RESUMO
The aim of the present study was to investigate the effects of 17beta-estradiol on expression of muscarinic acetylcholine receptor subtypes (M1 to M5) and estrogen receptor alpha, in the rat hippocampus. Hippocampi were obtained from rats in proestrus, rats ovariectomized for 15 days, rats ovariectomized for 15 days and then treated with 17beta-estradiol for 7 days, and rats ovariectomized and immediately treated with 17beta-estradiol for 21 days. Expression of M1 to M5 was increased in hippocampi of rats ovariectomized for 15 days compared to rats in proestrus. Although this effect was abolished when replacement with 17beta-estradiol started immediately after ovariectomy, the increased expression of M1, M3 and M5 receptor subtypes was unchanged when replacement with 17beta-estradiol started only 15 days after ovariectomy. The expression of estrogen receptor alpha in the hippocampus was also upregulated after ovariectomy when compared to rats in proestrus. This effect was abolished when 17beta-estradiol was replaced immediately after ovariectomy, and slightly reduced when the replacement started 15 days after ovariectomy. The replacement with estrogen also had beneficial effects on cognitive function, as suggested by data obtained in the plus-maze discriminative avoidance task. In conclusion, the present results provide evidence that 17beta-estradiol regulates the expression of muscarinic acetylcholine receptor subtypes and estrogen receptor alpha. The immediate replacement with estrogen seems critical to restore the expression of these receptors after hormonal deprivation. The understanding of the regulation of expression and intracellular signaling of the muscarinic acetylcholine receptor subtype M1 and the estrogen receptor alpha may be helpful to elucidate the mechanisms involved in changes of cognitive function in postmenopausal women and in neurodegenerative diseases.
Assuntos
Estradiol/farmacologia , Receptor alfa de Estrogênio/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Subunidades Proteicas/biossíntese , Receptores Muscarínicos/biossíntese , Animais , Feminino , Hipocampo/efeitos dos fármacos , Ovariectomia , Ratos , Ratos Wistar , Receptores Muscarínicos/classificaçãoRESUMO
One important contributing factor in the high prevalence of drug abuse disorders seen among schizophrenic patients seems to be related to chronic treatment with typical neuroleptics. We have previously demonstrated that withdrawal from long-term treatment with the typical neuroleptic haloperidol, but not the atypical neuroleptic ziprasidone, potentiated the hyperlocomotor effect induced by a single cocaine injection and cocaine-induced conditioned place preference in mice. In the present study we investigated whether withdrawal from long-term treatment with these same neuroleptics would also modify cocaine-induced hyperlocomotion sensitization, which has been proposed as an animal model for the intensification of drug craving in cocaine addiction. Swiss male mice were i.p. treated with haloperidol (1.0 mg/kg) or ziprasidone (4.0 mg/kg) for 15 days. Twenty-four hours after the last injection, animals received an i.p. injection of cocaine (10 mg/kg) for 5 consecutive days, being placed after each injection in the open-field apparatus in order to perform a drug-environment conditioning. Seven days after the last drug-environment conditioning procedure, the animals were challenged with an i.p. injection of cocaine (10 mg/kg), placed in the open-field apparatus and had their locomotor activity quantified. Withdrawal from haloperidol (but not ziprasidone) potentiated cocaine-induced behavioral sensitization. These results are suggested to be a consequence of the development of the dopaminergic supersensitivity phenomenon by long-term treatment with the typical compound. Our findings provide additional support for the use of atypical agents like ziprasidone in the treatment of schizophrenic patients with comorbid substance abuse disorder.
Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Transtornos Relacionados ao Uso de Cocaína , Haloperidol/farmacologia , Atividade Motora/efeitos dos fármacos , Piperazinas/farmacologia , Síndrome de Abstinência a Substâncias , Tiazóis/farmacologia , Animais , Antipsicóticos/uso terapêutico , Cocaína/farmacologia , Haloperidol/uso terapêutico , Humanos , Masculino , Camundongos , Piperazinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Tiazóis/uso terapêuticoRESUMO
The differential outcomes of social isolation and crowding environment on the effects of single or repeated administration of ethanol on open-field behavior were examined in female mice. Whereas housing conditions did not alter the increase in locomotor activity induced by ethanol single administration, behavioral sensitization (a progressive increase of a drug effect following repeated drug administration) to the locomotor activating effect of ethanol was significantly greater in crowded mice as compared to isolated and control groups. Single administration of ethanol significantly decreased rearing frequency and increased immobility duration, there being tolerance to these ethanol behavior effects after repeated treatment. Social isolation attenuated the increase in immobility behavior induced by single administration of ethanol and potentiated the tolerance of ethanol-induced rearing decrease, verified after repeated treatment. These results point out that both sensitization and tolerance to the behavioral effects of ethanol can be critically influenced by housing conditions.