RESUMO
The role of the phosphorylation of hippocampal extracellular signal-regulated kinase 1/2 in spatial working memory in rats was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay. Phosphorylated extracellular signal-regulated kinase 1/2 levels were significantly and transiently increased in the hippocampus by 60 min, and then returned to the control levels 120 min after the training phase. Bilateral microinjections of the PD98059, an inhibitor of the extracellular signal-regulated kinase 1/2 kinase MEK, into the hippocampus impaired performance in the test phase of the delayed spatial win-shift task at 5-min delay. These results suggest that extracellular signal-regulated kinase 1/2 activation in the hippocampus plays a crucial role in spatial working memory.
Assuntos
Hipocampo/enzimologia , Memória de Curto Prazo/fisiologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Comportamento Espacial/fisiologia , Animais , Comportamento Animal , Western Blotting/métodos , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Microinjeções/métodos , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Comportamento Espacial/efeitos dos fármacos , Estatísticas não ParamétricasRESUMO
BACKGROUND: Recent clinical studies have suggested that chronic use of methamphetamine (METH) induces long-term cognitive deficits. To clarify the mechanism of METH-induced cognitive impairment, we investigated the effect of METH on cognitive function in mice. METHODS: Mice were repeatedly administered METH for 7 days, and their cognitive function was assessed using a novel-object recognition task. Therapeutic effects of clozapine and haloperidol on METH-induced cognitive impairment were investigated. Western blotting and specific inhibitors were employed to determine the role of extracellular signal-regulated kinase 1/2 (ERK1/2). RESULTS: Repeated METH treatment induced an impairment of recognition of novel objects and behavioral sensitization. These effects persisted for at least 28 days after the drug withdrawal. Clozapine, but not haloperidol, reduced METH-induced cognitive impairment. Hyperphosphorylation of ERK1/2 was found in the prefrontal cortex of mice exposed to the novel objects, but was abolished in mice treated with METH. Inhibition of ERK1/2 by the microinjection of PD98059 into the prefrontal cortex resulted in cognitive impairment. CONCLUSIONS: These results suggest that repeated METH treatment induces cognitive impairment, which is associated with the dysfunction of the ERK1/2 pathway in the prefrontal cortex.
Assuntos
Inibidores da Captação de Dopamina/administração & dosagem , Comportamento Exploratório/fisiologia , Transtornos da Memória/fisiopatologia , Metanfetamina/administração & dosagem , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Western Blotting/métodos , Inibidores da Captação de Dopamina/efeitos adversos , Esquema de Medicação , Interações Medicamentosas , Ativação Enzimática/efeitos dos fármacos , Masculino , Transtornos da Memória/induzido quimicamente , Metanfetamina/efeitos adversos , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Testes Neuropsicológicos/estatística & dados numéricos , Fosforilação/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Fatores de TempoRESUMO
We investigated the effects of memantine and donepezil on amyloid beta (Abeta)-induced memory impairment in rats, which was assessed by a delayed-matching to position (DMPT) paradigm in three-lever operant chambers. Aggregated Abeta1-40 was microinjected bilaterally (1 nmol/side) into both CA1 and CA3 subfields of the hippocampus in rats that had previously performed the DMTP task. Memantine (20 mg/(kg day), s.c.) was continuously infused by an osmotic minipump for 4 weeks from 3 days before the microinjection of Abeta. Donepezil (2.5 mg/kg, p.o.) was administered 60 min before the DMTP test session. Bilateral microinjections of Abeta1-40 into the hippocampus resulted in a delayed, but persistent impairment of DMTP performance, which appeared more than 50 days after the injection. Memantine prevented the development of Abeta-induced memory impairment, while donepezil symptomatically alleviated the deficits. Because of a ceiling effect, the combination of donepezil with memantine failed to produce any additive or synergic effects. These results support the clinical data showing that memantine and donepezil are effective for the treatment of Alzheimer's disease. Moreover, it is suggested that memantine is effective for preventing Abeta-induced short-term memory impairment.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Inibidores da Colinesterase/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Indanos/administração & dosagem , Memantina/administração & dosagem , Transtornos da Memória , Fragmentos de Peptídeos/toxicidade , Piperidinas/administração & dosagem , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Donepezila , Vias de Administração de Medicamentos , Interações Medicamentosas , Privação de Alimentos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/fisiopatologia , Ratos , Ratos Endogâmicos F344 , Tempo de Reação/efeitos dos fármacos , Fatores de TempoRESUMO
In the central nervous system, tissue plasminogen activator (tPA) plays a role in synaptic plasticity and remodeling. Our recent study has suggested that tPA participates in the rewarding effects of morphine by regulating dopamine release. In this study, we investigated the role of tPA in methamphetamine (METH)-related reward and sensitization. Repeated METH treatment dose-dependently induced tPA mRNA expression in the frontal cortex, nucleus accumbens, striatum and hippocampus, whereas single METH treatment did not affect tPA mRNA expression in these brain areas. The METH-induced increase in tPA mRNA expression in the nucleus accumbens was completely inhibited by pre-treatment with R(+)-SCH23390 and raclopride, dopamine D1 and D2 receptor antagonists, respectively. In addition, repeated METH treatment increased tPA activity in the nucleus accumbens. There was no difference in METH-induced hyperlocomotion between wild-type and tPA-deficient (tPA-/-) mice. On the other hand, METH-induced conditioned place preference and behavioral sensitization after repeated METH treatment were significantly reduced in tPA-/- mice compared with wild-type mice. The defect of behavioral sensitization in tPA-/- mice was reversed by microinjections of exogenous tPA into the nucleus accumbens. Our findings suggest that tPA is involved in the rewarding effects as well as the sensitization of the locomotor-stimulating effect of METH.