In vivo imaging of dopamine reuptake sites in the primate brain using single photon emission computed tomography (SPECT) and iodine-123 labeled RTI-55.
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Animals↗
Biomedical subjects
G A Ricaurte
Publications and source records attributed to G A Ricaurte.
[123/125I]RTI-55, an in vivo label for the serotonin transporter.
[123I]RTI-55, an iodinated derivative of the cocaine analog 3 beta-phenyltropane-2 beta-carboxylic acid methyl ester, was evaluated as an agent for in vivo labeling of the serotonin transporter. Labeling of the precursor of RTI-55 with I-123 was efficient and yielded a high specific activity product. After intravenous injection of [123I]RTI-55 into rats, the tracer accumulated in regions with high densities of serotonin and dopamine uptake sites. The distribution of [123I]RTI-55 binding in areas rich in serotonin uptake sites correlated with [3H]serotonin uptake measured in vitro in the same regions. Specific [123I]RTI-55 binding to serotonin uptake sites was inhibited by paroxetine but not by GBR 12,909. Treatment of rats with neurotoxic doses of fenfluramine caused decreases of 66% (in the hypothalamus) to 83% (in the superior colliculi) of specific [125I]RTI-55 binding in all areas except in the striatum and the olfactory tubercles (regions rich in dopamine transporters). These results indicate that [123/125I]RTI-55 binds, although not selectively, to the serotonin transporter in vivo. Furthermore, they suggest that [123I]RTI-55 holds promise as a SPECT imaging agent for the study of the serotonin transporter in humans in health and disease.
Animals↗
Reinforcing effects of enantiomers of N,N-dimethylamphetamine in squirrel monkeys.
Reinforcing effects of the (+)- and (-)-enantiomers of N,N-dimethylamphetamine, a drug that is abused in humans, were studied in squirrel monkeys (Siamiri sciureus) trained under schedules of intermittent cocaine reinforcement. During training, each 30th response produced an injection of cocaine (fixed-ratio schedule), which was followed by a 1-min period during which lights were out and responses had no scheduled consequences (timeout). Sessions in which cocaine injections were scheduled alternated in an irregular sequence with sessions in which saline injections were scheduled. After training, response rates were well maintained by cocaine (response rates approximated 1.4 responses per second) but occurred relatively infrequently during sessions in which saline was injected (response rates approximated 0.3 responses per second). Doses of 10 to 56 micrograms/kg/injection of (+)-N,N-dimethylamphetamine maintained rates of responding significantly higher than those maintained by saline. The (-)-enantiomer did not maintain rates of responding that were higher than those maintained by saline when tested at doses up to 100 micrograms/kg/injection. These findings support previous results indicating that N,N-dimethylamphetamine will function as a reinforcer in laboratory animals. Further, they suggest that the significant reinforcing activity of this drug is restricted to the (+)-enantiomer.
Animals↗
Repeated administration of MDMA causes transient down-regulation of serotonin 5-HT2 receptors.
The present study examined short- and long-term effects of MDMA (3,4-methylene-dioxymethamphetamine) on serotonin (5-HT2 and 5-HT1c) receptors in the brain of the rat. N1-Methyl-2-[125I]lysergic acid diethylamide ([125I]MIL) was used to label these receptors in vitro and in vivo. The usefulness of [125I]MIL for in vivo detection of changes in 5-HT2 receptors was confirmed in preliminary experiments in which rats were treated chronically with mianserin (5 mg/kg, once daily for 10 days). Decreases in specific in vivo binding of [125I]MIL, after treatment with mianserin were found to be of the same magnitude as those determined by others, using in vitro methods. The MDMA (8 doses; 5-20 mg/kg each) was administered to rats over a period of 4 days. At various times after administration of the last dose of MDMA, the binding of [125I]MIL was measured. Acutely, treatment with MDMA (20 mg/kg) reduced specific in vivo binding of [125I]MIL in all regions of brain studied. For example, in the frontal cortex, specific binding of [125I]MIL was decreased by 80% at 6 hr and by 62% at 24 hr, after cessation of treatment with MDMA. Twenty-one days after administration of MDMA however, the number of binding sites for [125I]MIL was back to control levels. Reductions in in vivo binding of [125I]MIL in frontal cortex were dependent on the dose of MDMA injected and were associated with decreases in the number of binding sites for [125I]MIL (Bmax values) in tissue homogenates of the same area. Autoradiographic studies of MDMA-treated rats confirmed the decreased density of 5-HT2 receptors and also suggested that the 5-HT1c receptor of the choroid plexus was not affected. These results indicate that repeated administration of MDMA caused transient down-regulation of 5-HT2 receptors in the brain of the rat. Further, they demonstrated that [125I]MIL is a suitable radioligand for labeling 5-HT2 receptors, both in vitro and in vivo. Once labeled with an appropriate radionuclide for SPECT (single photon emission computed tomography) or PET (positron emission tomography), MIL should prove useful for monitoring changes in the density of serotonin receptors in the living mammalian brain.
3,4-Methylenedioxyamphetamine↗
Chronic 3,4-methylenedioxymethamphetamine (MDMA) use: effects on mood and neuropsychological function?
3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a selective serotonin (5-HT) neurotoxin in animals. There is now preliminary evidence in humans of 5-HT deficits associated with extensive use of MDMA. In order to begin to describe the cognitive and mood effects of chronic MDMA use, nine individuals with extensive MDMA use histories were studied. Despite the absence of memory deficits on clinical examination, a pattern of mild-to-moderate impairment was observed on both the Initial and Delayed Paragraph Tests of the Wechsler Memory Scale; eight of the subjects had at least mild impairment on at least one test in the neuropsychological battery. Despite previously reported suggestive evidence of 5-HT deficit in this group, none reported depressed mood or met clinical criteria for an affective disorder at the time of testing. These preliminary findings raise concern about possible detrimental effects of MDMA use on neuropsychological function for future systematic study and they highlight important issues regarding the effects of 5-HT deficits on cognitive function and mood regulation.
3,4-Methylenedioxyamphetamine↗
Lasting effects of (+-)-3,4-methylenedioxymethamphetamine (MDMA) on central serotonergic neurons in nonhuman primates: neurochemical observations.
The purpose of this study was to assess the duration of (+-)-3,4-methylenedioxymethamphetamine's (MDMA's) effects on serotonin containing neurons in nonhuman primates. Fifteen squirrel monkeys were used: three served as controls, 12 received MDMA s.c. at a dose of 5 mg/kg twice daily for 4 consecutive days. Two weeks, 10 weeks, 8 months and 18 months after drug treatment, groups (n = 3) of MDMA-treated monkeys, along with controls, were examined for regional brain content of serotonin and 5-hydroxyindoleacetic acid, and for the number of [3H] paroxetine-labeled serotonin uptake sites. Two weeks after MDMA treatment, monkeys showed profound reductions in all three serotonergic presynaptic markers. By 10 weeks, there was evidence of partial recovery in some brain regions (e.g., hippocampus, caudate nucleus, frontal cortex). However, by 18 months, it was evident that recovery did not continue, as serotonergic deficits returned to the level of severity observed 2 weeks after MDMA treatment. This was the case in all brain regions examined except the thalamus and hypothalamus. In the thalamus, the level of serotonin increased to 63% of control, whereas that of 5-hydroxyindoleacetic acid recovered completely. In the hypothalamus, concentrations of serotonin and 5-hydroxyindoleacetic acid were 140 and 187% of control, respectively. These results suggest that MDMA produces lasting effects on serotonergic neurons in nonhuman primates, with most brain regions showing evidence of persistent denervation and some showing signs of reinnervation (thalamus) or possibly even hyperinnervation (hypothalamus). The morphological and functional correlates of these enduring neurochemical changes in the MDMA-treated primate remain to be delineated.
3,4-Dihydroxyphenylacetic Acid↗
Dexfenfluramine neurotoxicity in brains of non-human primates.
Dexfenfluramine, a drug prescribed for appetite suppression, was evaluated in non-human primates for its potential to produce toxic effects on brain serotonin (5-HT) neurons. Squirrel monkeys received dexfenfluramine subcutaneously twice daily for four days at doses of 1.25 or 5.00 mg/kg. Two weeks later, a dose-related depletion of 5-HT and 5-hydroxyindoleacetic acid was found, together with a reduced number of 5-HT uptake sites. Morphological studies showed acute pathological changes in 5-HT axons, followed by a persistent decrease in 5-HT axon density. Our findings indicate that dexfenfluramine damages central 5-HT neurons in monkeys and raise concern about the potential neurotoxicity of this drug in man.
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Major metabolites of (+/-)3,4-methylenedioxyamphetamine (MDA) do not mediate its toxic effects on brain serotonin neurons.
The two major metabolites of (+/-)3,4-methylenedioxyamphetamine (MDA), alpha-methyldopamine (alpha-MeDA) and 3-O-methyl-alpha-methyldopamine (3-O-Me-alpha-MeDA), were administered to rats intracerebroventricularly and into brain parenchyma. In addition, their precursors, (alpha-MeDOPA and 3-O-Me-alpha-MeDOPA, respectively) were administered systemically, individually and in combination. None of these treatments produced a lasting depletion of brain serotonin (5-HT). These findings suggest that neither of MDA's major metabolites mediate its toxic effects on 5-HT neurons and that either a minor metabolite is responsible or that alternate mechanisms are involved.
3,4-Methylenedioxyamphetamine↗
The effects of repeated administration of MDMA on the expression of sexual behavior in the male rat.
3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") is a potent neurotoxin which preferentially produces 5-HT nerve terminal degeneration in the CNS in both rodents and primates. Timely research on the behavioral effects of acute and long term treatment of MDMA is critical due to the neuropathological effects of MDMA and its abuse liability. Presently, there are no published reports that have systematically examined the effects of acute or chronic treatment of MDMA on animal sexual behavior. Accordingly, the effects of repeated systemic administration of MDMA on a variety of parameters of male sexual behavior in sexually vigorous male rats were studied. Treatment consisted of subcutaneous injections of MDMA (40 mg/kg) or saline (1 ml/kg) every 12 hours for 4 consecutive days. In addition, neurochemical assessments of brain 5-HT and 5-HIAA depletion following repeated MDMA treatment were also conducted using reverse phase liquid chromatography. The results of this study revealed that repeated systemic administration of MDMA to sexually vigorous male rats produced a transient disruption of the expression of male copulatory behavior. In addition, in MDMA-treated males that did display copulatory behavior, both the ejaculation latency and postejaculatory interval were dramatically lengthened when compared to saline injected controls. Surprisingly, one week after the first behavioral test, copulatory behavior in MDMA treated rats appeared unaffected despite a marked depletion of 5-HT and 5-HIAA content in the striatum, and hippocampus.
3,4-Methylenedioxyamphetamine↗
Lasting neuropsychiatric sequelae of (+-)methylenedioxymethamphetamine ('ecstasy') in recreational users.
Two persons are described who demonstrated prolonged neuropsychiatric syndromes after the ingestion of large doses of (+-)-3,4-methylenedioxymethamphetamine (MDMA), a recreationally used amphetamine analog. These cases suggest that MDMA, known to be neurotoxic to serotonin neurons in several experimental animals, may also produce untoward effects in humans. In addition, they provide evidence that ingestion of large doses of MDMA can produce lasting adverse functional consequences in vulnerable persons.
3,4-Methylenedioxyamphetamine↗
Paroxetine as an in vivo indicator of 3,4-methylenedioxymethamphetamine neurotoxicity: a presynaptic serotonergic positron emission tomography ligand?
The present study sought to determine whether [3H]paroxetine, a potent and selective inhibitor of serotonin uptake in vitro, could be used to label the serotonin transporter in the rat brain in vivo such that it might be employed to develop a presynaptic serotonergic positron emission tomography ligand. Tritium labeled paroxetine was administered intravenously to rats by means of tail vein injection. Four hours later, specific [3H]paroxetine binding was determined by subtracting non-specific binding in the cerebellum from total binding in other brain regions of interest. The distribution of specific [3H]paroxetine binding paralleled the distribution of serotonin uptake sites in all brain regions examined. Pretreatment with serotonin re-uptake inhibitors (citalopram or sertraline) reduced in vivo specific [3H]paroxetine binding by as much as 99%. Specific in vivo [3H]paroxetine binding was further characterized through the use of 5,7-dihydroxytryptamine (5,7-DHT), a known serotonergic neurotoxin. 5,7-DHT (200 micrograms, i.c.v.) caused a marked reduction in specific [3H]paroxetine binding, and induced a prolonged depletion of regional brain serotonin. In a final study, the feasibility of using in vivo [3H]paroxetine binding as an indicator of serotonergic damage induced by another neurotoxin (3,4-methylenedioxymethamphetamine, MDMA) was tested. MDMA-treated rats showed a profound reduction in in vivo [3H]paroxetine binding, along with a lasting depletion of regional brain serotonin. These results demonstrate that [3H]paroxetine can be used to label serotonin uptake sites in the rat brain in vivo, and that the damage induced by serotonergic neurotoxins can be detected using in vivo [3H]paroxetine binding as an indicator. Paroxetine (or one of its derivatives) therefore holds promise as a PET ligand for studying serotonergic neurons in the living human brain in health as well as after neurotoxic injury.
3,4-Methylenedioxyamphetamine↗
Modulating role of dopamine on anesthetic requirements.
The influence of dopamine on halothane anesthetic requirements was determined in mice. Halothane anesthetic requirement was defined as the minimum anesthetic concentration (MAC) that prevented 50% animals from moving in response to a supramaximal stimulus. Levodopa (L-DOPA) dose-dependently decreased halothane MAC to a maximum of 49% of control; over the same dose range L-DOPA increased striatal dopamine nearly 4-fold. The MAC-reducing effect of L-DOPA was attenuated by selective antagonism of the D2 dopamine receptor with YM-09151-2 while selective blockade of the D1 dopamine receptor with SCH-23390 did not alter L-DOPA's effect on the MAC for halothane. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) decreased striatal dopamine by 82% and increased the MAC for halothane by 27%. Repletion of striatal dopamine with L-DOPA, in MPTP-treated mice, restored the MAC for halothane back to the control state. The regression line derived from the plot of halothane MAC versus striatal dopamine content shows a highly significant correlation between the two variables (r2 = 0.94). These are the first results to suggest that anesthetic requirements can be modulated directly and precisely by increasing or decreasing the content of a single neurotransmitter in the central nervous system.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Aminergic metabolites in cerebrospinal fluid of humans previously exposed to MDMA: preliminary observations.
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3,4-Methylenedioxyamphetamine↗
Behavioral effects of N-methylamphetamine and N,N-dimethylamphetamine in rats and squirrel monkeys.
The N-methylated derivative of N-methamphetamine (MA), N,N-dimethylamphetamine (NNDMA), has recently been synthesized for illicit use. The present study compared the psychomotor stimulant, discriminative stimulus, reinforcing and lethal effects of these analogs in rats and squirrel monkeys. NNDMA was 6 to 12 times less potent than MA in decreasing rates of responding in rats or monkeys under fixed interval or fixed ratio schedules of food presentation. Both MA and NNDMA produced dose-dependent increases in the percentage of cocaine-lever responses in rats trained to discriminate 10 mg/kg of cocaine from saline, with NNDMA 12 times less potent than MA. Response-produced i.v. infusions of MA or NNDMA maintained rates of responding that were higher than those maintained by saline infusions in squirrel monkeys trained to self-administer cocaine; NNDMA was 10 times less potent than MA in producing these reinforcing effects. Both drugs increased fixed interval responding in squirrel monkeys; MA was more efficacious than NNDMA. MA also increased rates of responding in rats during time-out periods in which responses had no scheduled consequences, whereas NNDMA did not. Onset and time course data suggested that conversion of NNDMA to MA was probably not necessary for the behavioral effects of NNDMA. In contrast to the relative potencies in behavioral tests, NNDMA was only 3 times less potent than MA in its lethal effects in rats. However, lethality of both drugs was prevented by haloperidol. In general, MA displayed a wider separation in the doses required to produce behavioral vs. lethal effects than did NNDMA.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The amine-depleting effects of 5,7-dihydroxytryptamine (5,7-DHT) in C57BL/6 mice do not increase with age.
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.
5,7-Dihydroxytryptamine↗
Evaluation of the neurotoxic potential of N,N-dimethylamphetamine: an illicit analog of methamphetamine.
The purpose of this study was to evaluate the neurotoxic potential of N,N-dimethylamphetamine (N,N-DMA), a controlled substance analog that has recently appeared on the illicit drug market, and compare it to that of methamphetamine, a structurally related drug with known dopaminergic and serotonergic neurotoxic activity. Like methamphetamine, N,N-DMA induced degeneration of nerve terminals in the mouse striatum, but did not produce cell loss in the pars compacta of the substantia nigra. The dopamine-depleting effects of N,N-DMA were approximately one-eighth of those of methamphetamine. Assessment of N,N-DMA's effects on serotonergic neurons showed that it did not produce a long-lasting depletion of serotonin in either the mouse or rat brain. By contrast, equivalent doses of methamphetamine depleted serotonin in the rat brain by 82%. These results indicate that N,N-DMA, the N-methylated analog of methamphetamine, is considerably less potent than its parent compound both as a dopaminergic and serotonergic neurotoxin, and raise the question of whether or not it may be possible to dissociate the neurotoxic effects of methamphetamine from its reinforcing actions by means of N-methylation. Safety of N,N-DMA in humans remains to be investigated.
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Long-term effects of chronic methamphetamine administration in rhesus monkeys.
Biochemical and neuropathological effects of exposure to a high dose regimen of methamphetamine were evaluated in rhesus monkeys approximately 4 years after the last drug injection. Concentrations of dopamine and serotonin in caudate were below control levels as were concentrations of serotonin in several other brain regions. These changes were more severe in a monkey that was exposed twice to the drug regimen. A decrease in caudate synaptosomal uptake of both neurotransmitters as well as neuropathological changes were evident in that monkey. Although it is possible that partial recovery occurred, these results strongly suggest that methamphetamine-induced neurotoxicity may be permanent.
Animals↗
Neuroendocrine and mood responses to intravenous L-tryptophan in 3,4-methylenedioxymethamphetamine (MDMA) users. Preliminary observations.
3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a selective serotonin (5-HT) neurotoxin in laboratory animals. To assess its effects on 5-HT function in humans, serum prolactin (PRL) and mood responses to intravenous L-tryptophan were measured in nine recreational users of MDMA and compared with findings from nine matched healthy controls. L-Tryptophan induced a rise in the PRL concentration in controls, but not in MDMA users. Peak change and the area under the curve of the PRL response appeared to be blunted in MDMA users, but the difference from controls did not reach statistical significance. This study provides suggestive evidence of altered 5-HT function in MDMA users, but more definitive studies clearly are needed.
3,4-Methylenedioxyamphetamine↗