RESUMEN
High (+/-)-8-hydroxy-dipropylaminotetralin HBr (8-OH-DPAT)-sensitive (HDS) rats and low 8-OH-DPAT-sensitive (LDS) rats were selectively bred for differences in sensitivity to the hypothermic effect of the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agonist 8-OH-DPAT in 30 to 35-day-old rat pups. These rats were trained on the differential reinforcement of low rate 72-s operant schedule. On this schedule, LDS rats had a higher response rate and a lower reinforcement rate than HDS rats. Drugs with primary action on the 5-HT system, 8-OH-DPAT, ketanserin, and fluoxetine, decreased response rate of HDS and LDS rats but increased the reinforcement rate of only the LDS rats. However, a drug with primary action on the norepinephrine system, desipramine, decreased response rate and increased reinforcement rate of HDS and LDS rats, suggesting that norepinephrine function was similar in the two lines of rats. The finding with desipramine indicates that increases in reinforcers on the differential reinforcement of low rate 72-s task are not simply dependent on baseline response or reinforcement rate. We also observed that 8-OH-DPAT engenders a greater hypothermic response in adult (90-day-old) HDS rats than in adult LDS rats. The 5-HT(1A) receptor antagonist WAY-100635 antagonized the hypothermic response. Tissue levels of 8-OH-DPAT from several brain regions in LDS and HDS rats did not differ from each other at either 15- or 30-min postinjection. Because the LDS and HDS rats have different responses to 5-HT-acting drugs, these rats may be useful for studying the role of the serotonergic system in depression.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Conducta Animal/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/análisis , Inhibidores de Captación Adrenérgica/farmacología , Factores de Edad , Animales , Monoaminas Biogénicas/análisis , Química Encefálica/efectos de los fármacos , Condicionamiento Operante , Desipramina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Fluoxetina/farmacología , Hipotermia/inducido químicamente , Ketanserina/farmacología , Masculino , Ratas , Receptores de Serotonina/clasificación , Esquema de Refuerzo , Antagonistas de la Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Factores de TiempoRESUMEN
Administration of phentermine (Phen) together with (+/-) fenfluramine (Fen) enhances the weight reduction that is observed with either drug alone; consequently, these anorectic agents are commonly prescribed together for weight reduction. Repeated administration of Fen is known to cause long-term depletion of axonal serotonin (5-HT) and loss of 5-HT transporters, and is therefore considered neurotoxic. We now report that combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg, and 20 mg/kg/3.125 mg/kg) can enhance the neurotoxic effect of Fen (3.125 mg/kg) and Phen (5 mg/kg and 20 mg/kg) on central 5-HT systems. Rats were repeatedly treated once each hour for a total of four injections with saline, Phen (5 mg/kg and 20 mg/kg), Fen (3.125 mg/kg and 12.5 mg/kg), or combined Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg), and sacrificed either 7 or 28 days after cessation of treatment. Combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg) caused significantly greater reductions of 5-HT levels in the striatum, nucleus accumbens/olfactory tubercle, hypothalamus, amygdala, frontal parietal cortex, and hippocampus than either drug alone. Combined Phen/Fen at the higher drug-dose combination (20 mg/kg/3.125 mg/kg) was observed to reduce the density of 5-HT transporters in rat striatum at both 7 and 28 days after cessation of treatment. In addition, combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg) caused greater weight loss than that observed with either compound alone. Collectively, the present data demonstrate that combined Phen/Fen administration enhances the neurotoxicity of Phen or Fen on 5-HT neurons.
Asunto(s)
Sistema Nervioso Central/efectos de los fármacos , Sinergismo Farmacológico , Fenfluramina/farmacología , Fentermina/farmacología , Serotonina/metabolismo , Animales , Sistema Nervioso Central/metabolismo , Combinación de Medicamentos , Fenfluramina/administración & dosificación , Hipotálamo/efectos de los fármacos , Masculino , Fentermina/administración & dosificación , Ratas , Ratas Sprague-DawleyRESUMEN
The effects of a high dose methylenedioxymethamphetamine (MDMA) regimen on the serotonin (5-HT) system were evaluated over a 52-wk period. MDMA was administered to rats (20 mg/kg) 8 times at 12-hr intervals. Tissue concentrations of dopamine (DA) and 5-HT, and synaptosomal uptake of 3H-5-HT and 3H-DA were measured at 2, 8, 16, 32 or 52 wk posttreatment. Synaptosomal uptake of 3H-5-HT (hippocampus) was decreased at 2 and 8 wk, but not at 16, 32 or 52 wk after drug. 5-HT tissue concentrations were measured in frontal cortex, frontal-parietal cortex, occipital-temporal cortex, nucleus accumbens/olfactory tubercle, striatum, amygdala, hippocampus, septum, hypothalamus, ventral tegmentum/substantia nigra. Two weeks after MDMA treatment, all regions showed decreased 5-HT tissue concentrations except septum. Recovery over the 52-wk interval was noted for all depleted regions, but the rate and degree of recovery was region dependent. Frontal-parietal cortex, occipital-temporal cortex and hippocampus showed the least recovery, with significant depletions at 52 wk posttreatment. Hypothalamus showed an increase in 5-HT tissue concentrations relative to age-matched controls at 52 wk. These results indicate that a high-dose MDMA regimen results in long-lasting depletions of serotonin. The rate and degree of recovery of serotonin tissue concentrations seen over the 52-wk test period is region specific.
Asunto(s)
Química Encefálica/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Serotoninérgicos/toxicidad , Serotonina/metabolismo , Sinaptosomas/metabolismo , Animales , Dopamina/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Serotonina/análisis , Factores de TiempoRESUMEN
In our study, age-matched Holtzman Sprague-Dawley rats (275-300 g) received injections with either saline (0.9%) or 3,4-methylenedioxymethamphetamine (MDMA; 20 mg/kg free base, s.c) twice daily for 4 days and allowed to recover for 2, 8, 16, 32 and 52 wk after the final injection before death. Radioligand binding studies with 125I-RTI-55 to dopamine uptake sites in striatal homogenates showed no effect of MDMA on the density of dopamine uptake sites. In contrast, saturation binding studies with 125I-RTI-55 to 5-HT uptake sites in hippocampal and frontal-parietal homogenates showed a significant reduction in the number of uptake sites at 2 wk after MDMA treatment (34 and 25%, respectively of controls). By 16 wk, a partial recovery in the number of 5-HT uptake sites was observed in both tissues; however, only a full recovery of serotonin uptake sites was observed in hippocampus at the end of 52 wk. In more detailed studies using autoradiography with 125I-RTI-55, recovery of serotonin uptake sites varied from region to region. In particular, recovery of 5-HT uptake sites in cerebral cortex was observed to follow a rostral-caudal gradient. In addition, recovery of 5-HT uptake site in hippocampus also followed a rostral-caudal gradient. Different rates of recovery of 5-HT uptake sites were also observed for cingulate cortex, laterodorsal thalamus and ventromedial hypothalamus. No effect of MDMA was observed over lateral hypothalamus, substantia nigra and ventral tegmental area, or over serotonergic cell bodies such as dorsal raphe and median raphe. In conclusion, our study is consistent with previous studies describing the selective neurotoxicity of MDMA for serotonin neurons and presents evidence showing the rate of recovery of 5-HT uptake sites varies according to region and that recovery of 5-HT uptake sites in neocortex and hippocampus follows a rostral-caudal gradient.
Asunto(s)
N-Metil-3,4-metilenodioxianfetamina/toxicidad , Serotoninérgicos/toxicidad , Serotonina/metabolismo , Animales , Autorradiografía , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cocaína/análogos & derivados , Cocaína/metabolismo , Dopamina/metabolismo , Masculino , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 blocks the ability of D-methamphetamine (MA) to deplete striatal dopamine (DA). We now report that MK-801 attenuates decreases in serotonin (5-HT) concentration induced by MA and two other amphetamine analogues, 3,4-methylenedioxymethamphetamine (MDMA) and p-chloroamphetamine (PCA). Rats were injected with saline (1.0 ml/kg) or MK-801 (0.5, 1.0 or 2.5 mg/kg) followed by either saline (1.0 mg/kg), MA (4, 2 or 1 injection(s); 10.0, 20.0 or 40.0 mg/kg), MDMA (20.0 or 40.0 mg/kg) or PCA (5.0 or 10.0 mg/kg). In some experiments, two injections of MK-801 or saline were used. Seventy-two hours after the last injection rats were sacrificed and concentrations of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and DA were determined in hippocampus and striatum. MA caused a depletion of 5-HT to 33% of control in hippocampus and to 50% of control in striatum after the 4 x 10.0 mg/kg dose regimen. When MK-801 (2.5 mg/kg) was co-administered with MA, concentrations of 5-HT did not differ from control levels in either brain region. MDMA depleted 5-HT to approximately 58% of control in hippocampus and 66% of control in striatum at the 40 mg/kg dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
3,4-Metilenodioxianfetamina/análogos & derivados , Maleato de Dizocilpina/farmacología , Metanfetamina/antagonistas & inhibidores , N-Metilaspartato/antagonistas & inhibidores , Serotonina/metabolismo , p-Cloroanfetamina/antagonistas & inhibidores , 3,4-Metilenodioxianfetamina/antagonistas & inhibidores , 3,4-Metilenodioxianfetamina/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Metanfetamina/farmacología , N-Metil-3,4-metilenodioxianfetamina , Ratas , p-Cloroanfetamina/farmacologíaRESUMEN
Monoamine uptake inhibitors block the neurotoxic effects of methamphetamine (MA) upon dopaminergic and serotonergic neurons in the rat. The neurotoxic effects of MA upon dopaminergic neurons have previously been suggested to be mediated via formation of 6-hydroxydopamine (6-OHDA) from endogenous stores of dopamine (DA). In the present experiments, administration of the DA uptake inhibitor amfonelic acid (AFA, 10 mg/kg, i.p.) did not block the formation of 6-OHDA in rats treated with a single s.c. 100 mg/kg dose of MA. Consistent with the lack of effect by AFA on MA-induced 6-OHDA formation, neither AFA (10 mg/kg, i.p.) nor the DA and 5-hydroxytryptamine (5-HT) uptake inhibitor mazindol (40 mg/kg i.p., MAZ) blocked the depletion seen in neostriatal DA levels 1, 2 or 8 h following administration of a single 100 mg/kg dose of MA. In fact, AFA enhanced the DA depletions 2 and 8 h following MA administration. AFA also enhanced the MA-induced increase in locomotor activity in rats and this effect was blocked by lesions of dopaminergic neurons with i.v.t. (intraventricular) 6-OHDA in desipramine-pretreated rats. These results suggest that DA uptake inhibitors do not prevent the neurotoxic effect of MA on DA neurons by either preventing entry of MA into the cell or blocking the efflux of DA out of the cell. Instead, the DA uptake inhibitors appear to prevent the neurotoxic effect of MA upon dopaminergic neurons by blocking entry of 6-OHDA into the cell.
Asunto(s)
Encéfalo/metabolismo , Dopamina/metabolismo , Hidroxidopaminas/metabolismo , Metanfetamina/farmacología , Actividad Motora/fisiología , Inhibidores de la Captación de Neurotransmisores/farmacología , Serotonina/metabolismo , Animales , Encéfalo/efectos de los fármacos , Masculino , Mazindol/farmacología , Actividad Motora/efectos de los fármacos , Ácido Nalidíxico/análogos & derivados , Naftiridinas/farmacología , Oxidopamina , Ratas , Ratas EndogámicasRESUMEN
Depletion of brain dopamine (DA) by pretreatment with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMT) has been shown to prevent the long-term neurotoxic effects of methamphetamine (MA). In addition, it has recently been reported that the neurotoxins 6-hydroxydopamine (6-OHDA) and 5,6-dihydroxytryptamine (5,6-DHT) are formed endogenously in neostriatum and hippocampus, respectively, following a single neurotoxic dose of MA. We, therefore, have examined the ability of AMT pretreatment to prevent the MA-induced formation of 6-OHDA and 5,6-DHT. We report that AMT pretreatment significantly decreases the frequency with which 6-OHDA and 5,6-DHT are detected following MA administration. Neurotoxin formation is compared with brain levels of DA and 5-hydroxytryptamine (5-HT) 2 weeks after MA administration. It is concluded that the ability of AMT to attenuate both 6-OHDA formation and long-term depletions of DA is due to a decrease in the MA-releasable pool of DA. The effect of AMT on MA-induced depletions of 5-HT is less clear and may involve additional factors.
Asunto(s)
5,6-Dihidroxitriptamina/metabolismo , Encéfalo/metabolismo , Dopamina/metabolismo , Hidroxidopaminas/metabolismo , Metanfetamina/farmacología , Metiltirosinas/farmacología , Neurotoxinas/metabolismo , Animales , Encéfalo/efectos de los fármacos , Masculino , Neurotoxinas/farmacología , Oxidopamina , Ratas , Ratas Endogámicas , alfa-MetiltirosinaRESUMEN
Neostriatal 6-hydroxydopamine (6-OHDA) was detected in 6 of 13 rats pretreated 2 or 4 hr earlier with methamphetamine (MA; 100 mg/kg, SC) and pargyline (25 mg/kg, IP, 30 min before MA injection). Neostriatal 6-OHDA was detected in 2 of 16 rats treated 2 or 4 hr earlier with MA. These results suggest that pargyline pretreatment may enhance formation of 6-OHDA from endogenous stores of dopamine (DA) following MA administration. Alternatively, these results suggest that pargyline pretreatment may protect endogenously formed 6-OHDA from oxidative deamination by monoamine oxidase. Enhancement of MA-induced neostriatal 6-OHDA levels may be the mechanism by which pargyline enhances the long-term neurotoxic effects of MA upon dopaminergic nerve terminals. These observations support the hypothesis that MA toxicity to DA-containing fibers is caused by the conversion of released DA into 6-OHDA.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Hidroxidopaminas/metabolismo , Metanfetamina/farmacología , Pargilina/farmacología , Animales , Cuerpo Estriado/metabolismo , Sinergismo Farmacológico , Masculino , Oxidopamina , Ratas , Ratas EndogámicasRESUMEN
A single large dose (100 mg/kg, s.c.) of methamphetamine (MA) is known to exert neurotoxic effects on dopaminergic neurons. The potency at which a series of dopamine (DA) uptake inhibitors blocked MA-induced neostriatal depletions (amfonelic acid (AFA) much greater than mazindol (MAZ) greater than or equal to bupropion (BUP) greater than benztropine (BENZ)) was similar to their potency at blocking 6-hydroxydopamine (6-OHDA) neurotoxicity in rats. Amfonelic acid was able to block long-term neostriatal DA depletions when given 8 h, but not 16 h, after a single large MA dose. These results suggest that an intact and functional DA uptake site is necessary for the development of MA-induced long-term DA depletions.
Asunto(s)
Cuerpo Estriado/fisiología , Dopamina/fisiología , Indoles/farmacología , Mazindol/farmacología , Metanfetamina/toxicidad , Naftiridinas/farmacología , Neurotoxinas/farmacología , Inhibidores de la Captación de Neurotransmisores/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Hidroxidopaminas/toxicidad , Masculino , Ácido Nalidíxico/análogos & derivados , Oxidopamina , Ratas , Ratas Endogámicas , Serotonina/fisiologíaRESUMEN
The behavioral effect of single administration of +/- 3,4-methylene-dioxymethamphetamine (MDMA) on rats performing on the differential-reinforcement-of-low-rate 72-second schedule (DRL 72-sec) was compared before and after a period of repeated administration of MDMA known to deplete 5-hydroxytryptamine (5-HT) levels in the brain. Single administration of MDMA decreased reinforcement rate (1, 2, 4, 6 mg/kg) and increased response rate (4,6 mg/kg) of rats performing on the DRL 72-sec schedule. This effect is typical of amphetamines and other psychomotor stimulants. Four weeks after repeated administration of MDMA (6 mg/kg twice daily for 4 days) there was an increase in sensitivity to the effect of single administration of MDMA. Doses of 2, 4 and 6 mg/kg of MDMA resulted in increases in response rate that were significantly greater after repeated MDMA administration than before. Doses of 0.5, 2, and 6 mg/kg of MDMA resulted in decreases of reinforcement rate that were significantly greater after repeated MDMA administration than before. Repeated administration of MDMA resulted in long-term depletion of serotonin levels by 30-50% in the amygdala, neostriatum, hippocampus and the frontal cortex. Norepinephrine and dopamine (DA) levels were not significantly different from control in any of the brain regions analyzed. The behavioral and neurochemical results suggest that serotonergic neurons normally exert an inhibitory action upon the psychomotor stimulant effects of MDMA. Since the psychomotor stimulant effects of amphetamines appear to be mediated primarily by the dopamine system, these results provide evidence that 5-HT and DA may represent opposing systems in the DRL schedule-controlled behavior.
Asunto(s)
3,4-Metilenodioxianfetamina/farmacología , Anfetaminas/farmacología , Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Esquema de Refuerzo , Serotonina/deficiencia , 3,4-Metilenodioxianfetamina/administración & dosificación , 3,4-Metilenodioxianfetamina/análogos & derivados , Animales , Monoaminas Biogénicas/metabolismo , Condicionamiento Psicológico/efectos de los fármacos , Dopamina/análisis , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Masculino , N-Metil-3,4-metilenodioxianfetamina , Ratas , Ratas Endogámicas , Serotonina/análisis , Serotonina/metabolismo , Factores de TiempoRESUMEN
6-Hydroxydopamine (6-OHDA; 200 micrograms, 150 micrograms or 110 micrograms) or vehicle was infused stereotaxically into the lateral ventricles of rats, usually following pretreatment with desmethylimipramine (DMI). Various brain regions were then assayed for dopamine (DA), serotonin (5-HT) and norepinephrine (NE). As expected, 6-OHDA depleted DA in all brain regions examined. Unexpectedly, however, the two highest doses of 6-OHDA significantly decreased 5-HT levels in the hippocampus and increased 5-HT levels in the striatum. In addition, despite pretreatment with doses of DMI commonly considered adequate to block 6-OHDA-induced depletion of NE, all doses of 6-OHDA tested significantly reduced NE levels in the hippocampus, hypothalamus and septum. We interpret our data as suggesting that some brain regions are susceptible to nonspecific toxic effects of 6-OHDA at doses commonly employed. Furthermore, these nonspecific effects may or may not occur, depending on seemingly minor variations in experimental technique.
Asunto(s)
Encéfalo/efectos de los fármacos , Hidroxidopaminas/toxicidad , Simpatectomía Química , Animales , Aminas Biogénicas/metabolismo , Cuerpo Estriado , Desipramina/farmacología , Dopamina/metabolismo , Inyecciones , Inyecciones Intraventriculares , Masculino , Norepinefrina/metabolismo , Oxidopamina , Ratas , Ratas Endogámicas , Serotonina/metabolismoRESUMEN
In summary, we have shown that MA is toxic to both 5-HT and DA cells and we have proposed a mechanism that would account for this response, namely, the conversion of the transmitters to neurotoxins. In addition, brain depletions of DA seem regionally specific with larger depletions occurring in some areas than in others. The depletions, however, do not seem to depend entirely on the nuclei of origin, that is, substantia nigra versus VTA. 5-HT was depleted by different amounts in the various regions examined and the 5-HT depletions, although proportional to the DA depletions, were consistently greater. The reasons for this differential sensitivity of the 5-HT and DA systems to the toxic effect of MA is speculative, but may be related to the differential formation of toxins due to the differing availability of oxygen and superoxides at serotonergic and dopaminergic synapses.
Asunto(s)
Encéfalo/metabolismo , Dopamina/metabolismo , Metanfetamina/toxicidad , Serotonina/metabolismo , Anfetamina/farmacología , Animales , Encéfalo/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Sistema Límbico/efectos de los fármacos , Sistema Límbico/metabolismo , Mesencéfalo/efectos de los fármacos , Mesencéfalo/metabolismo , Metanfetamina/farmacología , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Especificidad de la Especie , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismoRESUMEN
Para-chloroamphetamine (PCA) has been used to deplete brain serotonin (5-HT) in numerous studies of serotonergic involvement in various behaviors and physiological functions. PCA is believed to cause long-lasting depletions of 5-HT by causing the selective degeneration of serotonergic nerve terminals, but the mechanism by which it exerts this neurotoxic effect is not understood. In this experiment, 5,6-dihydroxytryptamine (5,6-DHT), a serotonergic neurotoxin, was detected by high performance liquid chromatography in the rat hippocampus 0.5-4 h after a single 15 mg/kg i.p. injection of PCA. 5,6-DHT was also detected in the somatosensory cortex following PCA administration, but much less frequently than in the hippocampus. Degenerating nerve terminals were observed in the striatum and somatosensory cortex in silver-stained brain sections from rats injected with PCA 1 or 2 days prior to sacrifice. Laminae III and IV of the somatosensory cortex also contained degenerating neuronal perikarya. The neurochemical and histological effects of PCA are very similar to those produced by a large dose of methylamphetamine (MA) in that both drugs are toxic to serotonergic nerve terminals and neuronal perikarya in the somatosensory cortex. We hypothesize that the formation of 5,6-DHT, perhaps from endogenous 5-HT, may mediate the toxic effects of PCA, MA and other amphetamine-related drugs on serotonergic neurons and on a subpopulation of cortical neurons.
Asunto(s)
5,6-Dihidroxitriptamina/metabolismo , Anfetaminas/farmacología , Química Encefálica/efectos de los fármacos , Degeneración Nerviosa/efectos de los fármacos , Neurotoxinas/farmacología , p-Cloroanfetamina/farmacología , 5,6-Dihidroxitriptamina/fisiología , Animales , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Ácido Hidroxiindolacético/metabolismo , Inyecciones Intraperitoneales , Masculino , Neurotoxinas/metabolismo , Ratas , Ratas Endogámicas , Serotonina/metabolismo , Corteza Somatosensorial/efectos de los fármacos , Corteza Somatosensorial/metabolismo , Corteza Somatosensorial/patología , p-Cloroanfetamina/metabolismoRESUMEN
(+/-)-3,4-Methylenedioxymethylamphetamine (MDMA) was administered s.c. to rats (10, 20 or 40 mg/kg b. wt.) and guinea pigs (20 mg/kg) twice a day for 4 days, 2 weeks before decapitation. Norepinephrine, dopamine and serotonin (5-HT) levels were assayed in the hippocampus, hypothalamus, striatum and neocortex. In rats, MDMA produced dose-dependent reductions in 5-HT in all brain regions examined. The highest dose also reduced norepinephrine and/or dopamine in some regions. The 20-mg/kg dose of MDMA depleted 5-HT in all regions of the guinea pig brain assayed. In both species, repeated administration of 20 mg/kg of MDMA reduced the Vmax but not the Km of 5-HT uptake 2 weeks after administration. A single 40-mg/kg injection of MDMA depleted 5-HT 2 and 8 weeks after administration to rats in all regions of the brain examined except the hypothalamus. Administration of 80 mg/kg of MDMA twice a day for 2 days to rats depleted striatal 5-HT and dopamine. Brain sections from rats injected with MDMA according to this dosage regimen were stained by the Fink-Heimer method. Degenerating axon terminals and cell bodies were observed in the striatum and somatosensory cortex, respectively. These findings suggest that MDMA is toxic to serotonergic and, to a lesser extent, catecholaminergic neurons. Some neurons that do not contain these transmitters (neocortical neurons) are also affected.
Asunto(s)
3,4-Metilenodioxianfetamina/toxicidad , Anfetaminas/toxicidad , Encéfalo/citología , Neuronas/efectos de los fármacos , 3,4-Metilenodioxianfetamina/análogos & derivados , Animales , Encéfalo/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Cinética , Masculino , N-Metil-3,4-metilenodioxianfetamina , Norepinefrina/metabolismo , Ratas , Ratas Endogámicas , Serotonina/metabolismo , Corteza Somatosensorial/efectos de los fármacos , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Distribución TisularRESUMEN
Methamphetamine (MA) in high doses produces long-term toxic effects on the serotonergic system in the rat brain, including depletions of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid and reductions in 5-HT reuptake and tryptophan hydroxylase activity. In this study, the formation of 5,6-dihydroxytryptamine (5,6-DHT), a serotonergic neurotoxin, was observed in the rat hippocampus after a single 100 mg/kg injection of MA. The 5,6-DHT was detected by reverse-phase high-performance liquid chromatography with electrochemical detection in tissue samples taken 0.5-4 h after MA administration; the highest levels of 5,6-DHT (0.032 ng/mg wet tissue) were detected at 1 h. Following administration of MA, 5-HT was also depleted in the neocortex, but 5,6-DHT was not detected as frequently in this brain region as in the hippocampus. Comparisons were made between the long-term hippocampal 5-HT depletions seen either after an injection of MA or after intraventricular 5,6-DHT infusions and the levels of 5,6-DHT measured in the hippocampus shortly after each treatment. The amount of 5,6-DHT produced after MA administration appears to be adequate to cause the observed long-term 5-HT depletions. We suggest that 5,6-DHT formed from 5-HT may mediate the neurotoxic effects of MA on serotonergic nerve terminals.
Asunto(s)
5,6-Dihidroxitriptamina/biosíntesis , Encéfalo/metabolismo , 5,6-Dihidroxitriptamina/administración & dosificación , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ácido Hidroxiindolacético/metabolismo , Inyecciones Subcutáneas , Masculino , Metanfetamina/farmacología , Ratas , Ratas Endogámicas , Serotonina/metabolismo , Factores de TiempoRESUMEN
Male albino rats treated with 6-hydroxydopamine (6-OHDA) became more hyperactive than did vehicle-treated controls when both groups were water-deprived. Rats were treated with vehicle, 150 or 250 micrograms of 6-OHDA intraventricularly, after pretreatment with desmethylimpramine (25 mg/kg) and pargyline (50 mg/kg). Eleven days after these treatments, under ad libitum water conditions, the 6-OHDA-treated rats were slightly hypoactive. After several days of water-deprivation all three groups showed increased mean locomotor activity levels, but rats treated with 6-OHDA showed a much greater increase than did vehicle-treated rats. Under subsequent ad libitum and deprivation conditions, locomotor activity decreased and increased, respectively, in all 3 groups. Again, the changes in activity levels of the 6-OHDA-treated groups were greater than those of the vehicle-treated group. In addition, rats treated with 250 micrograms 6-OHDA seemed to become sensitized to the novel environment of the stabilimeter rather than habituating to it. Dopamine (DA) levels were decreased as a result of the injections of 6-OHDA, and significant correlations were found between DA levels in the caudate-putamen and nucleus accumbens, and locomotor activity levels. These results, as well as those obtained by others, suggest that there is an interaction among DA levels, deprivational states, and locomotor activity levels in rats.
Asunto(s)
Encéfalo/fisiología , Dopamina/fisiología , Hidroxidopaminas/farmacología , Actividad Motora/fisiología , Privación de Agua/fisiología , Animales , Mapeo Encefálico , Cuerpo Estriado/fisiología , Lóbulo Frontal/fisiología , Inyecciones Intraventriculares , Sistema Límbico/fisiología , Masculino , Oxidopamina , Ratas , Ratas EndogámicasRESUMEN
A method is described for the separation and quantitation of catecholamines, serotonin, and their major metabolites with use of reverse-phase, ion-pair liquid chromatography with electrochemical detection. This method employs columns packed with a microparticulate C-18 resin, octyl sodium sulfate as the ion-pairing agent, and isocratic elution with a citrate-phosphate buffer containing methanol. Conditions are described for the separation of norepinephrine, normetanephrine, 3-methoxy-4-hydroxyphenylglycol, epinephrine, metanephrine, dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, serotonin, and 5-hydroxyindole-3-acetic acid and for their quantitation in extracts of rat brain tissue.
Asunto(s)
Química Encefálica , Dopamina/análisis , Norepinefrina/análisis , Serotonina/análisis , Ácido 3,4-Dihidroxifenilacético/análisis , Animales , Núcleo Caudado/análisis , Cromatografía Líquida de Alta Presión , Electroquímica , Ácido Homovanílico/análisis , Ácido Hidroxiindolacético/análisis , Hipotálamo/análisis , Metoxihidroxifenilglicol/análisis , Normetanefrina/análisis , Putamen/análisis , RatasRESUMEN
We now report that 6-hydroxydopamine (0.39 +/- 0.31 nanograms/mg of tissue at 2 hr) is formed in the rat caudate nucleus after a single injection of methylamphetamine (100 mg/kg). The same dose of methylamphetamine causes approximately 50% depletion of caudate dopamine 2 weeks after the injection. We suggest that the formation of 6-hydroxydopamine from endogenous dopamine is responsible for the neurotoxicity to dopamine terminals seen after methylamphetamine administration.
Asunto(s)
Núcleo Caudado/metabolismo , Hidroxidopaminas/biosíntesis , Metanfetamina/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Núcleo Caudado/efectos de los fármacos , Dopamina/metabolismo , Masculino , Enfermedades del Sistema Nervioso/inducido químicamente , Oxidopamina , Ratas , Ratas EndogámicasRESUMEN
The accumulation of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), but not the serotonin metabolite 5-hydroxyindoleacetic acid, in the hypothalamus is increased in rats during the second, third and fourth hours of a four hour period of access to food following a 20 hour period of food deprivation. This metabolic change does not correlate with duration of access to food or with amount of food consumed. These results suggest that increased hypothalamic dopamine metabolism during feeding is not related in any simple way to either the onset or termination of feeding.
Asunto(s)
Dopamina/metabolismo , Ingestión de Alimentos , Hipotálamo/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Ácido Hidroxiindolacético/metabolismo , Masculino , Ratas , Ratas Endogámicas , Serotonina/metabolismo , Factores de TiempoRESUMEN
Although the performance of positively reinforced operant behavior is accompanied by increased turnover of brain dopamine in the rat, the accumulation of 3,4-dihydroxyphenylacetic acid (DOPAC), the major metabolic product of dopamine in brain, is not increased during operant performance. The hypothesis that the lack of increased DOPAC accumulation stems from an increase in the rate at which DOPAC is eliminated from the brain was tested by measuring the relative rate of DOPAC transport from brain in rats performing operant behavior and in control rats. The transport of DOPAC was estimated following inhibition of monoamine oxidase with pargyline. The pargyline-induced depletions of DOPAC in the caudate putamen and amygdala were significantly greater in rats that performed operant behavior than in control rats. In the caudate putamen, the concentrations of homovanillic acid and 5-hydroxyindoleacetic acid were also depleted by pargyline to a greater extent in operant performing rats than in controls. These results suggest that in addition to the increased turnover of dopamine in central neurons during operant behavior, the rate of elimination of acidic amine metabolites from brain is also accelerated.