RESUMO
Cognitive impairment or its recovery has been associated with the absence or reestablishment of estrogenic actions in the central nervous system of female experimental animals or women. It has been proposed that these cognitive phenomena are related to estrogen-mediated modulatory activity of synaptic transmission in brain structures involved in cognitive functions. In the present work a morphological study was conducted in adult female ovariectomized rats to evaluate estradiol-dependent dendritic spine sprouting in hippocampal pyramidal neurons, and changes in the presynaptic marker synaptophysin. Three or ten days after estradiol treatment (10 µg/day, twice) in the ovariectomized rats, a significant increase of synaptophysin was observed, which was coincident with a significant higher numerical density of thin (22%), stubby (36%), mushroom (47%) and double spines (125%), at day 3, without significant changes of spine density at day 10, after treatment. These results may be interpreted as evidence of pre- and postsynaptic plastic events that may be involved in the modulation of cognitive-related behavioral performance after estrogen replacement therapy.
Assuntos
Região CA1 Hipocampal/citologia , Espinhas Dendríticas/efeitos dos fármacos , Estradiol/farmacologia , Estrogênios/farmacologia , Células Piramidais/ultraestrutura , Análise de Variância , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Ovariectomia , Células Piramidais/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Coloração pela Prata , Sinaptofisina/metabolismoRESUMO
Some selective estrogen receptor modulators, such as raloxifene and tamoxifen, are neuroprotective and reduce brain inflammation in several experimental models of neurodegeneration. In addition, raloxifene and tamoxifen counteract cognitive deficits caused by gonadal hormone deprivation in male rats. In this study, we have explored whether raloxifene and tamoxifen may regulate the number and geometry of dendritic spines in CA1 pyramidal neurons of the rat hippocampus. Young adult male rats were injected with raloxifene (1 mg/kg), tamoxifen (1 mg/kg), or vehicle and killed 24 h after the injection. Animals treated with raloxifene or tamoxifen showed an increased numerical density of dendritic spines in CA1 pyramidal neurons compared to animals treated with vehicle. Raloxifene and tamoxifen had also specific effects in the morphology of spines. These findings suggest that raloxifene and tamoxifen may influence the processing of information by hippocampal pyramidal neurons by affecting the number and shape of dendritic spines.
Assuntos
Espinhas Dendríticas/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Espinhas Dendríticas/ultraestrutura , Masculino , Neurônios/fisiologia , Cloridrato de Raloxifeno/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/metabolismo , Tamoxifeno/farmacologiaRESUMO
Working memory may involve context-dependent allocentric or own movement-dependent egocentric strategies. While allocentric working memory can be disrupted by N-methyl-D-aspartate (NMDA) blockage, the possible effects of NMDA receptor manipulation on the egocentric strategy have not been studied. Because dendritic spine plasticity in part underlies working memory-related behavioral efficiency, egocentric working memory performance was evaluated in adult rats following NMDA receptor blockade with 10mg/kg of the NMDA-receptor antagonist CPP, i.p. Dendritic spine density and the proportion of different spine types (thin, stubby, mushroom, wide, branched and double) were assessed in third-layer pyramidal neurons of the dorsomedial prefrontal cortex, after behavioral testing. Working memory was evaluated by challenging the rats to resolve twelve trials per day in a single-day session over five consecutive days, in a "cross-arm" maze and according to a delayed match-to-sample procedure. In control animals, the dendritic spine density remained unchanged after behavioral testing, although the proportion of mushroom spines decreased while that of the branched spines increased. NMDA receptor blockade impaired the behavioral performance of rats and resulted in a decrease in dendritic spine density when compared to the control animals, and dendritic spine types were unchanged. These results suggest that behavioral efficiency of egocentric working memory is dependent on NMDA receptor activation, and that plastic changes in spine cytoarchitecture may play a key role in behavioral performance.
Assuntos
Espinhas Dendríticas/fisiologia , Transtornos da Memória/fisiopatologia , Memória de Curto Prazo/fisiologia , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/fisiopatologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Memória de Curto Prazo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
The mechanism of the antinociceptive action of the phosphodiesterase 5 inhibitor, sildenafil, was assessed in the formalin test. Local peripheral ipsilateral, but not contralateral, administration of sildenafil (50-200 microg/paw) produced a dose-related antinociception during both phases of the formalin test. The local peripheral pretreatment with protein kinase G inhibitor peptide (PKG inhibitor, 0.01-1 microg/paw), charybdotoxin (large- and intermediate-conductance Ca2+-activated K+ channel blocker, 0.01-1 microg/paw), apamin (small-conductance Ca2+-activated K+ channel blocker, 0.1-2 microg/paw), tolbutamide (ATP-sensitive K+ channel blocker, 12.5-50 microg/paw), and tetraethylammonium (non-selective voltage-dependent K+ channel blocker, 12.5-50 microg/paw), but not 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, inhibitor of guanylyl cyclase, 12.5-50 microg/paw) or saline, significantly diminished in a dose-dependent manner sildenafil-induced local peripheral antinociception. Given alone, local peripheral administration of inhibitors did not modify formalin-induced nociceptive behavior. Results suggest that sildenafil produces its local peripheral antinociceptive effect via activation of the cyclic GMP-PKG-K+ channel pathway.