RESUMO
The dorsal raphe nucleus (DRN) is an important brainstem source of 5-hydroxytryptamine (5-HT), and 5-HT plays a key role in the regulation of panic attacks. The aim of the present study was to determine whether 5-HT1A receptor-containing neurons in the medial hypothalamus (MH) receive neural projections from DRN and to then determine the role of this neural substrate in defensive responses. The neurotracer biotinylated dextran amine (BDA) was iontophoretically microinjected into the DRN, and immunohistochemical approaches were then used to identify 5HT1A receptor-labelled neurons in the MH. Moreover, the effects of pre-treatment of the dorsomedial hypothalamus (DMH) with 8-OH-DPAT and WAY-100635, a 5-HT1A receptor agonist and antagonist, respectively, followed by local microinjections of bicuculline, a GABAA receptor antagonist, were investigated. We found that there are many projections from the DRN to the perifornical lateral hypothalamus (PeFLH) but also to DMH and ventromedial (VMH) nuclei, reaching 5HT1A receptor-labelled perikarya. DMH GABAA receptor blockade elicited defensive responses that were followed by antinociception. DMH treatment with 8-OH-DPAT decreased escape responses, which strongly suggests that the 5-HT1A receptor modulates the defensive responses. However, DMH treatment with WAY-100635 failed to alter bicuculline-induced defensive responses, suggesting that 5-HT exerts a phasic influence on 5-HT1A DMH neurons. The activation of the inhibitory 5-HT1A receptor had no effect on antinociception. However, blockade of the 5-HT1A receptor decreased fear-induced antinociception. The present data suggest that the ascending pathways from the DRN to the DMH modulate panic-like defensive behaviours and mediate antinociceptive phenomenon by recruiting 5-HT1A receptor in the MH.
Assuntos
Núcleo Dorsal da Rafe/metabolismo , Núcleo Hipotalâmico Dorsomedial/metabolismo , Medo/fisiologia , Vias Neurais/fisiologia , Receptor 5-HT1A de Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina , Análise de Variância , Animais , Bicuculina/farmacologia , Biotina/análogos & derivados , Biotina/metabolismo , Dextranos/metabolismo , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Hipotalâmico Dorsomedial/efeitos dos fármacos , Relação Dose-Resposta a Droga , Reação de Fuga/efeitos dos fármacos , Medo/efeitos dos fármacos , Antagonistas de Receptores de GABA-A/farmacologia , Masculino , Microinjeções , Vias Neurais/efeitos dos fármacos , Medição da Dor , Piperazinas/farmacologia , Piridinas/farmacologia , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologiaRESUMO
Inhibitory connections among striatal projection neurons (SPNs) called "feedback inhibition," have been proposed to endow the striatal microcircuit with computational capabilities, such as motor sequence selection, filtering, and the emergence of alternating network states. These properties are disrupted in models of Parkinsonism. However, the impact of feedback inhibition in the striatal network has remained under debate. Here, we test this inhibition at the microcircuit level. We used optical and electrophysiological recordings in mice and rats to demonstrate the action of striatal feedback transmission in normal and pathological conditions. Dynamic calcium imaging with single-cell resolution revealed the synchronous activation of a pool of identified SPNs by antidromic stimulation. Using bacterial artificial chromosome-transgenic mice, we demonstrate that the activated neuron pool equally possessed cells from the direct and indirect basal ganglia pathways. This pool inhibits itself because of its own GABA release when stimuli are frequent enough, demonstrating functional and significant inhibition. Blockade of GABAA receptors doubled the number of responsive neurons to the same stimulus, revealing a second postsynaptic neuron pool whose firing was being arrested by the first pool. Stronger connections arise from indirect SPNs. Dopamine deprivation impaired striatal feedback transmission disrupting the ability of a neuronal pool to arrest the firing of another neuronal pool. We demonstrate that feedback inhibition among SPNs is strong enough to control the firing of cell ensembles in the striatal microcircuit. However, to be effective, feedback inhibition should arise from synchronized pools of SPNs whose targets are other SPNs pools.
Assuntos
Retroalimentação Fisiológica/fisiologia , Neostriado/patologia , Neurônios/fisiologia , Transtornos Parkinsonianos/patologia , Transmissão Sináptica/fisiologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Adrenérgicos/toxicidade , Anestésicos Locais/farmacologia , Animais , Animais Recém-Nascidos , Bicuculina/farmacologia , Biofísica , Cálcio/metabolismo , Modelos Animais de Doenças , Estimulação Elétrica , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas GABAérgicos/farmacologia , Proteínas de Fluorescência Verde/genética , Técnicas In Vitro , Lidocaína/análogos & derivados , Lidocaína/farmacologia , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Método de Monte Carlo , Neostriado/citologia , Neostriado/metabolismo , Inibição Neural/efeitos dos fármacos , Inibição Neural/genética , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Neurônios/efeitos dos fármacos , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Técnicas de Patch-Clamp , Piridazinas/farmacologia , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/genética , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genética , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética , Fatores de Tempo , Valina/análogos & derivados , Valina/farmacologia , Ácido gama-Aminobutírico/metabolismoRESUMO
The effects of a muscarinic antagonist (scopolamine), a muscarinic agonist (oxotremorine), an agonist at the N-methyl-D-aspartate receptor site (D-cycloserine), and a GABAa antagonist (bicuculline) on working memory were compared using rats performing a delayed matching-to-sample task. When administered on their own, oxotremorine, D-cycloserine, and bicuculline had no effect on performance in the current task. When administered concurrently with scopolamine, oxotremorine (at 1 dose) and bicuculline (at 2 doses) improved accuracy (in terms of percentage correct) by ameliorating the scopolamine-induced increase in response bias. None of the drugs, however, were successful in ameliorating the scopolamine-induced impairment in bias-free recognition performance per se (as measured by Log d). Therefore, none of the drugs examined were able to fully ameliorate all aspects of the memory impairment caused by scopolamine.
Assuntos
Bicuculina/farmacologia , Ciclosserina/farmacologia , Antagonistas GABAérgicos/farmacologia , Antagonistas de Receptores de GABA-A , Agonistas Muscarínicos/farmacologia , Oxotremorina/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , Antagonistas Muscarínicos/farmacologia , Ratos , Ratos Wistar , Escopolamina/farmacologiaRESUMO
Functional magnetic resonance imaging (fMRI) has been applied to study rat focal brain activation induced by intravenous administration of the GABA(A) antagonist bicuculline. Using magnetite nanoparticles as a blood pool contrast agent, local changes in cerebral blood volume (CBV) were assessed with high temporal (10 s) and spatial (0.35 x 0.6 mm(2)) resolutions. Upon infusion of the bicuculline region-specific increases in CBV have been observed, suggesting CBV to reflect brain activity. During the first 2 min, the signal increases were predominant in the cortex, followed by increases in other brain areas, such as the caudate putamen, thalamus and cerebellum. Ten minutes after the start of infusion, a dominant response was observed in the thalamus, while in the caudate putamen a biphasic response pattern was seen. The magnitude of the signal responses in all brain regions was dependent on the dose of bicuculline and, in general, matched the known distribution of GABA(A) binding sites. This study suggests that pharmacological fMRI, displaying brain function at the highly specific level of drug-receptor interaction, should foster our understanding of normal and pathological brain function.