RESUMO
N-methyl-d-aspartate receptor antagonist drugs (NMDA-A), such as dizocilpine (MK801), induce long-lasting behavioral disturbances reminiscent to psychotic disorders in humans. To identify cortical structures affected by NMDA-A, we used a single dose of MK801 (10 mg/kg) that caused low and high neurodegeneration in intact and orchiectomized male rats, respectively. Degenerating somas (neuronal death) and axonal/synaptic endings (terminal degeneration) were depicted by a silver technique, and functionally affected cortical neuronal subpopulations by Egr-1, c-Fos, and FosB/DeltaFosB-immunolabeling. In intact males, MK801 triggered a c-Fos induction that remained high for more than 24 h in selected layers of the retrosplenial, somatosensory and entorhinal cortices. MK801-induced neurodegeneration reached its peak at 72 h. Degenerating somas were restricted to layer IV of the granular subdivision of the retrosplenial cortex, and were accompanied by suppression of Egr-1 immunolabeling. Terminal degeneration extended to selected layers of the retrosplenial, somatosensory and parahippocampal cortices, which are target areas of retrosplenial cortex. Induction of FosB/DeltaFosB by MK801 also extended to the same cortical layers affected by terminal degeneration, likely reflecting the damage of synaptic connectivity. In orchiectomized males, the neurodegenerative and functional effects of MK801 were exacerbated. Degenerative somas in layer IV of the retrosplenial cortex significantly increased, with a parallel enhancement of terminal degeneration and FosB/DeltaFosB-expression in the mentioned cortical structures, but no additional areas were affected. These observations reveal that synaptic dysfunction/degeneration in the retrosplenial, somatosensory and parahippocampal cortices might underlie the long-lasting impairments induced by NMDA-A.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Maleato de Dizocilpina/toxicidade , Antagonistas de Aminoácidos Excitatórios/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Precoces/efeitos dos fármacos , Degeneração Neural/induzido quimicamente , Animais , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Proteína 1 de Resposta de Crescimento Precoce/efeitos dos fármacos , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Regulação da Expressão Gênica/fisiologia , Genes Precoces/fisiologia , Imuno-Histoquímica , Masculino , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Giro Para-Hipocampal/efeitos dos fármacos , Giro Para-Hipocampal/metabolismo , Giro Para-Hipocampal/patologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Terminações Pré-Sinápticas/patologia , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Córtex Somatossensorial/efeitos dos fármacos , Córtex Somatossensorial/metabolismo , Córtex Somatossensorial/patologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , TempoRESUMO
Opioid receptor binding was evaluated in parahippocampal cortex (PHC) obtained from patients with intractable mesial temporal lobe epilepsy (MTLE) with and without subacute high frequency electrical stimulation (HFS) in this brain area. Mu, delta and nociceptin receptor binding was determined by autoradiography in PHC of five patients (ESAE group) with MTLE history of 14.8 +/- 2.5 years and seizure frequency of 11 +/- 2.9 per month, two of them (40%) with mesial sclerosis. This group demonstrated antiepileptic effects following subacute HFS (130 Hz, 450 micros, 200-400 microA), applied continuously during 16-20 days in PHC. Values were compared with those obtained from patients with severe MTLE (history of 21.7 +/- 2.8 years and seizure frequency of 28.2 +/- 14 per month) in whom electrical stimulation did not induce antiepileptic effects (ESWAE group, n = 4), patients with MTLE in whom no electrical stimulation was applied (MTLE group, n = 4) and autopsy material acquired from subjects without epilepsy (n = 4 obtained from three subjects). Enhanced 3H-DAMGO (MTLE, 755%; ESAE, 375%; ESWAE, 693%), 3H-DPDPE (MTLE, 242%; ESAE, 80%; ESWAE, 346%) and 3H-nociceptin (MTLE, 424%; ESAE, 217%; ESWAE, 451%) binding was detected in the PHC of all epileptic groups. However, tissue obtained from ESAE group demonstrated lower opioid receptor binding (3H-DAMGO, 44.5%, p < 0.05; 3H-DPDPE, 47%, p < 0.05; 3H-nociceptin, 39.3%, p < 0.5) when compared with MTLE group. The present results indicate that a high effectiveness to the antiepileptic effects induced by HFS is associated with reduced opioid peptide binding.
Assuntos
Terapia por Estimulação Elétrica , Epilepsia do Lobo Temporal/metabolismo , Giro Para-Hipocampal/metabolismo , Receptores Opioides/metabolismo , Convulsões/prevenção & controle , Adulto , Anticonvulsivantes/uso terapêutico , Autorradiografia , Eletrofisiologia , Epilepsia do Lobo Temporal/patologia , Feminino , Humanos , Ligantes , Imageamento por Ressonância Magnética , Masculino , Giro Para-Hipocampal/patologia , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Receptor de NociceptinaRESUMO
The long term inhibition of masculine sexual behavior after repeated ejaculations is known as sexual satiety. To investigate the brain areas that may regulate sexual satiety, c-Fos expression was studied in different groups of sexually experienced male rats: controls not allowed to copulate, males allowed two or four ejaculations and animals allowed to reach sexual satiety. Interestingly, males that ejaculated two or four times had similar c-Fos densities in all the evaluated brain regions, except for the suprachiasmatic nucleus. Similarly, sexually satiated males had analogous c-Fos densities in all the evaluated brain areas independently of the number of ejaculations required to reach satiety. Sexual activity (evidenced in males that ejaculated two or four times) increased c-Fos levels in the anteromedial bed nucleus of the stria terminalis, claustrum, entorhinal cortex, medial preoptic area, nucleus accumbens core, suprachiasmatic nucleus and supraoptic nucleus; however, sexual satiety did not modify c-Fos expression in these regions. Sexually satiated males had increased c-Fos densities in the ventrolateral septum and the anterodorsal and posteroventral medial amygdala, compared with animals allowed to copulate but that did not reach sexual satiety, and decreased c-Fos density in the piriform cortex. These results suggest that the network that underlies sexual satiety is different from that which regulates copulation.