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Introduction It is well known that Parkinson’s disease is related to a deficit of dopamine (DA) in the region of the brain called the corpus striatum. The aim of this work is to demonstrate the possibility of in vitro closed-loop control of the DA concentration levels. Methods By applying the electrochemical technique of fast scan cyclic voltammetry (FSCV), the measured values were compared with previously selected ones, and the system made decisions to control infusion pumps by dynamically adjusting the DA concentration in a continuous flow injection cell. Low-cost hardware was used for the acquisition and control signals (Arduino board), whereas for processing the collected data, graphical programming software (LabView) was used. Results The resolution of the system was approximately 0.4 µmol/L, with a time correction of the concentration adjustable between 1 and 90 seconds. The system allowed control of the DA concentration between 1 and 10 µmol/L with an error of approximately +/– 0.8 µmol/L. Conclusion Although designed to control the DA concentration, the system could be used to control, within the range of the developed FSCV, the concentration of other substances or to turn on brain stimulators. These results encourage the possibility of using the system in clinical studies (in vivo).
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Currently, several studies addresses the novel link between sleep and dopaminergic neurotransmission, focusing most closely on the mechanisms by which Parkinson's disease (PD) and sleep may be intertwined. Therefore, variations in the activity of afferents during the sleep cycles, either at the level of DA cell bodies in the ventral tegmental area (VTA) and/or substantia nigra pars compacta (SNpc) or at the level of dopamine (DA) terminals in limbic areas may impact functions such as memory. Accordingly, we performed striatal and hippocampal neurochemical quantifications of DA, serotonin (5-HT) and metabolites of rats intraperitoneally treated with haloperidol (1.5 mg/kg) or piribedil (8 mg/kg) and submitted to REM sleep deprivation (REMSD) and sleep rebound (REB). Also, we evaluated the effects of REMSD on motor and cognitive parameters and SNpc c-Fos neuronal immunoreactivity. The results indicated that DA release was strongly enhanced by piribedil in the REMSD group. In opposite, haloperidol prevented that alteration. A c-Fos activation characteristic of REMSD was affected in a synergic manner by piribedil, indicating a strong positive correlation between striatal DA levels and nigral c-Fos activation. Hence, we suggest that memory process is severely impacted by both D2 blockade and REMSD and was even more by its combination. Conversely, the activation of D2 receptor counteracted such memory impairment. Therefore, the present evidence reinforce that the D2 receptor is a key player in the SNpc neuronal activation mediated by REMSD, as a consequence these changes may have direct impact for cognitive and sleep abnormalities found in patients with PD. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.
Assuntos
Neurônios/fisiologia , Receptores de Dopamina D2/fisiologia , Privação do Sono/fisiopatologia , Substância Negra/citologia , Substância Negra/fisiologia , Animais , Corpo Estriado/metabolismo , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Neuroimagem Funcional , Haloperidol/farmacologia , Hipocampo/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Piribedil/farmacologia , Ratos , Receptores de Dopamina D2/agonistas , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Serotonina , Privação do Sono/metabolismo , Substância Negra/efeitos dos fármacosRESUMO
The recently described intranigral rotenone model of Parkinson's disease (PD) in rodents provides an interesting model for studying mechanisms of toxin-induced dopaminergic neuronal injury. The relevance of this model remains unexplored with regard to sleep disorders that occur in PD. On this basis, the construction of a PD model depicting several behavioral and neurochemical alterations related to sleep would be helpful in understanding the association between PD and sleep regulation. We performed bilateral intranigral injections of rotenone (12 µg) on day 0 and the open-field test initially on day 20 after rotenone. Acquisition phase of the object-recognition test, executed also during day 20, was followed by an exact period of 24 hr of rapid eye movement (REM) sleep deprivation (REMSD; day 21). In the subsequent day (22), the rats were re-exposed to the open-field test and to the object-recognition test (choice phase). After the last session of behavioral tests, the rat brains were immediately dissected, and their striata were collected for neurochemical purposes. We observed that a brief exposure to REMSD was able to impair drastically the object-recognition test, similarly to a nigrostriatal lesion promoted by intranigral rotenone. However, the combination of REMSD and rotenone surprisingly did not inflict memory impairment, concomitant with a moderate compensatory mechanism mediated by striatal dopamine release. In addition, we demonstrated the existence of changes in serotonin and noradrenaline neurotransmissions within the striatum mostly as a function of REMSD and REMSD plus rotenone, respectively.
Assuntos
Comportamento Animal/fisiologia , Corpo Estriado/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Privação do Sono/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Cognição , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Injeções Intraventriculares , Aprendizagem/fisiologia , Masculino , Memória/fisiologia , Transtornos Parkinsonianos/metabolismo , Ratos , Ratos Wistar , Rotenona/administração & dosagem , Rotenona/toxicidade , Privação do Sono/metabolismo , Desacopladores/administração & dosagem , Desacopladores/toxicidadeRESUMO
Inflammation in Parkinson's disease (PD) is a continuous process and might be implicated in the progression of neuronal degeneration. Taking this into account, we proposed a new protocol with multiple and consecutive intranigral lipopolysaccharide (LPS) administration in order to analyze its effects on cognitive behavior. Additionally, striatal concentrations of the neurotransmitters dopamine (DA) and serotonin and their respective metabolites were assessed in three different time-points with the purpose of identifying the consecutive and cumulative effects of LPS infusions. We demonstrated that with a minimum administered dose there was stabilization of neuronal damage as revealed by absence of synergic effect on DA concentration. Although the DA decrease (-43%) generates an animal model of early phase of PD, without apparent motor impairment, the LPS group exhibited deficit in episodic-like memory behavior from the first time-point until the last one, indicating persisted disturbances in memory-recognition responses. These findings provide evidence that multiple intranigral LPS infusions are not sufficient to cause cumulative and progressive damage to dopaminergic neurons, but confirm that the LPS model can be adopted as a useful tool providing insight about the cognitive impairment observed in pre-motor phase of PD.
Assuntos
Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/metabolismo , Cognição/efeitos dos fármacos , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Substância Negra/efeitos dos fármacos , Animais , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Lipopolissacarídeos/administração & dosagem , Masculino , Microinjeções , Atividade Motora/efeitos dos fármacos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/metabolismo , Ratos , Reconhecimento Psicológico/efeitos dos fármacos , Serotonina/metabolismoRESUMO
We conducted an experiment in which hedonia, salience and prediction error hypotheses predicted different patterns of dopamine (DA) release in the striatum during learning of conditioned avoidance responses (CARs). The data strongly favor the latter hypothesis. It predicts that during learning of the 2-way active avoidance CAR task, positive prediction errors generated when rats do not receive an anticipated footshock (which is better than expected) cause DA release that reinforces the instrumental avoidance action. In vivo microdialysis in the rat striatum showed that extracellular DA concentration increased during early CAR learning and decreased throughout training returning to baseline once the response was well learned. In addition, avoidance learning was proportional to the degree of DA release. Critically, exposure of rats to the same stimuli but in an unpredictable, unavoidable, and inescapable manner, did not produce alterations from baseline DA levels as predicted by the prediction error but not hedonic or salience hypotheses. In addition, rats with a partial lesion of substantia nigra DA neurons, which did not show increased DA levels during learning, failed to learn this task. These data represent clear and unambiguous evidence that it was the factor positive prediction error, and not hedonia or salience, which caused increase in the tonic level of striatal DA and which reinforced learning of the instrumental avoidance response.
Assuntos
Aprendizagem da Esquiva/fisiologia , Condicionamento Operante/fisiologia , Corpo Estriado/metabolismo , Dopamina/metabolismo , Animais , Eletrochoque , Masculino , Microdiálise , Neurônios/metabolismo , Ratos , Ratos WistarRESUMO
Monoamine oxidase (MAO) inhibitors were the first antidepressant drugs to be prescribed and are still used today with great success, especially in patients resistant to other antidepressants. In this study, we evaluated the MAO inhibitory properties and the potential antidepressant action of 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in mice. We found that 2-DMPI inhibited both MAO isoforms (K(i) values were 1.53 (1.3-1.8) µM and 46.67 (31.8-68.4) µM for MAO-A and MAO-B, respectively) with 30-fold higher selectivity toward MAO-A. In relation to the nature of MAO-A inhibition, 2-DMPI showed to be a mixed and reversible inhibitor. The treatment with 2-DMPI (100-1000 µmol/kg, s.c.) caused a significant decrease in immobility time in the tail suspension test (TST) without affecting locomotor activity, motor coordination or anxiety-related activities. Conversely, moclobemide (1000 µmol/kg, s.c.) caused a significant increase in immobility time in the TST, which appeared to be mediated by a nonspecific effect on motor coordination function. 2-DMPI (300 µmol/kg, s.c.) decreased serotonin turnover in the cerebral cortex, hippocampus and striatum, whereas dopamine turnover was diminished only in the striatum, and norepinephrine turnover was not changed. The antidepressant-like effect of 2-DMPI was inhibited by the pretreatment of mice with methysergide (2 mg/kg, s.c., a non-selective serotonin receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) or haloperidol (0.05 mg/kg, i.p., a non-selective dopamine receptor antagonist). These results suggest that 2-DMPI is a prototype reversible and preferential MAO-A inhibitor with potential antidepressant activity, due to its modulatory effect on serotonergic and dopaminergic systems.
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Anisóis/farmacologia , Antidepressivos/farmacologia , Monoaminas Biogênicas/metabolismo , Depressão/metabolismo , Imidazolinas/farmacologia , Isoenzimas/antagonistas & inibidores , Inibidores da Monoaminoxidase/farmacologia , Animais , Anisóis/antagonistas & inibidores , Anisóis/uso terapêutico , Antidepressivos/antagonistas & inibidores , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Haloperidol/farmacologia , Imidazolinas/antagonistas & inibidores , Imidazolinas/uso terapêutico , Cinética , Masculino , Metisergida/farmacologia , Camundongos , Moclobemida/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Piperazinas/farmacologia , Piridinas/farmacologiaRESUMO
Rotenone exposure in rodents provides an interesting model for studying mechanisms of toxin-induced dopaminergic neuronal injury. However, several aspects remain unclear regarding the effects and the accuracy of rotenone as an animal model of Parkinson's disease (PD). In order to counteract these limitations, this study characterized a precise neurotoxin-delivery strategy employing the bilateral intranigral administration protocol of rotenone as a reliable model of PD. We performed bilateral intranigral injections of rotenone (12 µg) and subsequent general activity (1, 10, 20, and 30 days after rotenone) and cognitive (7, 8, 15, and 30 days after rotenone) evaluations followed by neurochemical and immunohistochemical tests. We have observed that rotenone was able to produce a remarkable reduction on the percentage of tyrosine hydroxylase immunoreactive neurons (about 60%) within the substantia nigra pars compacta. Dopamine (DA) was severely depleted at 30 days after rotenone administration, similarly to its metabolites. In addition, an increase in DA turnover was detected at the same time-point. In parallel, striatal serotonin and its metabolite were found to be increased 30 days after the neurotoxic insult, without apparent modification in the serotonin turnover. Besides, motor behavior was impaired, mainly 1 day after rotenone. Furthermore, learning and memory processes were severely disrupted in different time-points, particularly at the training and test session (30 days). We now provide further evidence of a time-dependent neurodegeneration associated to cognitive impairment after the single bilateral intranigral administration of rotenone. Thus, it is proposed that the current rotenone protocol provides an improvement regarding the existing rotenone models of PD.
Assuntos
Degeneração Neural/induzido quimicamente , Transtornos Parkinsonianos/induzido quimicamente , Rotenona/toxicidade , Substância Negra/efeitos dos fármacos , Desacopladores/toxicidade , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Comportamento Exploratório/efeitos dos fármacos , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Microinjeções/métodos , Atividade Motora/efeitos dos fármacos , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologia , Ratos , Ratos Wistar , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/metabolismo , Neurônios Serotoninérgicos/patologia , Serotonina/metabolismo , Substância Negra/metabolismo , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Previous studies suggest that sodium fluoride (NaF) can impair performance in some memory tasks, such as open-field habituation and two-way active avoidance. In the present study, we evaluated the effect of NaF intake (100 ppm in drinking water for 30 days) and its short-term (15 days) withdrawal on open-field habituation and brain monoamine level. Adult male rats were allocated to three groups: tap water (NaF 1.54 ppm) for 45 days (control group); 15 days of tap water followed by NaF for 30 days; and NaF for 30 days followed by 15 days of tap water. The results showed that NaF impairs open-field habituation and increases noradrenaline (NA) and serotonin (5-HT) in the striatum, hippocampus and neocortex. Dopamine (DA) increase was restricted to the striatum. Short-term NaF withdrawal did not reverse these NaF-induced changes, and both NaF treatments led to a mild fluorosis in rat incisors. No treatment effect was seen in body weight or fluid/water consumption. These results indicate that sodium fluoride induces memory impairment that outlasts short-term NaF withdrawal (2 weeks) and may be associated with NA and 5-HT increases in discrete brain regions.
Assuntos
Encéfalo/metabolismo , Dopamina/metabolismo , Transtornos da Memória/metabolismo , Norepinefrina/metabolismo , Serotonina/metabolismo , Fluoreto de Sódio/toxicidade , Animais , Monoaminas Biogênicas/metabolismo , Encéfalo/efeitos dos fármacos , Masculino , Transtornos da Memória/induzido quimicamente , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
The pedunculopontine tegmental nucleus (PPTg) targets nuclei in the basal ganglia, including the substantia nigra pars compacta (SNc), in which neuronal loss occurs in Parkinson's disease, a condition in which patients show cognitive as well as motor disturbances. Partial loss and functional abnormalities of neurons in the PPTg are also associated with Parkinson's disease. We hypothesized that the interaction of PPTg and SNc might be important for cognitive impairments and so investigated whether disrupting the connections between the PPTg and SNc impaired learning of a conditioned avoidance response (CAR) by male Wistar rats. The following groups were tested: PPTg unilateral; SNc unilateral; PPTg-SNc ipsilateral (ipsilateral lesions in PPTg and SNc); PPTg-SNc contralateral (contralateral lesions in PPTg and SNc); sham lesions (of each type). SNc lesions were made with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine HCl (MPTP, 0.6micromol); PPTg lesions with ibotenate (24nmol). After recovery, all rats underwent 50-trial sessions of 2-way active avoidance conditioning for 3 consecutive days. Rats with unilateral lesions in PPTg or SNc learnt this, however rats with contralateral (but not ipsilateral) combined lesions in both structures presented no sign of learning. This effect was not likely to be due to sensorimotor impairment because lesions did not affect reaction time to the tone or footshock during conditioning. However, an increased number of non-responses were observed in the rats with contralateral lesions. The results support the hypothesis that a functional interaction between PPTg and SNc is needed for CAR learning and performance.
Assuntos
Aprendizagem da Esquiva/fisiologia , Condicionamento Clássico/fisiologia , Vias Neurais/citologia , Núcleo Tegmental Pedunculopontino/citologia , Substância Negra/citologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Análise de Variância , Animais , Dopamina/metabolismo , Lateralidade Funcional/fisiologia , Ácido Ibotênico/farmacologia , Masculino , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Neurotoxinas/farmacologia , Núcleo Tegmental Pedunculopontino/efeitos dos fármacos , Núcleo Tegmental Pedunculopontino/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar , Tempo de Reação/fisiologia , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
Motor impairments of Parkinson's disease (PD) appear only after the loss of more than 70% of the DAergic neurons of the substantia nigra pars compacta (SNc). An earlier phase of this disease can be modeled in rats that received a unilateral infusion of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) into the SNc. Though these animals do not present gross motor impairments, they rotate towards the lesioned side when challenged with DAergic drugs, like amphetamine and apomorphine. The present study aimed to test whether these effects occur because the drugs disrupt compensatory mechanisms that keep extracellular levels of dopamine in the striatum (DA(E)) unchanged. This hypothesis was tested by an in vivo microdialysis study in awake rats with two probes implanted in the right and left striatum. Undrugged rats did not present turning behaviour and their basal DA(E) did not differ between the lesioned and sham-lesioned sides. However, after apomorphine treatment, DA(E) decreased in both sides, but to a larger extent in the lesioned side at the time the animals started ipsiversive turning behaviour. After amphetamine challenge, DA(E) increased in both sides, becoming significantly higher in the non-lesioned side at the time the animals started ipsiversive turning behaviour. These results are in agreement with the hypothesis that absence of gross motor impairments in this rat model of early phase PD depends on maintenance of extracellular DA by mechanisms that may be disrupted by events demanding its alteration to higher or lower levels.
Assuntos
Anfetamina/farmacologia , Apomorfina/farmacologia , Corpo Estriado/química , Dopamina/análise , Comportamento Estereotipado/efeitos dos fármacos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Corpo Estriado/efeitos dos fármacos , Dopaminérgicos/farmacologia , Masculino , Microdiálise , Ratos , Ratos Wistar , Gravação em VídeoRESUMO
The current investigation compared intranigral lipopolysaccharide (LPS), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) administrations, in the light of neurochemical, behavioral and endogenous antioxidant glutathione alterations. All the results were collected 1, 3 and 7 days after the lesions. LPS produced a delayed reduction of striatal dopamine, whereas homovanillic acid was drastically increased at the first time-point. Comparatively, MPTP promoted dopamine reduction 3 and 7 days with increase of homovanillic acid. Whilst, 6-OHDA generated initial increase of dopamine and homovanillic acid followed by subsequent decrease of this neurotransmitter accompanied by reductions of dopamine metabolites at the same periods. Furthermore, nigral glutathione demonstrated to be a far more sensitive target for LPS than for MPTP or 6-OHDA. Behavioral data indicated impairments induced by MPTP, 6-OHDA but not LPS. In conclusion, it is suggested that intranigral LPS can provide new insights about neuroinflammation, simulating features of the pre-motor phase of Parkinson's disease.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Comportamento Animal/efeitos dos fármacos , Dopamina/metabolismo , Glutationa/metabolismo , Lipopolissacarídeos/farmacologia , Oxidopamina , Doença de Parkinson/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Masculino , Doença de Parkinson/etiologia , Doença de Parkinson/psicologia , Ratos , Ratos Wistar , Substância Negra , Fatores de TempoRESUMO
Depression is a frequently encountered non-motor feature of Parkinson's disease (PD) and it can have a significant impact on patient's quality of life. Considering the differential pathophysiology of depression in PD, it prompts the idea that a degenerated nigrostriatal system plays a role in depressive-like behaviors, whilst animal models of PD are employed. Therefore, we addressed the question of whether dopamine (DA) depletion, promoted by the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), lipopolysaccharide (LPS) and rotenone are able to induce depressive-like behaviors and neurotransmitters alterations similarly that encountered in PD. To test this rationale, we performed intranigral injections of each neurotoxin, followed by motor behavior, depressive-like behaviors, histological and neurochemical tests. After the motor recovery period, MPTP, 6-OHDA and rotenone were able to produce anhedonia and behavioral despair. These altered behavioral responses were accompanied by reductions of striatal DA, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) restricted to the 6-OHDA group. Additionally, decreases on the hippocampal serotonin (5-HT) content were detected for the MPTP, 6-OHDA and rotenone groups. Notably, strong correlations were detected among the groups when 5-HT and DA were correlated with swimming (r=+0.97; P=0.001) and immobility (r=-0.90; P=0.012), respectively. Our data indicate that MPTP, 6-OHDA and rotenone, but not LPS were able to produce depressive-like behaviors accompanied primarily by hippocampal 5-HT reductions. Moreover, DA and 5-HT strongly correlated with "emotional" impairments suggesting an important participation of these neurotransmitters in anhedonia and behavioral despair after nigral lesions promoted by the neurotoxins.
Assuntos
Depressão/induzido quimicamente , Depressão/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Hipocampo/efeitos dos fármacos , Doença de Parkinson Secundária/induzido quimicamente , Serotonina/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Hipocampo/metabolismo , Lipopolissacarídeos , Masculino , Atividade Motora/efeitos dos fármacos , Oxidopamina , Distribuição Aleatória , Ratos , Ratos Wistar , RotenonaRESUMO
The roles of the nigrostriatal pathway are far beyond the simple control of motor functions. The tonic release of dopamine in the dorsal and ventral striatum controls the choice of proper actions toward a given environmental situation. In the striatum, a specific action is triggered by a specific stimulus associated with it. When the subject faces a novel and salient stimulus, the phasic release of dopamine allows synaptic plasticity in the cortico-striatal synapses. Neurons of different regions of cortical areas make synapses that converge to the same medium spine neurons of the striatum. The convergent associations form functional units encoding body parts, objects, locations, and symbolic representations of the subject's world. Such units emerge in the striatum in a repetitive manner, like a mosaic of broken mirrors. The phasic release of dopamine allows the association of units to encode an action of the subject directed to an object or location with the outcome of this action. Reinforced stimulus-action-outcome associations will affect future decision making when the same stimulus (object, location, idea) is presented to the subject in the future. In the absence of a minimal amount of striatal dopamine, no action is initiated as seen in Parkinson's disease subjects. The abnormal and improper association of these units leads to the initiation of unpurposeful and sometimes repetitive actions, as those observed in dyskinetic patients. The association of an excessive reinforcement of some actions, like drug consumption, leads to drug addiction. Improper associations of ideas and unpleasant outcomes may be related to traumatic and depressive symptoms common in many diseases, including Parkinson's disease. The same can be said about the learning and memory impairments observed in demented and nondemented Parkinson's disease patients.
Assuntos
Cognição/fisiologia , Dopamina/metabolismo , Mesencéfalo/citologia , Neurônios/fisiologia , Animais , Aprendizagem por Associação/fisiologia , Comportamento Aditivo/metabolismo , Comportamento Aditivo/patologia , Depressão/metabolismo , Depressão/patologia , Humanos , Movimento/fisiologiaRESUMO
The potential neuroprotective or neurotoxic effects of 3,4-dihydroxyphenylalanine (L-DOPA) are yet to be understood. We examined the behavioral, immunohistochemical, tyrosine hydroxylase (TH) expression and neurochemical parameters after an intranigral administration of L-DOPA (10 microM) in rats. L-DOPA elicited a 30.5% reduction in dopaminergic neurons, while 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (100 microg microL(-1)) produced a 53.6% reduction. A combined infusion of MPTP and L-DOPA generated a 42% reduction of nigral neurons. Motor parameters revealed that both the MPTP and L-DOPA groups presented impairments; however, the concomitant administration evoked a partial restorative effect. In addition, MPTP and L-DOPA separately induced reductions of TH protein expression within the substantia nigra. In contrast, the coadministration of MPTP and L-DOPA did not demonstrate such difference. The striatal levels of dopamine were reduced after MPTP or L-DOPA, with an increased turnover only for the MPTP group. In view of such results, it seems reasonable to suggest that L-DOPA could potentially produce dopaminergic neurotoxicity.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Antiparkinsonianos/uso terapêutico , Levodopa/uso terapêutico , Neurotoxinas , Transtornos Parkinsonianos , Substância Negra/efeitos dos fármacos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Análise de Variância , Animais , Contagem de Células , Modelos Animais de Doenças , Dopamina/metabolismo , Interações Medicamentosas , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Homovanílico/metabolismo , Masculino , Movimento/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurotoxinas/farmacologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/patologia , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Accidents involving Brown spider (Loxosceles sp.) venom produce a massive inflammatory response in injured region. This venom has a complex mixture of different toxins, and the dermonecrotic toxin is the major contributor to toxic effects. The ability of Loxosceles intermedia venom and a recombinant isoform of dermonecrotic toxin to induce edema and increase in vascular permeability was investigated. These toxins were injected into hind paws and caused a marked dose and time-dependent edema and increase in vascular permeability in mice. Furthermore, the enzymatic activity of venom toxins may be primal for these effects. A mutated recombinant isoform of dermonecrotic toxin, that has only residual enzymatic activity, was not able to induce these inflammatory events. Besides the previous heating of toxins markedly reduced the paw edema and vascular permeability showing that thermolabile constituents can trigger these effects. In addition, the ability of these venom toxins to evoke inflammatory events was partially reduced in compound 48/80-pretreated animals, suggesting that mast cells may be involved in these responses. Pretreating mice with histamine (prometazine and cetirizine) and serotonin (methysergide) receptor antagonists significantly attenuated toxins induced edema and vascular permeability. Moreover, HPLC analysis of whole venom showed the presence of histamine sufficient to induce inflammatory responses. In conclusion, these inflammatory events may result from the activation of mast cells, which in turn release bioamines and may be related to intrinsic histamine content of venom.
Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Edema/induzido quimicamente , Fosfolipase D/toxicidade , Diester Fosfórico Hidrolases/toxicidade , Venenos de Aranha/toxicidade , Aranhas , Animais , Degranulação Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Edema/imunologia , Histamina/análise , Antagonistas dos Receptores Histamínicos/farmacologia , Temperatura Alta , Injeções Subcutâneas , Mastócitos/efeitos dos fármacos , Camundongos , Mutação , Fosfolipase D/administração & dosagem , Fosfolipase D/genética , Fosfolipase D/isolamento & purificação , Diester Fosfórico Hidrolases/administração & dosagem , Diester Fosfórico Hidrolases/química , Diester Fosfórico Hidrolases/genética , Desnaturação Proteica , Proteínas Recombinantes/toxicidade , Serotonina/análise , Antagonistas da Serotonina/farmacologia , Venenos de Aranha/administração & dosagem , Venenos de Aranha/química , Venenos de Aranha/genética , Venenos de Aranha/isolamento & purificação , Fatores de Tempo , p-Metoxi-N-metilfenetilamina/farmacologiaRESUMO
In the present review we propose a model to explain the role of the basal ganglia in sensorimotor and cognitive functions based on a growing body of behavioural, anatomical, physiological, and neurochemical evidence accumulated over the last decades. This model proposes that the body and its surrounding environment are represented in the striatum in a fragmented and repeated way, like a mosaic consisting of the fragmented images of broken mirrors. Each fragment forms a functional unit representing articulated parts of the body with motion properties, objects of the environment which the subject can approach or manipulate, and locations the subject can move to. These units integrate the sensory properties and movements related to them. The repeated and widespread distribution of such units amplifies the combinatorial power of the associations among them. These associations depend on the phasic release of dopamine in the striatum triggered by the saliency of stimuli and will be reinforced by the rewarding consequences of the actions related to them. Dopamine permits synaptic plasticity in the corticostriatal synapses. The striatal units encoding the same stimulus/action send convergent projections to the internal segment of the globus pallidus (GPi) and to the substantia nigra pars reticulata (SNr) that stimulate or hold the action through a thalamus-frontal cortex pathway. According to this model, this is how the basal ganglia select actions based on environmental stimuli and store adaptive associations as nondeclarative memories such as motor skills, habits, and memories formed by Pavlovian and instrumental conditioning.
Assuntos
Gânglios da Base/anatomia & histologia , Gânglios da Base/fisiologia , Dopamina/fisiologia , Aprendizagem/fisiologia , Animais , Cognição/fisiologia , Dopamina/metabolismo , Humanos , Memória/fisiologia , Substância Negra/anatomia & histologia , Substância Negra/fisiologiaRESUMO
Different Parkinson's disease (PD) animal models reproduce the early phase of the disease, which deny the possible existence of a synergic effect of consecutive insults to the dopaminergic neurons. We proposed a novel protocol of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) nigrostriatal lesion, which consists in repeated MPTP intranigral administrations intending to differentiate effects of a single lesion in relation to repeated lesions. For this purpose, a schedule of 3-day intervals between the MPTP administrations, totalizing 3 infusions in 9 days were adopted. A persistent locomotor deficit was produced after the 2nd infusion, remaining until the last time-point. Tyrosine hydroxylase (TH) immunoreactive neurons were reduced in 50% 1 day after the 1st infusion and the neuronal loss remained constant even after the 2nd and 3rd MPTP infusions. In parallel, (TH) protein expression in the substantia nigra pars compacta (SNpc) revealed to be a sensitive target for MPTP, once it was found to be down-regulated immediately after the 1st MPTP exposure until the last time-point. These findings corroborate the concept of an early phase model of PD elicited by MPTP even when this neurotoxin was used according to the protocol currently proposed. The current protocol provided relevant insights about TH expression and irreversible locomotor impairment.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/administração & dosagem , Atividade Motora/efeitos dos fármacos , Neurotoxinas/administração & dosagem , Doença de Parkinson/etiologia , Doença de Parkinson/fisiopatologia , Substância Negra/efeitos dos fármacos , Análise de Variância , Animais , Comportamento Animal , Modelos Animais de Doenças , Esquema de Medicação , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Fatores de Tempo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Antidepressant drugs are effective in the treatment of panic in human panic disorder patients. One hypothesis is that the anti-panic effects of antidepressant drugs are mediated by an increase in the activity of serotonergic neurons within dorsal raphe nucleus (DRN) leading to an increase in serotonin-mediated inhibition of the dorsal periaqueductal gray (DPAG). In order to test this hypothesis, we investigated the effects of reversible inhibition of the DRN on behavior in the elevated T-maze (ETM) in control rats and rats chronically treated with imipramine. Rats were injected daily with imipramine (15 mg/kg i.p.) or saline for 24 days. A guide cannula was implanted in the DRN on day 14. Lidocaine (4%, 0.2 microL) or saline was injected into the DRN 10 min before the test in the ETM followed immediately by the open-field test (day 21). Three days later, the infusions were crossed-over, rats microinjected into the DRN with saline in the first trial received lidocaine and vice versa, and the behavioral tests were repeated (day 24). Chronic saline plus lidocaine in the DRN and chronic imipramine (plus saline or lidocaine in the DRN) impaired inhibitory avoidance, indicating an anxiolytic effect. In the one-way escape, lidocaine facilitated it, suggesting a panicogenic effect, while chronic imipramine impaired it, which is indicative of a panicolytic effect. Moreover, lidocaine blocked the facilitatory effect of chronic imipramine. The locomotor activity in the open field was not changed by any treatment compared to the control group. These effects were congruent with the hypothesis that the DRN has a dual effect on anxiety: increasing learned anxiety and decreasing innate anxiety. Moreover, they suggest that the DRN exerts a crucial role in the antipanic-like effect of chronic imipramine in the ETM.
Assuntos
Antidepressivos Tricíclicos/farmacologia , Imipramina/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Núcleos da Rafe/efeitos dos fármacos , Análise de Variância , Anestésicos Locais/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal , Vias de Administração de Medicamentos , Interações Medicamentosas , Lidocaína/farmacologia , Masculino , Aprendizagem em Labirinto/fisiologia , Núcleos da Rafe/fisiologia , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Fatores de TempoRESUMO
The effect of acute sodium valproate administration, an anxiolytic and putative panicolytic drug, was evaluated in rats tested in the elevated T-maze, an animal model that measures two defensive reactions: avoidance (inhibitory avoidance), related to generalized anxiety, and escape (escape from open arms), related to panic. Additionally, the involvement of gamma-aminobutyric acid (GABA) neurotransmission in sodium valproate effects was studied by picrotoxin co-administration. Sodium valproate (300 mg/kg, intraperitoneally, 30 min before the test) impaired both avoidance latency (time to leave the closed arm) and one-way escape (latency to enter the closed arm) indicating anxiolytic and panicolytic effects, respectively. Pre-treatment with picrotoxin (0.5 mg/kg, intraperitoneally, 5 min before sodium valproate administration) blocked the effects of sodium valproate on inhibitory avoidance and one-way escape. No locomotor effect was seen in the open-field. These data suggest that sodium valproate exerts anxiolytic-like and panicolytic-like effects in the elevated T-maze and that these effects were mediated by picrotoxin-sensitive GABA type A receptors.