RESUMO
Cocaine's ability to interact with sigma receptors suggests that these proteins mediate some of its behavioral effects. Therefore, three novel sigma receptor ligands with antagonist activity were evaluated in Swiss Webster mice: BD1018 (3S-1-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[4.3.0]nonane), BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine), and LR132 (1R,2S-(+)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)cyclohexylamine). Competition binding assays demonstrated that all three compounds have high affinities for sigma1 receptors. The three compounds vary in their affinities for sigma2 receptors and exhibit negligible affinities for dopamine, opioid, GABA(A) and NMDA receptors. In behavioral studies, pre-treatment of mice with BD1018, BD1063, or LR132 significantly attenuated cocaine-induced convulsions and lethality. Moreover, post-treatment with LR132 prevented cocaine-induced lethality in a significant proportion of animals. In contrast to the protection provided by the putative antagonists, the well-characterized sigma receptor agonist di-o-tolylguanidine (DTG) and the novel sigma receptor agonist BD1031 (3R-1-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[4.3.0]nonane) each worsened the behavioral toxicity of cocaine. At doses where alone, they produced no significant effects on locomotion, BD1018, BD1063 and LR132 significantly attenuated the locomotor stimulatory effects of cocaine. To further validate the hypothesis that the anti-cocaine effects of the novel ligands involved antagonism of sigma receptors, an antisense oligodeoxynucleotide against sigma1 receptors was also shown to significantly attenuate the convulsive and locomotor stimulatory effects of cocaine. Together, the data suggests that functional antagonism of sigma receptors is capable of attenuating a number of cocaine-induced behaviors.
Assuntos
Cocaína/antagonistas & inibidores , Etilaminas/farmacologia , Locomoção/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Oligodesoxirribonucleotídeos Antissenso/farmacologia , Pirrolidinas/farmacologia , Receptores sigma/efeitos dos fármacos , Análise de Variância , Animais , Ligação Competitiva , Cocaína/toxicidade , Masculino , Camundongos , Piperazinas/farmacologia , Receptores sigma/metabolismo , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Relação Estrutura-AtividadeRESUMO
Cocaine binds to sigma receptors with comparable affinity to its well-established interaction with dopamine transporters. Previous studies have shown BD1008 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) to have high affinity and selectivity for sigma receptors, and to additionally attenuate the locomotor stimulatory effects of cocaine. Therefore, in the present study, three N-alkyl substituted analogs of BD1008 were characterized in receptor binding and behavioral studies: BD1060 (N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)ethylamine), BD1067 (N-[2-(3,4-dichlorophenyl)ethyl]-N-ethyl-2-(1-pyrrolidinyl)ethylamine), and BD1052 (N-[2-(3,4-dichlorophenyl)ethyl]-N-allyl-2-(1-pyrrolidinyl)ethylamine). Similarly to BD1008, all three analogs exhibited high affinity and selectivity for sigma receptors. In behavioral studies, BD1008, BD1060 or BD1067 attenuated cocaine-induced convulsions and lethality in Swiss Webster mice. The protective effects appear to be mediated through sigma receptor antagonism because traditional sigma receptor antagonists with high to moderate affinity for these receptors also attenuated the behavioral toxicity of cocaine. In contrast, traditional and novel sigma receptor agonists such as di-o-tolylguanidine and BD1052 worsened the behavioral toxicity of cocaine. To further characterize the actions of the N-alkyl substituted compounds, they were microinjected into the rat red nucleus, a functional assay of sigma receptor activity, where they produced agonist vs. antagonist actions that were consistent with their effects on cocaine-induced behaviors. Together, the data demonstrate that BD1008, BD1060 or BD1067 can attenuate the behavioral toxicity of cocaine, most likely through functional antagonism of sigma receptors.
Assuntos
Cocaína/antagonistas & inibidores , Cocaína/toxicidade , Inibidores da Captação de Dopamina/antagonistas & inibidores , Inibidores da Captação de Dopamina/toxicidade , Etilaminas/farmacologia , Pirrolidinas/farmacologia , Receptores sigma/efeitos dos fármacos , Convulsões/induzido quimicamente , Alquilação , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Etilaminas/administração & dosagem , Etilaminas/química , Cobaias , Técnicas In Vitro , Injeções Intraventriculares , Ligantes , Masculino , Camundongos , Microinjeções , Pirrolidinas/administração & dosagem , Pirrolidinas/química , Ratos , Ratos Sprague-Dawley , Receptores sigma/agonistas , Receptores sigma/antagonistas & inibidores , Núcleo Rubro , Convulsões/prevenção & controleRESUMO
The ability of cocaine to interact with sigma receptors indicates that these sites may mediate the negative properties associated with cocaine use, such as toxicity and addiction. Previous studies have shown that the novel sigma receptor ligand, BD1008 (N-[2-(3,4-dicholophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylam ine), effectively protects against cocaine-induced convulsions and locomotor activity in mice. Therefore, BD1047 ([2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(diamino)ethylamine) and LR172 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-homopiperidinyl)eth ylamine), two analogs of BD1008, were tested to determine if they also have anti-cocaine properties. Receptor binding assays showed that BD1047 and LR172 both have high affinities for a receptors, but low to negligible affinities for dopamine, opioid, phencyclidine, and 5-HT2 sites. In behavioral studies, pretreatment of mice with BD1047 or LR172 reduced the convulsions, lethality, and locomotor activity produced by cocaine. The data indicates a possible role for sigma receptor ligands in the treatment of cocaine overdose and addiction.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cocaína/toxicidade , Etilenodiaminas/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores sigma/fisiologia , Animais , Ligação Competitiva , Encéfalo/efeitos dos fármacos , Cocaína/antagonistas & inibidores , Cobaias , Técnicas In Vitro , Ligantes , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Convulsões/prevenção & controleRESUMO
Cocaine interacts with sigma receptors, suggesting that these sites are important for many of its behavioral effects. Therefore, two novel sigma receptor ligands, BD1008 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) and BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine), were evaluated for their ability to attenuate cocaine-induced locomotor activity. Receptor binding studies showed that BD1008 and BD1063 have nanomolar affinities for sigma1 and sigma2 sites, but a 250-fold or lower affinity for nine other receptors, making them among the most selective sigma receptor ligands identified. In behavioral studies, pretreatment of mice with BD1008 or BD1063 produced a two-fold increase in the ED50 for the locomotor stimulatory effects of cocaine. These results suggest that sigma receptors are involved in the behavioral effects of cocaine.
Assuntos
Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Etilaminas/farmacologia , Atividade Motora/efeitos dos fármacos , Piperazinas/farmacologia , Pirrolidinas/farmacologia , Receptores sigma/efeitos dos fármacos , Animais , Ligação Competitiva , Etilaminas/metabolismo , Cobaias , Masculino , Camundongos , Piperazinas/metabolismo , Pirrolidinas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Receptores Opioides/efeitos dos fármacos , Receptores Opioides/metabolismo , Receptores da Fenciclidina/efeitos dos fármacos , Receptores da Fenciclidina/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Receptores sigma/metabolismoRESUMO
We report here the results of our study of the carbonic anhydrase inhibitor acetazolamide on cerebral vascular and metabolic function, correlated with the effects of this agent on systemic arterial blood gases and pH. We found that the effects of acetazolamide were to increase PaO2, decrease bicarbonate ion concentration and decrease pH. While these effects were maintained for many hours after both high and low dose acetazolamide, the cerebral metabolic and vascular effects of the drug were transient. The central effects of carbonic anhydrase inhibition were consistent with increased oxygen delivery and increased tissue oxygenation. Hypoxia such as encountered at altitude, represents a challenge to the mechanisms which control blood flow in the brain. The decreased arterial oxygen content at altitude is a ventilatory drive which has the effect of 1) increasing somewhat the PaO2; 2) decreasing the PaCO2; 3) alkalinizing the blood. The decreased PaCO2 then leads to decreased CBF compounding the problem of hypoxemia. In this situation, increasing CBF helps to relieve the tissue hypoxia. This has been done by either increased inhalation of CO2 (Harvey et al., 1988) or by acetazolamide (Cain and Dunn, 1966; Forwand et al., 1968). A common feature in both treatments might be increased tissue CO2 retention (Kjällquist et al., 1969; Meyer et al., 1961) and tissue acidification (Heuser et al., 1975). The two treatments are not identical since acetazolamide seems to have additional effects on cerebral metabolism that elevated CO2 does not. Thus, we can deduce that the primary pathologic effects of acute hypoxia are due to the decreased cerebral blood flow produced by hyperventilation-induced hypocapnia.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Acetazolamida/farmacologia , Córtex Cerebral/efeitos dos fármacos , Oxigênio/metabolismo , Acetazolamida/administração & dosagem , Animais , Bicarbonatos/sangue , Córtex Cerebral/metabolismo , Circulação Cerebrovascular/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Hipóxia Encefálica/fisiopatologia , Oxigênio/sangue , RatosRESUMO
A new thin-film, multisensor probe was used to determine tissue oxygen tension, tissue temperature, and electrical activity at two depths below the brain surface in chloral hydrate- or nitrous oxide/halothane-anesthetized rats. Brain tissue temperature at both depths was found to be lower than core temperature by 1-2 degrees C. Electrical activation, spreading depression, and pentylenetetrazol seizures all resulted in transient increases of brain tissue temperature of a few tenths degree centigrade. Vasodilation, induced by hypercapnia or hypoxia, caused a warming of brain tissue. Near-maximum oxygen metabolism, reached upon reoxygenation after severe hypoxia, was accompanied by tissue temperature rises of greater than 1 degree C. It was concluded that brain tissue temperature in the anesthetized rat is lower than core temperature due to extensive radiative and conductive heat loss to the environment through the head. Transient increases in tissue temperature during activation are caused by vasodilation and increased metabolism.
Assuntos
Anestesia , Temperatura Corporal/fisiologia , Encéfalo/fisiopatologia , Animais , Encéfalo/irrigação sanguínea , Hidrato de Cloral , Estimulação Elétrica , Eletroencefalografia , Halotano , Hipercapnia/fisiopatologia , Hipóxia/fisiopatologia , Óxido Nitroso , Pentilenotetrazol , Ratos , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , VasodilataçãoRESUMO
In summary, we can come to a number of meaningful conclusions regarding chronic exposure to hypobaric hypoxia in rats (refer to Figure 1). First, despite an increased hematocrit, and thus increased oxygen carrying capacity, regional cerebral blood flow is elevated after 4 weeks of chronic hypobaric hypoxia. This elevation in blood flow occurs even though the rat hyperventilates to lower than normal arterial CO2 content which would ordinarily decrease cerebral blood flow. Second, although blood flow is increased in both chronic and acute hypoxia, the increases can not be through similar mechanisms since in the acute hypoxic condition there is also an increase in local blood volume that is absent in the chronic response. Third, the effect of chronic hypoxic exposure on cerebral blood flow persists for at least 4 hours after the animal is returned to normobaric normoxia. Fourth, sometime between 4 and 24 hours of recovery is necessary to reverse the effect of chronic hypoxia on cerebral blood flow. One day after having been returned to normobaric normoxia cerebral blood flow had returned to control. On the other hand, hematocrit was still elevated in these rats. Thus, the change in hematocrit does not seem to be associated in any mechanistic manner with the blood flow response.
Assuntos
Circulação Cerebrovascular , Hipóxia/fisiopatologia , Animais , Pressão Sanguínea , Dióxido de Carbono/sangue , Cerebelo/irrigação sanguínea , Córtex Cerebral/irrigação sanguínea , Corpo Estriado/irrigação sanguínea , Hipocampo/irrigação sanguínea , Masculino , Especificidade de Órgãos , Oxigênio/sangue , Pressão Parcial , Ratos , Ratos Endogâmicos , Valores de Referência , Sacarose , Fatores de TempoRESUMO
Local brain tissue oxygen tension, temperature, and electrical potential were continuously and simultaneously measured at each of two different depths in anesthetized, paralyzed rat brain. Brain tissue temperature increases up to 1 degree C were recorded in response to direct electrical stimulation, spreading depression, PTZ-induced seizures, hypercapnia, and hypoxia. An increase in brain tissue temperature was also recorded during reoxygenation after hypoxia. Thus, we have shown that, in this preparation, increases in either blood flow or oxidative metabolism lead to transient warming of the brain.
Assuntos
Temperatura Corporal , Encéfalo/fisiologia , Animais , Encéfalo/fisiopatologia , Circulação Cerebrovascular , Estimulação Elétrica , Hipercapnia/fisiopatologia , Hipóxia/fisiopatologia , Ratos , Ratos Endogâmicos , Convulsões/fisiopatologiaRESUMO
Age-related alterations in the noradrenergic innervation of the cerebral cortex were investigated in young (3-4 months) and aged (28-29 months) Fischer-344 rats. The concentration of noradrenaline and the activity of tyrosine hydroxylase, the probable rate-limiting step in catecholamine biosynthesis, were significantly higher in the aged cerebral cortex, but no differences in L-3,4-dihydroxyphenylalanine decarboxylase activity were observed. The specific high-affinity uptake of noradrenaline by homogenates of the aged cerebral cortex exhibited higher maximal uptake, but lower affinity, than those of young rats. These results suggest increased presynaptic noradrenergic activity in the cerebral cortex of aged Fischer-344 rats.
Assuntos
Envelhecimento/metabolismo , Córtex Cerebral/crescimento & desenvolvimento , Norepinefrina/metabolismo , Animais , Córtex Cerebral/metabolismo , Dopa Descarboxilase/metabolismo , Masculino , Ratos , Ratos Endogâmicos F344 , Tirosina 3-Mono-Oxigenase/metabolismoAssuntos
Encéfalo/metabolismo , Animais , Encéfalo/citologia , Concentração de Íons de Hidrogênio , Cinética , Vermelho Neutro , Fotografação , RatosRESUMO
Reversible, total cerebral ischaemia of eight minutes duration was produced in a closed-chest dog model. Before, and at intervals after, this insult regional cerebral blood flow was determined by radiolabelled microsphere injection; and cerebral cortical capillary mean transit time was determined by reflection spectrophotometry. From these two measured parameters, cerebral cortical blood volume was calculated. After one hour of reperfusion following eight minutes of total cerebral ischaemia; cerebral blood flow was half of pre-ischaemic blood flow and mean transit time was increased by half. These results indicate that the delayed hypoperfusion following total cerebral ischaemia is accompanied by a decreased cerebral cortical blood volume mediated by vasoconstriction.
Assuntos
Isquemia Encefálica/fisiopatologia , Encéfalo/irrigação sanguínea , Animais , Velocidade do Fluxo Sanguíneo , Córtex Cerebral/irrigação sanguínea , Cães , Fluxo Sanguíneo Regional , VasoconstriçãoRESUMO
Intracellular pH in the intact, normally perfused rat brain cortex was determined by rapid scanning reflectance spectrophotometry of Neutral Red. Neutral Red, a pH indicator dye, was administered intraperitoneally to rats. Reflectance spectra recorded from the exposed dural surface of 11 anesthetized rats were used to calculate an intracellular pH of 7.04 +/- 0.01. Detailed studies on the interactions of the dye with brain tissue were carried out in vitro to define the in vivo calibration curves. In addition, the physiological effect of dye administration on systemic blood pressure was determined, as well as uptake curves for Neutral Red into plasma and brain. It is concluded that Neutral Red can be used as an in vivo brain intracellular pH indicator and compares favorably with other methods of brain intracellular pH measurement with respect to accuracy, sensitivity, noninvasiveness, and stability and has the potential to exceed any existing method in time resolution.