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G A Ricaurte

Publications and source records attributed to G A Ricaurte.

At least 55 records · Page 3Linked to original sources
PubMed1995

Positron emission tomography imaging of serotonin transporters in the human brain using [11C](+)McN5652.

This paper presents the first Positron Emission Tomography (PET) images of the serotonin (5-hydroxytryptamine, 5-HT) transporter in the living human brain. PET imaging was performed in three healthy subjects after administration of [11C](+)McN5652 (the (+) enantiomer of trans-1,2,3,5,6,10 beta-hexahydro- 6-[4-(methylthio) phenyl]pyrrolo-[2,1-a] -isoquinolone), a radioligand previously shown to selectively label the 5-HT transporter in vivo in the mammalian (mouse and baboon) brain. To demonstrate the specificity of [11C](+)McN5652 binding, additional images were obtained in the same subjects after injection of [11C](-)McN5652, the pharmacologically inactive enantiomer, and, in two of the subjects, with [11C](+)McN5652 after pretreatment with the 5-HT uptake site blocker fluoxetine. Highest accumulation of [11C](+)McN5652 was observed in the midbrain, putamen, caudate nucleus, hypothalamus, and thalamus, regions known to contain high densities of 5-HT transporters. In these areas [11C](+)McN5652 concentrations rose steadily over 120 min. In contrast, with [11C](-)McN5652 and when the [11C](+)McN5652 binding was inhibited with fluoxetine, radioactivity concentrations declined after reaching a maximum (at 20 to 30 min). Inhibition studies with fluoxetine suggest that only with [11C](+)McN5652, there is specific binding. In the cerebellum, a region relatively void of 5-HT transporters, both [11C](+)McN5652 with and without fluoxetine block and [11C](-)McN5652 were released at approximately the same rate. The results of the studies indicate that [11C](+)McN5652 labels 5-HT transporter sites in the human brain. Quantitative PET imaging studies with this new tracer should provide valuable information on the status of these sites in health and disease.

Adult↗
PubMed1995

Positron emission tomography of 5-HT transporter sites in the baboon brain with [11C]McN5652.

[11C]McN5652 is a new radioligand specific for 5-hydroxytryptamine (5-HT; serotonin) transporters. In this study we used [11C]McN5652 to image the 5-HT transporter sites in baboon brain by positron emission tomography (PET). Dynamic PET studies were performed in three Papio anubis baboons. The animals were injected intravenously first with 11C-labeled (+)-McN5652([11C](+)McN5652), then with pharmacologically inactive enantiomer 11C-labeled (-)-McN5652 ([11C](-)McN5652); two animals received a third study with [11C](+)McN5652 after pretreatment with the specific 5-HT uptake site inhibitor fluoxetine (5 mg/kg). Initial uptake into the brain was similar for both [11C](+)McN5652 and [11C](-)McN5652. At later times (45-120 min after injection), only [11C](+)McN5652 showed a distribution characteristic for 5-HT uptake sites. In contrast, in studies with [11C](-)McN5652 and in those with [11C](+)McN5652 after 5-HT uptake site blockade with fluoxetine, 11C radioactivity concentrations were significantly lower and the distribution pattern was relatively even. The differences between [11C](+)-and (-)McN5652 were calculated for the time interval 95-125 min postinjection and used to estimate specific binding. Specific binding correlated well (r = 0.95, p < 0.001) with the known density of 5-HT uptake sites in human brain. These results indicate that [11C](+)McN5652 is suitable for PET imaging of 5-HT uptake sites in primate brain.

Animals↗
PubMed1994

Highly potent indanamine serotonin uptake blockers as radiotracers for imaging serotonin uptake sites.

Two highly potent indanamine serotonin (5-HT) uptake blockers, trans-3'-(4'-bromophenyl)-1-indanamine (trans-[11C]DBPI or [11C]Lu 19-056) and its iodo analog, trans-3'(4'-[125I]iodophenyl)-1-indanamine (trans-[125I]DIPI) were evaluated as radiotracers for imaging 5-HT uptake sites in vivo Trans-[11C]DBPI was synthesized by N-methylation of the normethyl precursor with [11C]iodomethane. Trans-[125I]DIPI was synthesized by iododestannylation of the tributyltin precursor with [125I]NaI. Radiochemical yields for the [11C] and [125I] radiotracers were 34 and 40% with specific activities of 4000 and 1800 mCi/mumol, respectively. In vitro, the iodo analog, trans-DIPI, showed an IC50 value of 0.26 nM in inhibition of [3H]paroxetine binding to 5-HT uptake sites in rat cortex. The potency was found to be equivalent to that of paroxetine or McN5652. In vivo, after i.v. injection into mice, both radiotracers showed high uptake in brain (3-4% dose/whole brain at 15 min) and high accumulation into target tissues such as hypothalamus and olfactory tubercles (7-8% dose/g at 60 min). The binding was blocked by pre-injection of 5 mg/kg of peroxetine. While the in vivo distribution agreed with previously reported 5-HT uptake site distribution, the radiotracers showed high uptake in non-target tissues such as cerebellum, resulting in low target-to-non-target ratios (1.5-1.6 at 60 min). Since washout from non-target regions was slower than from target regions, longer-time observation with 125I up to 6 h did not improve the ratios. HPLC analyses of mouse brain homogenates and blocking studies indicated that the high uptake in non-target regions is not the result of metabolism or any interaction of the radiotracers with those tissues via specific binding sites. In spite of low target-to-non-target ratios, target regions with high density of 5-HT uptake sites, such as the raphe nuclei, superior colliculi and substantia nigra, were visualized with trans-[125I]DIPI by ex vivo autoradiography, since the radiotracer showed high specific binding (total mimus nonspecific binding).

Animals↗
PubMed1994

Serotonin neurotoxicity after (+/-)3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy"): a controlled study in humans.

(+/-)3,4-Methylenedioxymethamphetamine (MDMA; "Ecstasy"), an increasingly popular recreational drug, is known to damage brain serotonin 5-hydroxytryptamine (5-HT) neurons in experimental animals. Whether MDMA is neurotoxic in humans has not been established. Thirty MDMA users and 28 controls were admitted to a controlled inpatient setting for measurement of biologic and behavioral indexes of central 5-HT function. Outcome measures obtained after at least 2 weeks of drug abstinence included concentrations of monoamine metabolites in cerebrospinal fluid (CSF), prolactin responses to L-tryptophan, nociceptive responses to ischemic pain, and personality characteristics in which 5-HT has been implicated (i.e., impulsivity and aggression). Subjects with a history of MDMA exposure had lower levels of CSF 5-hydroxyindoleacetic acid (the major metabolite of 5-HT) than controls (p = .001). Although they resembled controls in their prolactin response to L-tryptophan and their response to ischemic pain, MDMA users had lower scores on personality measures of impulsivity (p = .004) and indirect hostility (p = .009). The CSF findings suggest that 5-HT neurotoxicity may be a potential complication of MDMA use. Further, differences in personality support the view that 5-HT systems are involved in modulating impulsive and aggressive personality traits. Additional studies of MDMA-exposed individuals are needed to confirm and extend the present findings. Such studies could help elucidate the role of 5-HT in normal brain function as well as in neuropsychiatric disease states.

3,4-Methylenedioxyamphetamine↗
PubMed1994

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"): pharmacology and toxicology in animals and humans.

(+/-)3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"), a ring-substituted amphetamine derivative first synthesized in 1914, has emerged as a popular recreational drug of abuse over the last decade. Pharmacological studies indicate that MDMA produces a mixture of central stimulant and psychedelic effects, many of which appear to be mediated by brain monoamines, particularly serotonin and dopamine. In addition to its pharmacologic actions, MDMA has been found to possess toxic activity toward brain serotonin neurones. Serotonergic neurotoxicity after MDMA has been demonstrated in a variety of experimental animals (including non-human primates). In monkeys, the neurotoxic dose of MDMA closely approaches that used by humans. While the possibility that MDMA is also neurotoxic in humans is under investigation, other adverse effects of MDMA in humans have been documented, including various systemic complications and a number of untoward neuropsychiatric sequelae. Notably, many of the adverse neuropsychiatric consequences noted after MDMA involve behavioral domains putatively influenced by brain serotonin (e.g., mood, cognition and anxiety). Given the restricted status of MDMA use, retrospective clinical observations from suspecting clinicians will probably continue to be a primary source of information regarding MDMA's effects in humans. As such, this article is intended to familiarize the reader with the behavioral pharmacology and toxicology of MDMA, with the hope that improved recognition of MDMA-related syndromes will provide insight into the function of serotonin in the human brain, in health as well as disease.

3,4-Methylenedioxyamphetamine↗
PubMed1994

Development of PET/SPECT ligands for the serotonin transporter.

There is a great need for PET and SPECT ligands with high affinity and selectivity for the serotonin uptake site. These imaging agents would be useful in screening human populations at risk (e.g., individuals exposed to neurotoxic amphetamines such as MDMA and fenfluramine). Moreover, these radioligands would allow the study of serotonergic function in the normal living human brain, and they also would be useful in the examination of altered serotonergic neurotransmission in diseases such as depression and obsessive-compulsive and other neuropsychiatric disorders. Over the past several years, a number of radioligands have been studied in several laboratories for their in vivo binding to 5-HT uptake sites. Although [3H]paroxetine showed promising binding characteristics, conversion of authentic paroxetine into a PET or SPECT tracer turned out to be difficult and has not been achieved yet. Analogs of paroxetine displayed considerable loss of binding affinity and were, therefore, not useful for imaging purposes. For [11C]fluoxetine, [11C]citalopram, and cis-[11C]DDPI, target-to-nontarget (hypothalamus-to-cerebellar) ratios remained less than 2.0:1 over a 90-min period after injection. The most promising PET agents identified today are [11C]RTI-55 and [11C]McN-5652-X. [11C]RTI-55 labels both 5-HT and DA uptake sites. [11C]McN-5652-X is highly selective for 5-HT uptake sites, and its distribution is consistent with the neuroanatomical distribution of the 5-HT uptake site. Because [11C]McN-5652-Z is a racemic mixture of two stereoisomers, of which the (+) isomer (McN-5652-X) binds to the 5-HT uptake site in vivo and the (-) isomer (McN-5652-W) does not, the possibility exists that regional-specific binding can be determined by subtracting nonspecific binding of the (-) isomer from total radioactivity counts obtained with the (+) isomer. [11C]McN-5652-X is the best PET radioligand for the 5-HT uptake site described thus far. This tracer warrants further testing in nonhuman primates. Efforts are underway to obtain an investigational new drug application for use of the tracer in humans. Promising candidates as SPECT imaging agents for the 5-HT uptake site are [123I]RTI-55 and [123I]-iodo-6-nitroquipazine. Both agents are under intense investigation in different laboratories in the United States.

Animals↗
PubMed1993

In vivo imaging of baboon and human dopamine transporters by positron emission tomography using [11C]WIN 35,428.

[11C]WIN 35,428 was evaluated as a specific in vivo radioligand for the dopamine transporter site by PET scanning in nonhuman primates and humans. In studies with a baboon (Papio anubis), [11C]WIN 35,428 accumulated in brain regions containing dopamine transporters, i.e., the striata. This accumulation was partially blocked by prior administration of (-)cocaine (4 mg/kg, i.v.). Placement of a unilateral lesion of dopamine-containing nerve terminals with MPTP resulted in a unilateral reduction in [11C]WIN 35,428 accumulation in the striatum on the side of the lesion. Imaging of D2 dopamine receptors with [11C]NMSP in the same MPTP-treated animals showed much less reduction in the postsynaptic D2 dopamine receptors as compared to the much larger reduction in the dopamine transporters labeled with [11C]WIN 35,428. A total of ten normal human volunteers (five males and five females) with ages ranging from 19 to 81 years were studied. The caudate/cerebellar and putamen/cerebellar ratios ranged from 4.4 to 5.7 90 min after injection of the tracer. Preliminary kinetic modeling with arterial plasma sampling resulted in an average binding potential (k3/k4) of 4.98 in the caudate nucleus and 5.13 in putamen. To demonstrate in vivo blockade with dopamine reuptake inhibitors, two subjects received prior oral doses of 6 mg mazindol. Subject 5 had significant reductions of 29% in the caudate/cerebellar ratio at 90 min, 35% in the putamen/cerebellar ratio at 90 min, 45% in the caudate k3/k4 ratio from 6.7 to 3.7, and 46% in the putamen k3/k4 from 4.7 to 2.5. Subject 8 had significant reductions of 20% in both the caudate/cerebellar ratio and the putamen/cerebellar ratio at 90 min. During the human PET studies, a number of neuropsychological tests and physiological measurements were performed. No significant changes were found after administration of the [11C]WIN 35,428 alone. Taken together, these data indicate that [11C]WIN 35,428 is a promising radioligand for future studies of neuropsychiatric disorders that involve the dopamine transporter site.

Adult↗
PubMed1993

Strategies for detecting subclinical monoamine depletions in humans.

Given the reported increase in the recreational use of controlled substance analogs such as MDMA and related drugs, it is important to determine whether these drugs produce neurotoxic effects in humans. Several strategies available for detecting preclinical neurotoxicity to dopamine and serotonin neurons have been discussed, and their strengths and limitations have been listed. In addition, some promising strategies that are still in the development stage (e.g., PET) have been mentioned. None of the available methods for detecting neurotoxicity is conclusive; therefore, converging lines of evidence will be essential to provide convincing indication of subclinical neurotoxicity in humans. Such studies will help define the public health risk of recreationally used drugs. Furthermore, documentation and determination of drug-induced neurotoxic changes may shed light on the pathophysiology of idiopathic neurodegenerative diseases involving monoaminergic neurons in humans and could be useful in the development of new treatment strategies. Finally, detailed neuropsychiatric evaluation of individuals with confirmed subclinical serotonergic neurotoxicity may enhance knowledge regarding the functional role of brain serotonin neurons in health and disease.

Brain↗
PubMed1993

Persistent effects of (+/- )3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") on human sleep.

(+/- )3,4-methylenedioxymethamphetamine (MDMA) is a recreational drug of abuse which damages serotonin neurons in animals. It is not known whether MDMA is also neurotoxic in humans, and if so, whether there are functional consequences. Given the putative role of serotonin in sleep, it was hypothesized that one manifestation of serotonin neurotoxicity in humans might be disturbances of sleep. To determine whether MDMA use has effects on sleep, all-night polysomnograms of 23 MDMA users were compared to those of 22 age- and sex-matched controls. On average, MDMA users had 19 minutes less total sleep and 23.2 minutes less non-REM (NREM) sleep than controls. These statistically significant differences in NREM sleep were due primarily to an average of 37 minutes less stage 2 sleep, with no significant differences noted in stages 1, 3 or 4. Although it is not known whether the alterations in sleep observed in MDMA users are due to serotonin neurotoxicity, the present findings suggest that MDMA use can lead to persistent changes in CNS structures involved in human sleep generation.

3,4-Methylenedioxyamphetamine↗
PubMed1993

Serotonergic recovery after (+/-)3,4-(methylenedioxy) methamphetamine injury: observations in rats.

(+/-)-3,4-Methylenedioxymethamphetamine (MDMA) is a recreational drug of abuse which damages serotonin (5-HT) neurons in animals. In monkeys, the damage appears to be permanent. By contrast, in rats there is indication that neuronal recovery takes place, although there is question as to whether the recovery is sustained. The purpose of the present study was to examine the fate of 5-HT neurons in MDMA-treated rats, and to compare findings in the rat with those in the monkey. Rats were treated with MDMA (10 mg/kg i.p.) every 2 hr for a total dose of 40 mg/kg. Two, 8, 16, 32 and 52 weeks later, groups (n = 8) of MDMA-treated rats, along with age-matched controls (n = 8), were analyzed for regional brain 5-HT, 5-hydroxyindoleacetic acid and [3H]paroxetine-labeled 5-HT uptake sites. Two weeks after MDMA, 5-HT neuronal markers were reduced markedly. Reductions ranged from 42 to 82% depending on brain region. By 16 weeks, there was evidence of recovery in some brain regions (e.g., hypothalamus and striatum) and by 32 weeks, recovery was nearly complete in most brain regions examined. One year after MDMA, recovery was still evidence in all brain regions evaluated, although closer inspection of the group data revealed that whereas most MDMA-treated rats recovered, some did not. These few animals had severe and enduring serotonergic deficits in multiple brain regions. Morphologic immunocytochemical studies yielded results which corroborated the neurochemical findings.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Methylenedioxyamphetamine↗
PubMed1993

Reinforcing subjective effects of (+/-) 3,4-methylenedioxymethamphetamine ("ecstasy") may be separable from its neurotoxic actions: clinical evidence.

(+/-)3,4-Methylenedioxymethamphetamine (MDMA), a synthetic amphetamine derivative used recreationally by humans, damages brain serotonin neurons in experimental animals. In preclinical studies, serotonin reuptake inhibitors block MDMA-induced serotonin release; they also block MDMA neurotoxicity. Whether serotonin reuptake inhibitors also block MDMA's psychoactive effects in humans has not been established. Reported herein are four individuals who describe their experiences after ingesting fluoxetine, a potent and selective serotonin reuptake inhibitor, before MDMA ingestion. Their reports indicate that fluoxetine does not block MDMA's reinforcing subjective effects and raise the possibility that MDMA's psychoactive effects may be separable from its neurotoxic actions.

3,4-Methylenedioxyamphetamine↗
PubMed1993

3,4-Methylenedioxymethamphetamine, serotonin and memory.

The recreational drug (+/-)-3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") is toxic to central serotonin (5-HT) neurons, but few long-term functional consequences of MDMA neurotoxicity have been identified. Because 5-HT has been implicated in learning and memory, the present study was undertaken to examine whether MDMA, by damaging 5-HT neurons, altered mnemonic function on a long-term basis. Rats were treated with saline, MDMA or 5,7-dihydroxytryptamine/desmethylimipramine. The latter treatment group was included to assess the effects of larger 5-HT neuronal lesions than are possible with MDMA. Four weeks after drug treatment, memory was assessed in three different variations of spatial alternation in a T-maze: acquisition with a constant and short delay interval, performance with variable delays and treatment with scopolamine. Upon completion of the behavioral studies, the neurotoxic effects of the drugs were assessed chemically and anatomically. MDMA, which produced a substantial and selective reduction of brain 5-HT, had no effect on choice accuracy. 5,7-dihydroxytryptamine/desmethylimipramine which produced a near-total reduction of 5-HT and a modest reduction of norepinephrine, impaired choice accuracy in all three variations of the task. These data suggest that selective damage to the 5-HT system, like that produced by MDMA, is not sufficient to impair memory, but that combined damage to the 5-HT and norepinephrine systems can disrupt performance in tasks that require recent memory. Because Alzheimer's disease involves impairments in acetylcholine, 5-HT and norepinephrine systems, animals with combined lesions may provide a useful model to study the mnemonic dysfunctions characteristic of this disease.

3,4-Methylenedioxyamphetamine↗
PubMed1993

A PET radiotracer for studying serotonin uptake sites: carbon-11-McN-5652Z.

A radioligand for imaging central serotonin (5-hydroxytryptamine; 5-HT) uptake sites by positron emission tomography (PET) has yet to be developed. Such a tracer would be useful for the study of normal and altered serotonergic neurotransmission as well as for the detection of serotonergic neurotoxicity. This paper describes the labeling of the highly potent serotonin (5-HT) uptake blocker, McN-5652-Z (trans-1,2,3,5,6,10 beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]-isoquinoline; racemic mixture), with 11C and the evaluation of this radiotracer in rodents with respect to its in vivo binding characteristics. In mouse brain, 11C-McN-5652-Z accumulated rapidly in regions with high densities of 5-HT uptake sites. The ratio between hypothalamus and cerebellum was 1.5:1 at 15 min and increased with time to 4.6:1 at 90 min after injection. The distribution of 11C-McN-5652 in rat brain at 60 min correlated well with regional concentrations of 5-HT uptake sites (r = 0.86). The specificity and selectivity of 11C-McN-5652 binding to the 5-HT transporter were tested by preinjecting blocking doses of known 5-HT, dopamine and norepinephrine uptake inhibitors, and a 5-HT2 receptor blocker before injection of the radiotracer. Preinjection of increasing doses of unlabeled McN-5652-Z inhibited 11C-McN-5652-Z binding in a dose-dependent fashion. These results suggest that the in vivo binding of the radiotracer was specific, selective for 5-HT uptake sites, saturable and that 11C-McN-5652-Z holds promise as a radiotracer for PET imaging of 5-HT uptake sites in the mammalian brain.

Animals↗
PubMed1992

Evaluation of the neurotoxicity of N-methyl-1-(4-methoxyphenyl)-2-aminopropane (para-methoxymethamphetamine, PMMA).

These studies assessed the neurotoxic potential of N-methyl-1-(4-methoxyphenyl)-2-aminopropane (para-methoxymethamphetamine; PMMA), an amphetamine analog that has surfaced in the illicit drug market. Repeated subcutaneous injections of PMMA caused lasting, dose-related reductions in regional brain concentrations of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), and in the density of [3H]paroxetine-labelled 5-HT uptake sites. Comparison of the neurotoxic potential of PMMA to that of para-methoxyamphetamine (PMA) and 3,4-methyl-enedioxymethamphetamine (MDMA) showed that equivalent doses of PMMA and PMA (80 mg/kg) produced comparable depletions of 5-HT, but that these depletions were not as pronounced as those induced by a lower dose of MDMA (20 mg/kg). Striatal DA was not affected on a long-term basis by any of the ring-substituted amphetamines evaluated in this study. These data suggest that PMMA, like PMA and MDMA, produces long-term (possibly neurotoxic) effects on brain serotonin neurons, but that PMMA is less potent than MDMA as a 5-HT neurotoxin. Further, they raise concern over the illicit use of PMMA since humans could be more sensitive than rodents to the 5-HT neurotoxic effects of PMMA and related drugs.

3,4-Methylenedioxyamphetamine↗
PubMed1992

Neurotoxic amphetamine analogues: effects in monkeys and implications for humans.

A wealth of evidence has accrued over the last 20 years indicating that certain amphetamine analogues have the potential to damage central monoaminergic neurons. For example, amphetamine has been shown to be toxic to dopamine neurons, MDMA to serotonin neurons, and methamphetamine to both (Table 1). In rodents, the toxic effects of amphetamines appear to be limited to axon terminals, and regenerative sprouting tends to be the rule. By contrast, in primates, nerve cell bodies appear to be affected, and the deleterious effects of amphetamine derivatives tend to be longer lasting, and possibly permanent (Fig. 2). Although findings in animals are compelling, observations in humans are less clear. In particular, it remains to be determined whether amphetamine analogues damage central monoaminergic neurons in humans and, if they do, whether functional consequences ensue. Also, the mechanism by which amphetamines damage monoaminergic neurons remains to be defined. Further insight into these basic and clinical aspects of amphetamine neurotoxicity should enhance our understanding of central monoaminergic systems in normal brain function, and their role in the pathophysiology of neuropsychiatric disorders.

3,4-Methylenedioxyamphetamine↗