Ketamine reversed short-term memory impairment and depressive-like behavior in animal model of Parkinson's disease.

The most common features of Parkinson's disease (PD) are motor impairments, but many patients also present depression and memory impairment. Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to be effective in patients with treatment-resistant major depression. Thus, the present study evaluated the action of ketamine on memory impairment and depressive-like behavior in an animal model of PD. Male Wistar rats received a bilateral infusion of 6 µg/side 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta (SNc). Short-term memory was evaluated by the social recognition test, and depressive-like behaviors were evaluated by the sucrose preference and forced swimming tests (FST). Drug treatments included vehicle (i.p., once a week); ketamine (5, 10 and 15 mg/kg, i.p., once a week); and imipramine (20 mg/kg, i.p., daily). The treatments were administered 21 days after the SNc lesion and lasted for 28 days. The SNc lesion impaired short-term social memory, and all ketamine doses reversed the memory impairment and anhedonia (reduction of sucrose preference) induced by 6-OHDA. In the FST, 6-OHDA increased immobility, and all doses of ketamine and imipramine reversed this effect. The anti-immobility effect of ketamine was associated with an increase in swimming but not in climbing, suggesting a serotonergic effect. Ketamine and imipramine did not reverse the 6-OHDA-induced reduction in tyrosine hydroxylase immunohistochemistry in the SNc. In conclusion, ketamine reversed depressive-like behaviors and short-term memory impairment in rats with SNc bilateral lesions, indicating a promising profile for its use in PD patients.

Schizophrenia: effects of aripiprazole in metabolic syndrome

Schizophrenia, in general, is characterized by severe and disabling mental alterations, characterized by the impairment of one's mental, behavioral and social activities, developing certain clinical symptoms, relevant to the diagnosis. The drugs used for the reversion of the symptoms cause several adverse effects that affect the patient's health and well-being, such as motor, endocrine and cardiovascular damages. For a long time, little was known about the origin and the treatment of schizophrenia, which has become a curiosity for science, originating countless researches and theories that are background for several treatments. It is known that alterations in dopaminergic pathways are related to the development of the symptoms of the disease, and evaluating these symptoms, the diagnosis is made and the treatment is initiated. The insertion of new drugs with different characteristics and mechanisms tends to be an advance in the treatment of schizophrenia, as well as reducing the occurence of adverse effects or not worsening already existing cases. Aripiprazole is an innovative atypical antipsychotic employed in the pharmacotherapy of schizophrenia, which tends to attenuate the symptoms, inducing few adverse effects compared to other drugs that are already used, and promotes better quality of life to patients.

Sex-specific effects of Cacna1c haploinsufficiency on object recognition, spatial memory, and reversal learning capabilities in rats.

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.

Diazepam blocks 50 kHz ultrasonic vocalizations and stereotypies but not the increase in locomotor activity induced in rats by amphetamine.

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.

Effects of ketamine on vocal impairment, gait changes, and anhedonia induced by bilateral 6-OHDA infusion into the substantia nigra pars compacta in rats: Therapeutic implications for Parkinson's disease.

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.

Evaluation of 50-kHz ultrasonic vocalizations in animal models of mania: Ketamine and lisdexamfetamine-induced hyperlocomotion in rats.

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.

Effects of Hypericum perforatum on turning behavior in an animal model of Parkinson's disease

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the slow and progressive death of dopaminergic neurons in the (substantia nigra pars compact). Hypericum perforatum (H. perforatum) is a plant widely used as an antidepressant, that also presents antioxidant and anti-inflammatory properties. We evaluated the effects of H. perforatum on the turning behavior of rats submitted to a unilateral administration of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle as an animal model of PD. The animals were treated with H. perforatum (100, 200, or 400 mg/kg, v.o.) for 35 consecutive days (from the 28th day before surgery to the 7th day after). The turning behavior was evaluated at 7, 14 and 21 days after the surgery, and the turnings were counted as contralateral or ipsilateral to the lesion side. All tested doses significantly reduced the number of contralateral turns in all days of evaluation, suggesting a neuroprotective effect. However, they were not able to prevent the 6-OHDA-induced decrease of tyrosine hydroxylase expression in the lesioned striatum. We propose that H. perforatum may counteract the overexpression of dopamine receptors on the lesioned striatum as a possible mechanism for this effect. The present findings provide new evidence that H. perforatum may represent a promising therapeutic tool for PD.

A Doença de Parkinson é uma doença neurodegenerativa relacionada à idade, caracterizada pela morte lenta e progressiva de neurônios dopaminérgicos da substância negra pars compacta. O Hypericum perforatum (H. perforatum) é um fitoterápico utilizado como antidepressivo, apresentando propriedades antioxidantes, anti-inflamatórias e nootrópicas. Neste trabalho, avaliaram-se os efeitos do tratamento com H. perforatum no comportamento rotatório de ratos no modelo da doença de Parkinson induzido pela administração unilateral de 6-OHDA no feixe prosencefálico medial. Ratos Wistar machos foram tratados com H. perforatum (100, 200 ou 400 mg/kg, v.o.) por 35 dias (do 28º dia antes até o 7º dia após a lesão). As rotações ipsilaterais e contralaterais à lesão foram registradas no 7º, 14º e 21º dias após a cirurgia. As três doses de H. perforatum utilizadas reduziram o número de rotações contralaterais, indicando um possível efeito neuroprotetor da planta. Porém, o H. perforatum não impediu a redução na expressão da enzima tirosina hidroxilase no estriado lesionado, quantificada por Western blot. Propomos que o H. perforatum possa bloquear o aumento da expressão dos receptores dopaminérgicos no estriado lesionado com 6-OHDA. Entretanto, estudos adicionais são necessários para identificar o mecanismo exato pelo qual o H. perforatum reduziu o número de rotações contralaterais. Os resultados do presente estudo sugerem o H. perforatum como um potencial agente terapêutico para a doença de Parkinson.