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Biomedical subjects

U D McCann

Publications and source records attributed to U D McCann.

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

The effects of L-dihydroxyphenylalanine on alertness and mood in alpha-methyl-para-tyrosine-treated healthy humans. Further evidence for the role of catecholamines in arousal and anxiety.

Treatment with alpha-methyl-para-tyrosine (AMPT), a catecholamine synthesis inhibitor, has been shown to produce pronounced increases in sleepiness and mild increases in negative mood and anxiety when administered to healthy male adults. The present study was conducted to ascertain whether these effects of AMPT are secondary to decreases in brain catecholamines or whether they represent nonspecific drug effects. Forty-one healthy males were randomized to one of four treatment groups. (1) Treatment with AMPT alone (AMPT/placebo); (2) treatment with AMPT plus L-dopa/carbidopa (AMPT plus L-dopa/carbidopa); (3) treatment with L-dopa/carbidopa alone (placebo plus L-dopa/carbidopa); or (4) treatment with placebo alone (placebo plus placebo). Repeated measures of alertness, mood, and anxiety were obtained over a three-day period of drug treatment and following drug discontinuation. As before, AMPT treatment led to increased sleepines. In addition, AMPT treatment led to decreased calmness, increased tension and anger, and a trend for increased depression. Replacement of catecholamine stores with L-dopa reversed the effects of AMPT and was associated with a more rapid recovery from AMPT's effects. These findings indicate that AMPT's effects on alertness and anxiety are catecholamine-specific. Further, they provide additional evidence that catecholamines are involved in the regulation of normal states of arousal, and they are consistent with the view that brain catecholaminergic dysregulation is involved in pathological anxiety states.

Adult↗
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↗
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

Effects of catecholamine depletion on alertness and mood in rested and sleep deprived normal volunteers.

Alpha-methyl-para-tyrosine (AMPT), a tyrosine hydroxylase inhibitor, was used to evaluate the physiologic role of central nervous system catecholamines in modulating alertness and mood. Forty healthy males were randomized to one of four conditions: AMPT in a rested condition; AMPT plus 40.5 hours of total sleep deprivation; placebo plus sleep deprivation; or placebo in a rested condition. Repeated measures of alertness and mood revealed that treatment with AMPT or sleep deprivation increased sleepiness, and combined treatment produced greater sleepiness than either treatment alone. In contrast, although combined treatment with AMPT and sleep deprivation led to large increases in negative mood, neither treatment alone produced consistent mood changes. These findings are consistent with the view that sleep deprivation is associated with decreased functional catecholamine neurotransmission. Furthermore, mood effects following sleep deprivation plus AMPT suggest that catecholamines may be involved in mood changes during sleep deprivation.

Adult↗
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

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↗
PubMed1992

Sleep deprivation and impaired cognition. Possible role of brain catecholamines.

To assess the role of brain catecholamines in cognitive decline associated with sleep deprivation, 40 healthy male volunteers were randomized to conditions of total sleep deprivation or 40.5 h of rest. Within each sleep condition, subjects were further randomized to treatment with a 2-day regimen of placebo or alpha-methyl-para-tyrosine (AMPT), a catecholamine synthesis inhibitor. Cognitive performance was measured repeatedly over time using a computerized performance assessment battery. Treatment with AMPT or treatment with sleep deprivation increased sleepiness without producing marked or consistent deterioration in performance. By contrast, subjects who received both treatments reported greater sleepiness than those receiving either treatment alone, and developed severe cognitive impairment on a variety of tasks. These findings, along with previous evidence that catecholamine-enhancing drugs improve performance in sleep-deprived individuals, support the view that decline in cognitive performance during sleep deprivation may be mediated by brain catecholamines.

Adult↗
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↗
PubMed1991

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↗
PubMed1991

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↗
PubMed1990

Acute dystonic reaction in normal humans caused by catecholamine depletion.

Five of 24 (21%) normal men (volunteers) administered alpha-methyl-para-tyrosine (AMPT), a catecholamine-depleting agent, developed acute dystonic reactions. The finding that catecholamine depletion without receptor blockade is sufficient to cause acute dystonia suggests that a variety of neurotransmitter imbalances may lead to idiopathic primary dystonia.

Acute Disease↗
PubMed1990

Successful treatment of nonpurging bulimia nervosa with desipramine: a double-blind, placebo-controlled study.

Twenty-three women with nonpurging bulimia underwent a 12-week, double-blind, placebo-controlled trial of desipramine hydrochloride. Repeated standardized rating scales, mood assessments, and self-reports of dietary habits were used to measure changes in binge frequency and cognitive processes associated with food intake. The women who received desipramine reduced their frequency of binge eating by 63%, but women receiving placebo increased their frequency of binge eating by 16%. Twelve weeks after initiating treatment, 60% of the treatment group but only 15% of the placebo group abstained from binge eating. The women who received desipramine showed significantly more dietary restraint and reported significantly less hunger, suggesting that desipramine acts to suppress appetite. These preliminary findings suggest that the therapeutic effects of desipramine established in the treatment of purging bulimia nervosa extend to patients with nonpurging bulimia.

Appetite↗
PubMed1985

What does the dexamethasone suppression test identify?

The authors studied the Dexamethasone Suppression Test (DST) in chronic pain patients with and without major depression, using items from a modified version of the Hamilton Depression Scale, the Hamilton Anxiety Scale, and the Montgomery-Asberg Depression Rating Scale. The purpose of the study was to identify the factor or factors which discriminated DST suppressors from nonsuppressors. The data suggest that depression and its profile are efficient discriminators of suppressors and nonsuppressors. Anxiety-related items were not as good as discriminators. The items that identified nonsuppression were the items that are often seen in combination in endogenous depression.

Adult↗
PubMed1984

Iodothyronine deiodination reaction types in several rat tissues: effects of age, thyroid status, and glucocorticoid treatment.

Two types of iodothyronine 5'-deiodination have been characterized previously in rat tissues. They can be distinguished by inhibition of type I but not type II by 6-n-propylthiouracil, by the relative suitability of T4 and rT3 as substrates, rT3 much better than T4 for type I and T4 as good as, or better than, rT3 for type II, and by the concentration of T4 required to inhibit deiodination of rT3, 1-10 microM for type I and 1-10 nM for type II. Type I activity (6-n-propylthiouracil sensitive) is most abundant in liver and kidney. Type II activity has, to date, been identified only in the pituitary, central nervous system, and brown adipose tissue. Iodothyronine tyrosyl deiodination has also been identified in homogenates of rat brain, liver, and placenta. It is not clear how many different enzymes carry out this latter reaction. In the present studies, we have extended previous work by determining maturational patterns of the deiodinating pathways in several thyroid hormone-responsive rat tissues, possible modulation of those patterns by glucocorticoids, and the age of onset of responsivity of the deiodinases to hypothyroidism. Iodothyronine 5'-deiodinating activity was found in rat lung and eye, and the reaction was all or nearly all type I in both. Activity in the eye was virtually absent from the lens and vitreous humor. In immature rat cerebrum, pituitary, lung, and eye, between gestational day 17 and postnatal day 21, there was a uniform pattern of an increase in type I 5'-deiodination activity over time, until adult levels were attained. The ages at which adult activity levels were reached varied from tissue to tissue, however. Type II activity was present at the earliest ages tested in the cerebrum (gestational day 17), pituitary, and brown adipose tissue (day of birth). In cerebral cortex, type II activity was highest at day 21 postnatally and equal at birth and in adulthood, and in pituitary and brown adipose tissue it was higher in adulthood than at birth. T3 tyrosyl ring deiodinating activity was several times greater in homogenates of eye and placenta than in cerebral homogenates. In all three tissues, there was similar, dose-dependent inhibition of [125I]T3 tyrosyl deiodination by 5 nM and 20 nM nonradioactive T3. In the eye and brain, T3 tyrosyl deiodination rates decreased progressively with age from gestational day 17 to postnatal day 7.(ABSTRACT TRUNCATED AT 400 WORDS)

Adipose Tissue, Brown↗