not change locomotor activity. Moreover, L-arginine pretreatment prevented this anxiolytic-like effect on marble-burying test. Finally, C. sinensis essential oil reduced the NADPH-d positive cells. Thus, the nitrergic neurotransmission plays a relevant role in the anxiolytic-like effect C. sinensis essential oil.


Assuntos
Ansiolíticos/farmacologia , Aromaterapia/métodos , Óleos Vegetais/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Animais , Ansiedade/tratamento farmacológico , Modelos Animais de Doenças , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos
4.
Neuropharmacology ; 144: 233-243, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30385254

RESUMO

Previous clinical and pre-clinical studies suggest the involvement of ventromedial orbitofrontal cortex (vmOFC) and glutamatergic neurotransmission in obsessive-compulsive disorder (OCD). Ketamine, an NMDA glutamatergic receptor antagonist, has shown a rapid and long-lasting antidepressant effect, but its anti-compulsive effect has been scarcely investigated. The antidepressant effect of ketamine involves NMDA receptor blockade, AMPA receptor activation, increased serotonin (5-HT) release and attenuation of nitric oxide (NO) synthesis. It is not known if these mechanisms are involved in ketamine-induced anti-compulsive effect. Therefore, we firstly investigated the effect of S-ketamine in the marble-burying test (MBT), a model for screening of drugs with potential to treat OCD. Then, we evaluated whether ketamine effects in the MBT would involve the vmOFC, be dependent on AMPA receptors, facilitation of serotonergic neurotransmission and inhibition of nitrergic pathway. Our results showed that single systemic (10 mg/kg) and intra-vmOFC (10 nmol/side) administration of S-ketamine reduces marble burying behaviour (MBB) without affecting spontaneous locomotors activity. Pre-treatment with NBQX (3 mg/kg; AMPA receptor antagonist) blocked the reduction of MBB induced by S-ketamine. However, pre-treatment with p-CPA (150 mg/kg/day; a 5-HT synthesis inhibitor), WAY100635 (3 mg/kg; a 5-HT1A receptor antagonist), or L-arginine (500 mg/kg; a nitric oxide precursor) did not counteract S-ketamine effect in the MBT. In contrast, associating sub-effective doses of L-NAME (10 mg/kg; NOS inhibitor) and S-ketamine (3 mg/kg) decreased MBB. In conclusion, the reduction of MBB by S-ketamine strengthens its possible anti-compulsive effect. The vmOFC is involved in this S-ketamine effect, which is dependent on the activation of AMPA receptors.


Assuntos
Ketamina/farmacologia , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Psicotrópicos/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo/metabolismo , Córtex Pré-Frontal/metabolismo , Distribuição Aleatória , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
5.
Artigo em Inglês | MEDLINE | ID: mdl-29981775

RESUMO

Mania is characterized by elevated drive and mood but animal models of mania have often neglected elevated mood. Ultrasonic vocalizations (USV) of 50-kHz emitted by rats are thought to index the subject's positive affective state. Fifty-kHz USV emission is increased by amphetamine, an effect blocked by lithium administration. Sleep deprivation (SD) is an environmental model of mania and the present study evaluated SD effects on behavioral activity and USV emission, together with the impact of lithium treatment. Adult rats were submitted to 24h or 72h SD, and locomotor activity and USV emission were assessed. To test their sensitivity to a standard antimanic drug, these behavioral parameters were also evaluated after acute administration of lithium carbonate (25, 50 or 100 mg/kg, i.p.). Striatal monoamine content was measured post-mortem. SD (24h and 72h) led to increased locomotor activity, rearing behavior and 50-kHz USV emission, together with a change in the call profile characterized by an increase in the percentage of frequency-modulated 50-kHz USV, which may indicate the mania-like consequences of SD. Importantly, all SD effects were reverted by lithium administration. SD also led to a decrease in dopamine content in the ventral striatum, while increasing dopamine turnover. In conclusion, SD increased 50-kHz USV emission, an effect prevented by acute lithium administration. This suggests 50-kHz USV as a new marker for mania-like elevated mood, which shows construct validity (associated with increased dopaminergic tone), face validity (reflecting increased positive affect) and predictive validity (high sensitivity to lithium treatment).


Assuntos
Transtorno Bipolar/etiologia , Privação do Sono/complicações , Vocalização Animal/fisiologia , Animais , Antimaníacos/uso terapêutico , Monoaminas Biogênicas/metabolismo , Transtorno Bipolar/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Carbonato de Lítio/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Comportamento Materno/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de Tempo , Estriado Ventral/efeitos dos fármacos , Estriado Ventral/metabolismo
6.
Rev. bras. psiquiatr ; 40(4): 449-458, Oct.-Dec. 2018. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-959255

RESUMO

Objective: Amantadine blocks N-methyl-D-aspartate (NMDA) receptors and has dopaminergic and noradrenergic action, a neurochemical profile that suggests its potential as an antidepressant drug. We conducted a systematic review of preclinical and clinical studies addressing the effects of amantadine in animal models of depression and in patients with depression. Methods: PubMed, Science Direct, and Web of Science were searched up to September 1, 2017 to identify clinical and preclinical studies. The following search terms were used: "amantadine AND depress*"; "amantadine AND mood"; "amantadine AND animal models AND antidepres*"; and "amantadine AND (forced swim, learned helplessness, reserpine, chronic mild stress, anhedonia, sucrose preference)." Results: Amantadine had antidepressant-like effects in animal models and appeared to potentiate the antidepressant effects of other antidepressants. These preclinical findings have received some support from the results of small open-label clinical trials, suggesting that amantadine can reduce depressive symptomatology and potentiate the antidepressant effects of monoaminergic drugs. In addition to its glutamatergic and dopaminergic effects, the potential antidepressant-like effects of amantadine have been linked to molecular and cellular actions, such as increased expression of neurotrophic factors (e.g., brain-derived neurotrophic factor), activation of σ1 receptors, decreased corticosterone levels, and decreased inflammatory response to stress. Conclusion: Amantadine is an interesting candidate as new antidepressant drug for the treatment of depression.

7.
Braz J Psychiatr ; 40(4): 449-458, 2018 Oct-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29898194

RESUMO

OBJECTIVE: Amantadine blocks N-methyl-D-aspartate (NMDA) receptors and has dopaminergic and noradrenergic action, a neurochemical profile that suggests its potential as an antidepressant drug. We conducted a systematic review of preclinical and clinical studies addressing the effects of amantadine in animal models of depression and in patients with depression. METHODS: PubMed, Science Direct, and Web of Science were searched up to September 1, 2017 to identify clinical and preclinical studies. The following search terms were used: "amantadine AND depress*"; "amantadine AND mood"; "amantadine AND animal models AND antidepres*"; and "amantadine AND (forced swim, learned helplessness, reserpine, chronic mild stress, anhedonia, sucrose preference)." RESULTS: Amantadine had antidepressant-like effects in animal models and appeared to potentiate the antidepressant effects of other antidepressants. These preclinical findings have received some support from the results of small open-label clinical trials, suggesting that amantadine can reduce depressive symptomatology and potentiate the antidepressant effects of monoaminergic drugs. In addition to its glutamatergic and dopaminergic effects, the potential antidepressant-like effects of amantadine have been linked to molecular and cellular actions, such as increased expression of neurotrophic factors (e.g., brain-derived neurotrophic factor), activation of σ1 receptors, decreased corticosterone levels, and decreased inflammatory response to stress. CONCLUSION: Amantadine is an interesting candidate as new antidepressant drug for the treatment of depression.


Assuntos
Amantadina/uso terapêutico , Antidepressivos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Animais , Monoaminas Biogênicas , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos
8.
Neurobiol Learn Mem ; 2018 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-29800644

RESUMO

The CACNA1C gene is strongly implicated in the etiology of multiple major neuropsychiatric disorders, such as bipolar disorder, major depression, and schizophrenia, with cognitive deficits being a common feature. It is unclear, however, by which mechanisms CACNA1C variants advance the risk of developing neuropsychiatric disorders. This study set out to investigate cognitive functioning in a newly developed genetic Cacna1c rat model. Specifically, spatial and reversal learning, as well as object recognition memory were assessed in heterozygous Cacna1c+/- rats and compared to wildtype Cacna1c+/+ littermate controls in both sexes. Our results show that both Cacna1c+/+ and Cacna1c+/- animals were able to learn the rewarded arm configuration of a radial maze over the course of seven days. Both groups also showed reversal learning patterns indicative of intact abilities. In females, genotype differences were evident in the initial spatial learning phase, with Cacna1c+/- females showing hypo-activity and fewer mixed errors. In males, a difference was found during probe trials for both learning phases, with Cacna1c+/- rats displaying better distinction between previously baited and non-baited arms; and regarding cognitive flexibility in favor of the Cacna1c+/+ animals. All experimental groups proved to be sensitive to reward magnitude and fully able to distinguish between novel and familiar objects in the novel object recognition task. Taken together, these results indicate that Cacna1c haploinsufficiency has a minor, but positive impact on (spatial) memory functions in rats.

9.
Psychopharmacology (Berl) ; 235(7): 1887-1896, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29572651

RESUMO

RATIONALE: We have recently shown that the benzodiazepine diazepam inhibits dopamine release in the NAc and blocks the increased release of dopamine induced by DL-amphetamine. Rewarding stimuli and many drugs of abuse can induce dopamine release in the nucleus accumbens as well as 50-kHz ultrasonic vocalizations (USVs) in rats. OBJECTIVES: In the present study, we tested the hypothesis that diazepam can also block the increase in locomotor activity and USVs elicited by amphetamine. METHODS: Fifty-kilohertz USVs, stereotypy, and locomotor behavior were scored in adult male Wistar rats treated with i.p. injections of saline, 3 mg/kg DL-amphetamine, 2 mg/kg diazepam, 0.2 mg/kg haloperidol, or a combination of these drugs. RESULTS: In agreement with previous studies, amphetamine caused significant increases in the number of USV calls, stereotypies, and locomotor activity. The D2 dopamine receptor antagonist haloperidol blocked the effects of amphetamine on USVs, stereotypy, and locomotor activity. Diazepam blocked the effect of amphetamine on USV and stereotypy, but not on horizontal locomotion. CONCLUSIONS: These results suggest that diazepam blocks the rewarding effect of amphetamine. This finding is promising for basic research regarding treatments of substance use disorders and evaluation of the impact of benzodiazepines on motivation.

10.
Physiol Behav ; 188: 298-310, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29458117

RESUMO

Parkinson's disease (PD) patients often suffer from circadian locomotor rhythms impairment and depression, important non-motor symptoms. It is known that toxin-based animal models of PD can reproduce these features. In a 6-hydroxydopamine (6-OHDA) intranigral model, we first investigated the possible disturbances on circadian rhythms of locomotor activity. The rats were divided into 6-OHDA and Sham groups. After a partial dopaminergic lesion, the 6-OHDA group showed slight alterations in different circadian locomotor rhythms parameters. In a second experiment, we hypothesized agomelatine, an melatoninergic antidepressant with potential to resynchronize disturbed rhythms, could prevent neuronal damage and rhythm alterations in the same 6-OHDA model. The animals were divided into four groups: 6-OHDA+vehicle, 6-OHDA+ago, Sham+vehicle and 6-OHDA+ago. However, the treated animals (agomelatine 50 mg/kg for 22 days) showed an impaired rhythm robustness, and agomelatine did not induce significant changes in the other circadian parameters nor neuroprotection. Finally, in a third experiment, we examined the effects of agomelatine in the 6-OHDA model regarding depressive-like behavior, evaluated by sucrose preference test. The animals were also divided into four groups: 6-OHDA+vehicle, 6-OHDA+ago, Sham+vehicle and 6-OHDA+ago. The toxin infused animals showed a decrease in sucrose preference in comparison with the vehicle infused animals, however, agomelatine did not prevent this decrease. Our findings indicate that agomelatine worsened circadian locomotor rhythm and was not able to reverse the depressive-like behavior of rats in the 6-OHDA PD model.

11.
Behav Brain Res ; 342: 1-10, 2018 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-29307665

RESUMO

Parkinson's disease is a chronic neurodegenerative disorder characterized by cardinal motor features, such as bradykinesia, but also vocal deficits (e.g. difficulties to articulate words and to keep the tone of voice) and depression. In the present study, rats with bilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta were evaluated for changes in the emission of 50-kHz ultrasonic vocalizations, gait impairment (catwalk test), and depressive-like behaviour (sucrose preference test). Furthermore, we evaluated the effect of repeated treatment (28 days) with ketamine (5, 10, and 15 mg/kg, ip, once per week) or imipramine (15 mg/kg, ip, daily). The lesion had prominent effects on the production of 50-kHz ultrasonic vocalizations (reduced call numbers, call durations, total calling time, and increased latency to start calling), led to gait impairment (increased run duration and stand of right forelimb) and induced anhedonia (reduced sucrose preference). Also, significant correlations between gait changes, sucrose preference, and ultrasonic calling were found, yet, except for run duration and sucrose preference, these correlations were low indicating that these associations are weak. Importantly, ketamine and imipramine reversed lesion-induced anhedonia and improved gait impairments, but neither drug improved ultrasonic calling. In conclusion, the substantia nigra lesion with 6-hydroxydopamine induced subtle motor and non-motor manifestations, reflecting key features of the wide clinical spectrum of early Parkinson's disease. Furthermore, the present results suggest a potential efficacy of ketamine on depression and gait alterations in Parkinson's disease.


Assuntos
Anedonia/efeitos dos fármacos , Marcha/efeitos dos fármacos , Ketamina/farmacologia , Vocalização Animal/efeitos dos fármacos , Animais , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Imipramina/farmacologia , Masculino , Degeneração Neural/patologia , Oxidopamina/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Parte Compacta da Substância Negra/efeitos dos fármacos , Ratos , Ratos Wistar , Substância Negra/efeitos dos fármacos
12.
Int J Biol Macromol ; 109: 1147-1153, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29157904

RESUMO

A fraction composed of an arabinan-rich pectin was extracted from acerola fruit (Malpighia emarginata) and named ACWS. This fraction presented 93% of total carbohydrate, relative molecular weight of 7.5×104g/mol, galacturonic acid, arabinose, galactose, xylose and rhamnose in 52.1:32.4:7.2:4.8:3.5 molar ratio and had its structure confirmed by NMR analysis. The anti-fatigue activity of ACWS was evaluated using the weight load swim test on trained mice. ACWS was orally administered at doses of 50mg/kg, 100mg/kg and 200mg/kg for 28days. Plasma biochemical parameters, respiration of permeabilized skeletal muscle fibers, and GSH levels and lipoperoxidation in the brain (pre-frontal cortex, hippocampus, striatum and hypothalamus) were determined. ACWS could lengthen the swimming time, increase the plasma levels of glucose, triglycerides, lactate, and the GSH levels in the hippocampus at all tested doses. The mitochondrial respiratory capacity of the skeletal muscle was increased at middle and high ACWS doses. This study provides strong evidence that M. emarginata pectic polysaccharide supplementation has anti-fatigue activity, can modify the kinetics of energy substrates (carbohydrate and fat) mobilization and the respiratory capacity of the skeletal muscle, as well the antioxidant status in the hippocampus of ACWS treated animals.


Assuntos
Malpighiaceae/química , Pectinas/química , Pectinas/farmacologia , Polissacarídeos/química , Animais , Biomarcadores , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Respiração Celular/efeitos dos fármacos , Frutas/química , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Músculos/efeitos dos fármacos , Músculos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/farmacologia , Espécies Reativas de Oxigênio/metabolismo
13.
Neuropharmacology ; 125: 220-230, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28754373

RESUMO

Pharmacological interventions able to modulate a fear memory while it is consolidated could have therapeutic value in tempering those maladaptively overconsolidated. Animal and human studies have shown the intensity of unconditioned stimulus delivered during fear conditioning influences qualitative and quantitative aspects of the memory to be established. By varying the shock intensity used for contextual pairing in rats, here we induced specific and more generalized long-term fear memories to investigate whether, how and where in the brain the cannabidiol (CBD; 3.0-30 mg/kg i.p.) could impair their consolidation and related outcomes. When given immediately after their acquisition, it reduced respectively the conditioned fear expression, and fear generalization, ultrasonic vocalizations at 22-kHz and the relative resistance to extinction. CBD had no effects on short-term fear memory, and its delayed treatment no longer affected the consolidation process. As the dorsal hippocampus (DH) modulates fear memory specificity and generalization, and cannabinoid type-1 (CB1) and type-2 (CB2) receptors contribute to consolidation, we investigated their involvement in CBD effects. Both systemic and intra-DH treatment with the CB1 receptor antagonist/inverse agonist AM251 or the CB2 receptor antagonist/inverse agonist AM630 prevented the disrupting CBD effects on consolidation. Since the CBD effects on the endocannabinoid transmission are probably indirect, we investigated and demonstrated the FAAH inhibitor URB597 induced effects similar to those of CBD when given systemically or intra-DH. Altogether, the present results suggest the CBD disrupts the consolidation of different fear memories via anandamide-mediated activation of DH CB1 and CB2 receptors.


Assuntos
Canabidiol/farmacologia , Moduladores de Receptores de Canabinoides/farmacologia , Medo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , Psicotrópicos/farmacologia , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Animais , Ácidos Araquidônicos/metabolismo , Benzamidas/farmacologia , Carbamatos/farmacologia , Endocanabinoides/metabolismo , Inibidores Enzimáticos/farmacologia , Medo/fisiologia , Hipocampo/metabolismo , Indóis/farmacologia , Masculino , Consolidação da Memória/fisiologia , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/metabolismo , Pirazóis/farmacologia , Distribuição Aleatória , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismo
14.
Behav Brain Res ; 326: 173-186, 2017 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-28284945

RESUMO

There is an urgent need to understand the pathophysiological mechanisms related to anxiety associated with diabetes, seeking more effective alternative treatments to treat it. For that, the effect of a preventive and prolonged treatment with fish oil (FO), a source of omega-3 polyunsaturated fatty acid, was tested in streptozotocin-diabetic (DBT) rats submitted to the anxiety tests. Additionally, an immunohistochemistry for neuronal NO synthase (nNOS) was performed in brain areas related to anxiety, such as lateral amygdala (AMY), hippocampus (HIP) and dorsolateral periaqueductal gray (dlPAG). Lastly, the effect of NO precursor L-arginine (L-Arg) or nNOS inhibitor 7-nitroindazole (7-NI) was tested in DBT animals treated with vehicle (VEH) or FO. Our data demonstrated that vehicle-treated DBT animals exhibited a more pronounced anxiogenic-like response and also presented high nNOS levels in the AMY, HIP and rostral dlPAG, what were both significantly prevented by FO treatment. This treatment was able to prevent the impairment in locomotor activity besides improving the high glycemic levels in DBT rats. Interestingly, while injection of 7-NI or L-Arg in VEH-treated DBT animals induced an anxiogenic-like and anxiolytic-like effect, respectively; the previous treatment with both L-Arg and 7-NI in FO-DBT animals abolished the anxiolytic-like effect induced by FO treatment. Altogether, our data support the hypothesis that a dysregulation in the NO production in brain areas as AMY, HIP and dlPAG may contribute to the mechanisms that link anxiety and diabetes, and the prevention of nNOS brain expression changes induced by a prolonged treatment with FO may be an important mechanism related to its anxiolytic-like effect.


Assuntos
Tonsila do Cerebelo/metabolismo , Ansiedade/metabolismo , Ansiedade/prevenção & controle , Diabetes Mellitus Experimental/metabolismo , Óleos de Peixe/farmacologia , Hipocampo/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico/metabolismo , Substância Cinzenta Periaquedutal/metabolismo , Animais , Arginina/farmacologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Óleos de Peixe/administração & dosagem , Indazóis/farmacologia , Masculino , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Ratos , Ratos Wistar , Estreptozocina/farmacologia
15.
Sci Rep ; 7: 40399, 2017 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-28071711

RESUMO

Industrialisation greatly increased human night-time exposure to artificial light, which in animal models is a known cause of depressive phenotypes. Whilst many of these phenotypes are 'direct' effects of light on affect, an 'indirect' pathway via altered sleep-wake timing has been suggested. We have previously shown that the Period3 gene, which forms part of the biological clock, is associated with altered sleep-wake patterns in response to light. Here, we show that both wild-type and Per3-/- mice showed elevated levels of circulating corticosterone and increased hippocampal Bdnf expression after 3 weeks of exposure to dim light at night, but only mice deficient for the PERIOD3 protein (Per3-/-) exhibited a transient anhedonia-like phenotype, observed as reduced sucrose preference, in weeks 2-3 of dim light at night, whereas WT mice did not. Per3-/- mice also exhibited a significantly smaller delay in behavioural timing than WT mice during weeks 1, 2 and 4 of dim light at night exposure. When treated with imipramine, neither Per3-/- nor WT mice exhibited an anhedonia-like phenotype, and neither genotypes exhibited a delay in behavioural timing in responses to dLAN. While the association between both Per3-/- phenotypes remains unclear, both are alleviated by imipramine treatment during dim night-time light.


Assuntos
Relógios Circadianos/genética , Ritmo Circadiano/genética , Proteínas Circadianas Period/genética , Transtornos do Sono-Vigília/tratamento farmacológico , Anedonia/efeitos dos fármacos , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Ritmo Circadiano/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiologia , Humanos , Imipramina/administração & dosagem , Camundongos , Camundongos Knockout , Atividade Motora/genética , Atividade Motora/fisiologia , Fotoperíodo , Sono/genética , Sono/fisiologia , Transtornos do Sono-Vigília/genética , Transtornos do Sono-Vigília/fisiopatologia
16.
Life Sci ; 171: 1-8, 2017 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-28104366

RESUMO

AIMS: Increases in protein kinase C (PKC) and oxidative stress have been related to mania. Drugs with antioxidant effects or inhibitory actions on PKC may have antimanic effects. The flavonoid quercetin has antioxidant and PKC-inhibiting effects that resemble those of lithium, the first-line treatment for mania in bipolar disorder. We hypothesized that quercetin may have antimanic-like effects in an animal model. MAIN METHODS: In the present study, we investigated the effects of acute and chronic treatment with quercetin (2.5, 5, 10, and 40mg/kg, i.p.) in male Swiss mice that were subjected to methylphenidate (5mg/kg, i.p.)-induced hyperlocomotion, an animal model of mania. Lithium (100mg/kg, i.p.) and diazepam (5mg/kg, i.p.) were used as positive and negative controls, respectively. We also evaluated the effects of these treatments on methylphenidate-induced oxidative stress in the brain by measuring reduced glutathione (GSH) and lipid peroxidation (LPO) levels in the prefrontal cortex, hippocampus, and striatum. KEY FINDINGS: Acute and chronic (21-day) treatment with lithium and diazepam reduced methylphenidate-induced hyperlocomotion. Chronic but not acute treatment with quercetin (10 and 40mg/kg) blocked methylphenidate-induced hyperlocomotion. These effects of lithium and quercetin occurred at doses that did not alter spontaneous locomotor activity, whereas diazepam reduced spontaneous locomotor activity. Chronic treatment with lithium and quercetin blocked the methylphenidate-induced increase in LPO levels in the striatum. SIGNIFICANCE: These results suggest that chronic quercetin treatment has antimanic-like and antioxidant effects, thus encouraging further studies of quercetin as a putative new antimanic drug.


Assuntos
Locomoção/efeitos dos fármacos , Metilfenidato/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Quercetina/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos
17.
Behav Brain Res ; 316: 59-65, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27569185

RESUMO

Myricitrin (MYR) is a natural flavonoid that inhibits nitric oxide (NO) transmission and has an atypical antipsychotic-like profile in animal models. Considering that several NO inhibitors exert antidepressant-like effects, the present study evaluated the antidepressant-like effect of MYR (3-30mg/kg) in the tail suspension test (TST). Because of the putative relationship between adult neurogenesis and antidepressant activity, we also assessed cell proliferation, survival, and differentiation in adult neurogenic niches, including the subgranular zone (SGZ) and subventricular zone (SVZ). Similar to the positive control imipramine (IMI; 10mg/kg), repeated treatment with 10mg/kg MIR but not acute treatment reduced immobility time in the TST, indicating an antidepressant-like effect. No effect on general motor activity was observed. Myricitrin also facilitated cell proliferation in the SGZ of the hippocampal dentate gyrus and SVZ. In the SGZ, MYR increased the number of doublecortin- and 5-bromo-2'-deoxyuridine/neuronal nuclei-positive cells. Our results suggest that MYR facilitates hippocampal neurogenesis, which might contribute to its antidepressant-like effect and atypical antipsychotic-like profile.


Assuntos
Antidepressivos/farmacologia , Giro Denteado/efeitos dos fármacos , Flavonoides/farmacologia , Neurogênese/efeitos dos fármacos , Animais , Bromodesoxiuridina/metabolismo , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Elevação dos Membros Posteriores , Antígeno Ki-67/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Associadas aos Microtúbulos/metabolismo , Neuropeptídeos/metabolismo , Fosfopiruvato Hidratase/metabolismo
18.
Eur Neuropsychopharmacol ; 26(12): 1900-1908, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27842942

RESUMO

Drug-induced hyperlocomotion in rodents is frequently used as a behavioral model for mania. However, the use of locomotor activity as the single parameter in these animal models of mania may pose some limitations for developing new pharmacological treatments. Thus, alternative behavioral markers are required. Fifty-kHz ultrasonic vocalizations (USV), which are thought to represent positive affect, are increased by the administration of the psychostimulant d-amphetamine, an effect that can be prevented by lithium treatment, the gold standard antimanic drug for treating bipolar disorder. The aim of this study was to evaluate 50-kHz USV in two other pharmacological-induced animal models of mania: ketamine (KET)- and lisdexamfetamine (LDX)-induced hyperlocomotion. After systemic injection of LDX (10mg/kg, ip), racemic-ketamine (25mg/kg, ip) or S-ketamine (25mg/kg, ip), locomotor activity and 50-kHz USV emission were evaluated in rats. Furthermore, the effects of an antimanic treatment, namely lithium carbonate (100mg/kg, ip), on LDX-induced 50-kHz USV and hyperlocomotion were tested. Rats treated with racemic KET and S-KET showed increased locomotor activity, but these drug treatments did not significantly affect 50-kHz USV emission rates. On the other hand, LDX administration increased both locomotor activity and 50-kHz USV with both effects being reversed by lithium administration. The present findings suggest that 50-kHz USV can differentiate between drug-induced models of mania, which may represent different types of manic episodes. Thus, measuring 50-kHz USV might serve as an additional valuable behavioral variable to assess mania-like phenotypes in rat models.


Assuntos
Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Ketamina/farmacologia , Dimesilato de Lisdexanfetamina/farmacologia , Vocalização Animal/efeitos dos fármacos , Animais , Antimaníacos/farmacologia , Antimaníacos/uso terapêutico , Transtorno Bipolar/psicologia , Modelos Animais de Doenças , Hipercinese/psicologia , Carbonato de Lítio/farmacologia , Carbonato de Lítio/uso terapêutico , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar
19.
Free Radic Biol Med ; 99: 79-86, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27475725

RESUMO

Quercetin is a known antioxidant and protein kinase C (PKC) inhibitor. Previous studies have shown that mania involves oxidative stress and an increase in PKC activity. We hypothesized that quercetin affects manic symptoms. In the present study, manic-like behavior (hyperlocomotion) and oxidative stress were induced by 24h paradoxical sleep deprivation (PSD) in male Swiss mice. Both 10 and 40mg/kg quercetin prevented PSD-induced hyperlocomotion. Quercetin reversed the PSD-induced decrease in glutathione (GSH) levels in the prefrontal cortex (PFC) and striatum. Quercetin also reversed the PSD-induced increase in lipid peroxidation (LPO) in the PFC, hippocampus, and striatum. Pearson's correlation analysis revealed a negative correlation between locomotor activity and GSH in the PFC in sleep-deprived mice and a positive correlation between locomotor activity and LPO in the PFC and striatum in sleep-deprived mice. These results suggest that quercetin exerts an antimanic-like effect at doses that do not impair spontaneous locomotor activity, and the antioxidant action of quercetin might contribute to its antimanic-like effects.


Assuntos
Antimaníacos/farmacologia , Antioxidantes/farmacologia , Transtorno Bipolar/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Agitação Psicomotora/tratamento farmacológico , Quercetina/farmacologia , Animais , Transtorno Bipolar/etiologia , Transtorno Bipolar/metabolismo , Transtorno Bipolar/fisiopatologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Esquema de Medicação , Glutationa/agonistas , Glutationa/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Agitação Psicomotora/etiologia , Agitação Psicomotora/metabolismo , Agitação Psicomotora/fisiopatologia , Privação do Sono/complicações , Privação do Sono/metabolismo , Privação do Sono/fisiopatologia
20.
Eur Neuropsychopharmacol ; 26(10): 1601-9, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27554635

RESUMO

The mechanisms underpinning the persistence of emotional memories are inaccurately understood. Advancing the current level of understanding with regards to this aspect is of potential translational value for the treatment of post-traumatic stress disorder (PTSD), which stems from an abnormal aversive memory formation. Tamoxifen (TMX) is a drug used in chemotherapy for breast cancer and associated with poor cognitive performances. The present study investigated whether the systemic administration of TMX (1.0-50mg/kg) during and/or beyond the reconsolidation time-window could attenuate a reactivated contextual fear memory in laboratory animals. When administered 0, 6 or 9h (but not 12h) post-memory retrieval and reactivation, TMX (50mg/kg) reduced the freezing behavior in male rats re-exposed to the paired context on day 7, but not on day 1, suggesting a specific impairing effect on memory persistence. Importantly, this effect lasts up to 21 days, but it is prevented by omitting the memory retrieval or memory reactivation. When female rats in the diestrous or proestrous phase were used, the administration of TMX 6h after retrieving and reactivating the fear memory also impaired its persistence. Altogether, regardless of the gender, the present results indicate that the TMX is able to disrupt the persistence of reactivated fear memories in an expanded time-window, which could shed light on a new promising therapeutic strategy for PTSD.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Medo/psicologia , Tamoxifeno/efeitos adversos , Animais , Condicionamento (Psicologia)/efeitos dos fármacos , Ciclo Estral/fisiologia , Feminino , Masculino , Memória/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Ratos , Ratos Wistar , Caracteres Sexuais , Fatores de Tempo
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