RESUMEN
The role of nitric oxide (NO) in the long-term, amine-depleting effects of methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) was investigated in the rodent central nervous system. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) antagonized the dopamine- and serotonin-depleting effects of both METH and MDMA. The protective actions of L-NAME in METH-treated mice were reversed by prior administration of the NO generator isosorbide dinitrate. However, pretreatment with N(G)-monomethyl-L-arginine or N(G)-nitro-L-arginine, two other NO synthase inhibitors, failed to block the neurotoxic effects of METH or MDMA. L-NAME was also the only NO synthase inhibitor that antagonized the hyperthermic effects of METH, reducing colonic temperatures in mice by a mean of 3 degrees C, in comparison with control. Moreover, if the hypothermic effects of L-NAME in METH-treated mice were prevented by raising the ambient room temperature, the dopamine-depleting actions of the stimulant were fully restored. The latter findings suggest that it is the hypothermic actions of L-NAME, rather than its NO inhibitory properties, that are responsible for the prevention of neurotoxicity. Together with the results of the N(G)-monomethyl-L-arginine and N(G)-nitro-L-arginine experiments, the data suggest that NO plays little or no role in the toxic mechanism of action of METH or MDMA.
Asunto(s)
Encéfalo/metabolismo , Catecolaminas/metabolismo , Dinitrato de Isosorbide/farmacología , Metanfetamina/toxicidad , N-Metil-3,4-metilenodioxianfetamina/toxicidad , NG-Nitroarginina Metil Éster/farmacología , Neurotoxinas , Óxido Nítrico/fisiología , Nitroarginina/farmacología , Serotonina/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Análisis de Varianza , Animales , Temperatura Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Lóbulo Frontal/metabolismo , Hipocampo/metabolismo , Ácido Homovanílico/metabolismo , Ácido Hidroxiindolacético/metabolismo , Masculino , Ratones , Ratones Endogámicos , Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ratas , Ratas Sprague-DawleyRESUMEN
Several amphetamine analogues are reported to increase striatal glutamate efflux in vivo, whereas other data indicate that glutamate is capable of stimulating the efflux of dopamine (DA) in the striatum via a glutamate receptor-dependent mechanism. Based on these findings, it has been proposed that the ability of glutamate receptor-blocking drugs to antagonize the effects of amphetamine may be explained by their capacity to inhibit DA release induced by glutamate. To examine this possibility further, we investigated in vivo the ability of glutamate antagonists to inhibit DA release induced by either methamphetamine (METH) or 3,4-methylenedioxymethamphetamine (MDMA). Both METH and MDMA increased DA efflux in the rat striatum and, in animals killed 1 week later, induced persistent depletions of DA and serotonin in tissue. Pretreatment with MK-801 or CGS 19755 blocked the neurotoxic effects of METH and MDMA but did not significantly alter striatal DA efflux induced by either stimulant. Infusion of 6-cyano-7-nitro-quinoxaline-2,3-dione into the striatum likewise did not alter METH-induced DA overflow, and none of the glutamatergic antagonists affected the basal release of DA when given alone. The findings suggest that the neuroprotective effects of NMDA antagonists do not involve an inhibition of DA release, nor do the data support the proposal that glutamate tonically stimulates striatal DA efflux in vivo. Whether phasic increases in glutamate content might stimulate DA release, however, remains to be determined.
Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Antagonistas de Aminoácidos Excitadores , Metanfetamina/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Aminas/antagonistas & inhibidores , Animales , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Ácidos Pipecólicos/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Older mice are much more susceptible to the dopamine-depleting actions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an effect that has been correlated with age-related increases in the central nervous system activity of the enzyme responsible for its bioactivation, monoamine oxidase type B (MAO B). To characterize the involvement of MAO B further in the age-related effects of MPTP, a neurotoxic analog of MPTP, 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP), was used. This drug produced much larger depletions of striatal dopamine in 10-month-old mice than in 2-month-old animals, which indicated that the effects of 2'CH3-MPTP, like those of MPTP, are age related. Different from MPTP, however, neither the inhibition of MAO B (selegiline) nor MAO A (clorgiline) blocked the dopamine-depleting effects of 2'CH3-MPTP; rather, the simultaneous inhibition of both forms of the enzyme was required. These data indicate that both MAO A and B participate in the bioactivation of 2'CH3-MPTP. Based on these findings, the ability of selective inhibitors of MAO A and B to block the age-related effects of 2'CH3-MPTP was investigated. 2'CH3-MPTP produced equivalent depletions of striatal dopamine in 2- and 10-month-mice after both groups were pretreated with selective inhibitors of MAO B; that is, MAO B inhibition abolished the age-dependent effects of the neurotoxin. By contrast, older mice continued to display much larger 2'CH3-MPTP-induced depletions of striatal dopamine than did younger rodents after the inhibition of MAO A.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/análogos & derivados , Envejecimiento/metabolismo , Clorgilina/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Selegilina/farmacología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Ratones , Ratones Endogámicos C57BLRESUMEN
The calcium channel antagonists verapamil nifedipine and flunarizine all increased the threshold for convulsions induced by N-methyl-D-aspartate in rats. By contrast, only flunarizine blocked the long-term serotonin-depleting effects of 3,4-methylenedioxymethamphetamine. Flunarizine was also the only drug that antagonized methamphetamine-induced stereotypy. These findings suggest that calcium influx through L-type channels does not participate in the neurotoxic mechanism of MDMA, and that the neuroprotective actions of flunarizine are probably related to its anti-dopaminergic activity.
Asunto(s)
3,4-Metilenodioxianfetamina/análogos & derivados , Bloqueadores de los Canales de Calcio/farmacología , Serotonina/metabolismo , 3,4-Metilenodioxianfetamina/antagonistas & inhibidores , 3,4-Metilenodioxianfetamina/farmacología , Animales , Química Encefálica/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Flunarizina/farmacología , Haloperidol/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Metanfetamina/antagonistas & inhibidores , Metanfetamina/farmacología , N-Metil-3,4-metilenodioxianfetamina , Nifedipino/farmacología , Ratas , Ratas Sprague-Dawley , Convulsiones/inducido químicamente , Convulsiones/prevención & control , Conducta Estereotipada/efectos de los fármacos , Verapamilo/farmacologíaRESUMEN
Anisomycin and cycloheximide were used to investigate the role of protein synthesis in the mechanism of behavioral sensitization to the stereotypic effects of cocaine and amphetamine in mice. The drugs completely antagonize induction and partially block expression of the sensitization. Because these drugs were found to be neither antidopaminergic nor antiglutamatergic, it seems that they disrupt sensitization at a novel locus. The antagonism of expression is limited to that quantitative fraction of the response derived from the sensitization reaction; the acute response is unaffected by the inhibitors of protein synthesis. The results differ from those obtained with haloperidol which can completely block either the acute or sensitized response to the stimulants. These results suggest that the sensitized response is functionally different from that of the acute response. The blockage of sensitization induction by the protein synthesis inhibitors may be related to other reports that the stimulants induce the transcription of immediate early genes; however, the relationship between the activation of immediate early genes and behavioral sensitization remains to be determined.
Asunto(s)
Anfetamina/antagonistas & inhibidores , Conducta Animal/efectos de los fármacos , Cocaína/antagonistas & inhibidores , Inhibidores de la Síntesis de la Proteína/farmacología , Anfetamina/farmacología , Animales , Anisomicina/farmacología , Cocaína/farmacología , Cicloheximida/farmacología , Inyecciones Intraperitoneales , Masculino , Ratones , Convulsiones/inducido químicamente , Convulsiones/prevención & control , Conducta Estereotipada/efectos de los fármacosRESUMEN
Recent clinical studies suggest that selegiline (L-deprenyl) is useful in retarding the progress of Parkinson's disease, an effect that may be related to its inhibition of monoamine oxidase type B (MAO-B). Selegiline is also reported to prevent the toxic effects of the noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). This article reviews recent studies on the role of MAO-B and its inhibition in this neuroprotective action of selegiline. Male C57Bl/6 mice were given DSP-4 (50 mg/kg) 1 h, 24 h, or 4 days after the administration of selegiline (10 mg/kg) or the selective MAO-B inhibitor MDL 72974 (1.25 mg/kg) and then killed 1 week later for the assay of norepinephrine in the hippocampus. The MAO-B-inhibiting effects of selegiline or MDL 72974 were also determined after these same intervals. Selegiline and MDL 72974 produced comparable degrees of enzyme inhibition 1 h (> 95%), 24 h (> 90%), or 4 days (> 70%) after their administration. Given 1 h before, selegiline totally blocked the norepinephrine-depleting effects of DSP-4, but this protection declined sharply when 24 h or 4 days was allowed to elapse between selegiline and DSP-4 administration. MDL 72974 failed to protect at any time point. In vitro, no activity was observed when DSP-4 was used as a substrate for MAO. All of these findings suggest that the ability of selegiline to protect against DSP-4-induced neuronal degeneration does not depend on its inhibition of MAO-B.
Asunto(s)
Bencilaminas/toxicidad , Encéfalo/efectos de los fármacos , Isoenzimas/fisiología , Monoaminooxidasa/fisiología , Degeneración Nerviosa/efectos de los fármacos , Neurotoxinas , Selegilina/farmacología , Animales , Encéfalo/fisiología , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos BALB C , Degeneración Nerviosa/fisiología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Norepinefrina/fisiologíaRESUMEN
The mechanism by which the amphetamines damage selectively nigrostriatal dopaminergic neurons in experimental animals remains uncertain. The observation that neuronal cell death during embryogenesis involves an activation of gene expression and new protein synthesis, coupled with recent reports indicating that the amphetamines are capable of inducing neuropeptide biosynthesis, offers a possible clue as to their neurotoxic mechanism of action. Based on these considerations, we evaluated the effects of two different inhibitors of protein synthesis, cycloheximide and anisomycin, on the long-term, amine-depleting effects of methamphetamine (METH) in mice and rats. Both inhibitors were found to block the amine-depleting effects of METH in these species. In other experiments, cycloheximide did not affect the functional integrity of dopaminergic or glutamatergic neurons, transmitter systems previously implicated in the neurotoxic mechanism of action of METH. These findings raise the possibility that the neuronal-damaging effects of METH are mediated via a synthesis of 'neurotoxic' proteins.
Asunto(s)
Anisomicina/farmacología , Encéfalo/efectos de los fármacos , Cicloheximida/farmacología , Dopamina/metabolismo , Metanfetamina/toxicidad , Proteínas del Tejido Nervioso/biosíntesis , Animales , Masculino , Ratones , Ratas , Ratas Sprague-DawleyRESUMEN
Although the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice have been reported to increase with age, they have not been characterized in the full spectrum of ages. Thus, in spite of a considerable body of scientific literature on the subject, previous reports leave unanswered the question of whether or not the increased susceptibility of fully mature mice is part of the aging process or simply a consequence of maturation. In the present study, the age-related effects of MPTP on striatal dopamine were studied in groups of C57BL/6 mice from young maturity to old age. The major increase in the effects of MPTP occurred between 2 and 10 months of age (equivalent to adolescence and young adulthood in humans). A slight additional increase was observed between 10 and 16 months (young adulthood and middle age) and the dopamine-depleting effects of MPTP significantly declined in truly aged animals (24 months). Of note also is the fact that normal concentrations of striatal dopamine did not decline in the later ages. Additional studies indicated that while neuronal sensitivity to the effects of 1-methyl-4-phenylpyridinium (MPP+; the putative toxic metabolite of MPTP) appears to remain constant, age-related changes in the activity of striatal monoamine oxidase type B (MAO B) paralleled the dopamine-depleting effects of MPTP in the 4 age groups. Indeed, MAO B activity increased between 2 and 16 months and declined slightly, but significantly, between 16 and 24 months. This pattern of age-related changes in MAO B, striatal dopamine and the sensitivity of the nigrostriatal system to toxic insult may provide insights into factors which have been implicated in age-related neurodegeneration and idiopathic Parkinson's disease.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Envejecimiento/fisiología , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Monoaminooxidasa/metabolismo , 1-Metil-4-fenilpiridinio/farmacología , Animales , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Dextromethorphan, an agent that blocks the neuronal-damaging effects of hypoxemia in vitro, was tested for its ability to prevent the neurotoxic effects of p-chloroamphetamine (PCA). Rats were treated with either saline, PCA, dextromethorphan, or the combination of PCA and increasing doses of dextromethorphan. Dextromethorphan provided a dose-related protection against the serotonin (5-HT)-depleting effects of PCA. These observations may offer a clue as to the mechanism responsible for PCA-induced neurotoxicity.
Asunto(s)
Dextrometorfano/farmacología , Sistema Nervioso/efectos de los fármacos , p-Cloroanfetamina/farmacología , Animales , Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Hipocampo/metabolismo , Masculino , Ratas , Ratas Endogámicas , Antagonistas de la Serotonina/farmacología , p-Cloroanfetamina/antagonistas & inhibidoresRESUMEN
The MPTP-treated monkey has become an important model for the study of Parkinson's disease. However, studies on the acute evolution of the neurotoxic effects of MPTP in primates are lacking. In the present study, 17 squirrel monkeys were given a single subcutaneous injection of MPTP (2.5 mg/kg). The behavioral effects and the concentrations of dopamine (DA), dihydroxyphenylacetic acid and homovanillic acid were determined in caudate, putamen and substantia nigra 1, 3, 5 (n = 3/time point) and 10 days (n = 6) after drug administration. Two animals were studied neuropathologically 8 and 9 days after MPTP. Profound parkinsonism was evident in all animals after 1 day and neuropathological examination revealed severe nerve cell destruction in the substantia nigra. Surprisingly, although 50-75% reductions in nigral DA were observed 1 and 3 days after MPTP, caudate DA was not reduced and putaminal DA was increased at these time points. The temporal sequence of these events differs markedly from that which occurs in the MPTP-treated mouse and suggests that, in the monkey, nigral cell bodies may represent an important initial site of MPTP-induced damage. Five and 10 days after MPTP, nigral DA depletions remained greater than 60% of control and striatal DA was reduced 50-85%. At these time points, the putamen was always more affected than the caudate. This interregional pattern of striatal DA deficits is similar to that seen in idiopathic Parkinson's disease.
Asunto(s)
Núcleo Caudado/metabolismo , Actividad Motora/efectos de los fármacos , Putamen/metabolismo , Sustancia Negra/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/patología , Dopamina/metabolismo , Ácido Homovanílico/metabolismo , Masculino , Monoaminooxidasa/metabolismo , Putamen/efectos de los fármacos , Putamen/patología , Valores de Referencia , Saimiri , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Clinical studies suggest that deprenyl may retard the progression of Parkinson's disease, an effect that may be related to its monoamine oxidase (MAO) inhibiting properties. Deprenyl also protects against the neurodegenerative effects of the noradrenergic toxin DSP-4. In this study we investigated the role of MAO B inhibition in this protection. C57BL/6 mice were given DSP-4 (50 mg/kg i.p.) 1 h. 24 h or 4 days after the administration of deprenyl (10 mg/kg i.p.) or the selective MAO B inhibitor MDL 72974 (1.25 mg/kg), and then killed 1 week later for assay of hippocampal norepinephrine. The MAO B inhibiting effects of deprenyl or MDL 72974 were also determined after these same intervals of time. Deprenyl and MDL 72974 produced comparable degrees of enzyme inhibition 1 h (greater than 95%), 24 h (greater than 90%) or 4 days (greater than 70%) after their administration. Given 1 h before, deprenyl totally blocked the norepinephrine-depleting effects of DSP-4, but this protection declined sharply when 24 h or 4 days was allowed to elapse between deprenyl and DSP-4 administration. MDL 72974 failed to protect at any time point. In vitro, we detected no activity using DSP-4 as a substrate for MAO. These findings suggest that the ability of deprenyl to protect against DSP-4-induced neuronal degeneration may not depend on its MAO B inhibiting properties.
Asunto(s)
Compuestos Alílicos , Bencilaminas/antagonistas & inhibidores , Inhibidores de la Monoaminooxidasa/farmacología , Enfermedades del Sistema Nervioso/inducido químicamente , Selegilina/farmacología , Animales , Bencilaminas/metabolismo , Bencilaminas/toxicidad , Butilaminas/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Cinética , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedades del Sistema Nervioso/fisiopatología , Norepinefrina/metabolismoAsunto(s)
3,4-Metilenodioxianfetamina/análogos & derivados , Aminas Biogénicas/líquido cefalorraquídeo , Drogas de Diseño/farmacología , Trastornos Relacionados con Sustancias , 3,4-Metilenodioxianfetamina/farmacología , Adulto , Femenino , Ácido Homovanílico/líquido cefalorraquídeo , Humanos , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Masculino , Metoxihidroxifenilglicol/líquido cefalorraquídeo , Persona de Mediana Edad , N-Metil-3,4-metilenodioxianfetamina , Valores de ReferenciaRESUMEN
Using the systemically active, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dextrorphan, we explored the role of the NMDA receptor-calcium channel complex in the toxic mechanism of action of 3,4-methylenedioxymethamphetamine (MDMA). Rats were treated with MDMA, dextrorphan, or the combination of MDMA and increasing doses of dextrorphan, and then killed 10 days later for the assay of serotonin and dopamine in the striatum, hippocampus, and cortex. Dextrorphan totally prevented the serotonin-depleting effects of MDMA in the straitum, with a lessened but still significant blockade noted in the hippocampus and cortex. These findings may provide a clue to the molecular events underlying MDMA-induced neurotoxicity.
Asunto(s)
3,4-Metilenodioxianfetamina/antagonistas & inhibidores , Anfetaminas/antagonistas & inhibidores , Dextrorfano/farmacología , Morfinanos/farmacología , Receptores de Neurotransmisores/antagonistas & inhibidores , 3,4-Metilenodioxianfetamina/administración & dosificación , 3,4-Metilenodioxianfetamina/análogos & derivados , 3,4-Metilenodioxianfetamina/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Calcio/metabolismo , Masculino , N-Metil-3,4-metilenodioxianfetamina , Ratas , Ratas Endogámicas , Receptores de N-Metil-D-Aspartato , Receptores de Neurotransmisores/metabolismoRESUMEN
A recent approach to identifying the factors that predispose neurons to an early death in Parkinson's or Alzheimer's disease has been to study how the effect of specific neurotoxins are altered by increasing maturity. We determined the dose-related serotonin and norepinephrine-depleting effects of the selective neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), in C57BL/6 mice of 2 different ages. Norepinephrine and serotonin in the hippocampus were assayed 1 week after the intracerebroventricular (i.c.v.) administration of 5,7-DHT. 5,7-DHT produced an equivalent, dose-related depletion of hippocampal norepinephrine in both age groups. Since the effects of 5,7-DHT on noradrenergic neurons may, at least in part, depend on the monoamine oxidase (MAO)-generated formation of hydrogen peroxide and associated oxy-radicals, this result suggests that noradrenergic neurons do not become more vulnerable to oxidative stress with aging. We also found that the noradrenergic-depleting effects of 5,7-DHT were blocked by the non-selective MAO inhibitor pargyline (50 mg/kg, i.p.), while the selective MAO B inhibitor deprenyl (10 mg/kg, i.p.) failed to prevent this depletion. These latter results suggest that it is the A form of MAO that plays an important role in the mechanism of 5,7-DHT-induced noradrenergic toxicity. Somewhat unexpectedly, older mice were found to be less susceptible to the serotonin-depleting effects of 5,7-DHT. Although the mechanism by which this compound damages serotonergic neurons is uncertain, our results show that the increased susceptibility of serotonergic neurons to 5,7-DHT in young animals extends well beyond the neonatal period.
Asunto(s)
5,7-Dihidroxitriptamina/farmacología , Envejecimiento/metabolismo , Monoaminas Biogénicas/metabolismo , Dihidroxitriptaminas/farmacología , Hipocampo/metabolismo , Neurotoxinas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Hipocampo/efectos de los fármacos , Hipocampo/crecimiento & desarrollo , Ratones , Ratones Endogámicos C57BLRESUMEN
Recent studies suggest that 3,4-methylenedioxymethylamphetamine (MDMA), when administered subcutaneously, is toxic to central serotonergic neurons in rats. Because humans typically self-administer this drug orally, we compared this route to the s.c. route of administration. Orally administered MDMA produced a dose-related depletion of serotonin comparable to that produced by the s.c. route. These findings suggest that MDMA, when given orally, retains it neurotoxic activity and that humans using MDMA may be at risk for developing a persistent depletion of brain serotonin.
Asunto(s)
3,4-Metilenodioxianfetamina/farmacología , Anfetaminas/farmacología , Encéfalo/metabolismo , Serotonina/metabolismo , 3,4-Metilenodioxianfetamina/administración & dosificación , 3,4-Metilenodioxianfetamina/análogos & derivados , Administración Oral , Animales , Encéfalo/efectos de los fármacos , Inyecciones Subcutáneas , Masculino , N-Metil-3,4-metilenodioxianfetamina , Ratas , Ratas Endogámicas , Valores de Referencia , Factores de TiempoRESUMEN
The dopamine-depleting effects of intracerebroventricularly administered 6-hydroxydopamine (6-OHDA) were studied in young mature (6-8 weeks), older (8-12 months) and aged (18-24 months) mice. No differences were noted between age groups. To rule out the possibility that higher levels of monoamine oxidase (which degrades 6-OHDA) in older animals might be masking an increased sensitivity of older neurons to 6-OHDA, experiments were repeated after treatment with pargyline (50 mg/kg). Again, no differences between age groups were noted. We conclude that aging does not increase the sensitivity of dopaminergic neurons to 6-OHDA.
Asunto(s)
Envejecimiento/metabolismo , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Hidroxidopaminas/toxicidad , Animales , Cuerpo Estriado/metabolismo , Hidroxidopaminas/administración & dosificación , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos C57BL , Monoaminooxidasa/metabolismo , Oxidopamina , PargilinaRESUMEN
Two analogs of the nigrostriatal neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were examined for their deleterious effects on nigrostriatal neurons. 1,2,3,6-Tetrahydro-1-methyl-4-(methylpyrrol-2-yl)pyridine (TMMP), but not 1-methyl-4-(1-methylpyrrol-2-yl)-4-piperidinol, caused persistent depletion of striatal dopamine and induced histologic evidence of nerve terminal degeneration in mice. These findings differ diametrically from results previously reported for the two analogs. TMMP produced larger dopamine depletions than MPTP when the two drugs were given in equivalent doses. Further experiments demonstrated that TMMP is preferentially oxidized by mouse brain monoamine oxidase B to a water-soluble compound, most likely the pyridinium ion species. Prior treatment of mice with either the monoamine oxidase inhibitor pargyline or the dopamine reuptake inhibitor bupropion blocked the ability of TMMP to deplete striatal dopamine. Thus, the pharmacologic profile of TMMP closely resembles that of MPTP. That TMMP and MPTP induce dopamine depletions by a similar mechanism tends to support the proposed neurochemical sequence of events thought to lead to the expression of MPTP-induced neurotoxicity. The authors' observations provide further evidence that MPTP is not unique in its capability to damage nigrostriatal neurons.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Dopamina/análisis , Piperidinas/toxicidad , Piridinas/toxicidad , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Biotransformación , Cuerpo Estriado/análisis , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , Inhibidores de la Monoaminooxidasa/farmacología , Piperidinas/metabolismo , Piridinas/metabolismo , Relación Estructura-ActividadRESUMEN
Because both long-term adrenoceptor agonist administration and antidepressant treatment in animals down-regulate CNS beta-adrenoceptors and attenuate brain adenylate cyclase activity, beta-adrenoceptor agonists may also possess antidepressant properties. We compared the effects of the centrally acting beta-adrenoceptor agonist clenbuterol (5, 10 and 35 mg/kg per day), and the combination of propranolol (5 mg/kg per day) and clenbuterol (10 mg/kg per day), with desipramine (15 mg/kg per day) on forced swim test performance and on cortical beta-adrenoceptors in rats following 7 days of drug administration. Desipramine (15 mg/kg per day), and clenbuterol (10 and 35 mg/kg per day, but not 5 mg/kg per day) both significantly reduced immobility in the forced swim test. Frontal cortex beta-adrenoceptors were significantly down-regulated after desipramine and all 3 doses of clenbuterol. The co-administration of propranolol (5 mg/kg per day) blocked both the reduction in immobility and down-regulation of cortical beta-receptors induced by clenbuterol (10 mg/kg per day). Propranolol (5 mg/kg per day) alone up-regulated frontal cortex beta-adrenoceptors, but had no significant effect on swimming performance. These data suggest that the physiological consequences of beta-adrenoceptor down-regulation are important in the mechanism of action of antidepressants. The results also suggest that clenbuterol may be useful in the treatment of depression.
Asunto(s)
Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Clenbuterol/farmacología , Desipramina/farmacología , Etanolaminas/farmacología , Desempeño Psicomotor/efectos de los fármacos , Animales , Conducta Exploratoria/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas , Receptores Adrenérgicos beta/efectos de los fármacos , NataciónRESUMEN
The long-term neurochemical and behavioral effects of repeated d-methylamphetamine (d-MA) administration were investigated using four male rhesus monkeys trained to lever-press for food on a DRL-40s schedule of reinforcement. Dose-response curves for d-MA (0.0625-2.0 mg/kg), apomorphine (0.025-0.4 mg/kg), and haloperidol (0.005-0.04 mg/kg) on responding showed that repeated d-MA administration (0.5-16.0 mg/kg/day) decreased sensitivity to d-MA and to apomorphine but increased sensitivity to haloperidol. At 3-6 months after the last injection of d-MA, a 48.1% decrease in caudate dopamine (DA) was observed, with the frontal cortex, midbrain, and pons-medulla showing no significant change. A trend toward increasing concentrations of norepinephrine was noted in the same brain areas, but only in the frontal cortex did this change reach significance. Specific binding of 3H-spiroperidol to caudate membrane preparations was not changed, while the Vmax of the caudate DA re-uptake process declined 32%, with no change in Km. These results suggest that exposure of DA neurons in the caudate nucleus to high concentrations of d-MA can lead to nerve terminal degeneration.