Polyamine pathway contributes to the pathogenesis of Parkinson disease.

The full complement of molecular pathways contributing to the pathogenesis of Parkinson disease (PD) remains unknown. Here we address this issue by taking a broad approach, beginning by using functional MRI to identify brainstem regions differentially affected and resistant to the disease. Relying on these imaging findings, we then profiled gene expression levels from postmortem brainstem regions, identifying a disease-related decrease in the expression of the catabolic polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1). Next, a range of studies were completed to support the pathogenicity of this finding. First, to test for a causal link between polyamines and α-synuclein toxicity, we investigated a yeast model expressing α-synuclein. Polyamines were found to enhance the toxicity of α-synuclein, and an unbiased genome-wide screen for modifiers of α-synuclein toxicity identified Tpo4, a member of a family of proteins responsible for polyamine transport. Second, to test for a causal link between SAT1 activity and PD histopathology, we investigated a mouse model expressing α-synuclein. DENSPM (N1, N11-diethylnorspermine), a polyamine analog that increases SAT1 activity, was found to reduce PD histopathology, whereas Berenil (diminazene aceturate), a pharmacological agent that reduces SAT1 activity, worsened the histopathology. Third, to test for a genetic link, we sequenced the SAT1 gene and a rare but unique disease-associated variant was identified. Taken together, the findings from human patients, yeast, and a mouse model implicate the polyamine pathway in PD pathogenesis.

Magnesium pemoline: enhancement of learning and memory of a conditioned avoidance response.

Magnesium pemoline, a mild stimulant of the central nervous system, enhances the acquisition and retention of a conditioned avoidance response in rats. Methamphetamine and methylphenidate do not have this effect.

Effects of magnesium pemoline and dextroamphetamine on human learning.

Two central nervous system stimulants, magnesium pemoline and dextroamphetamine, were tested to see if they facilitate learning in human subjects. Subjects under placebo learned faster than the subjects under any of the several doses of magnesium pemoline; however, none of these differences reached statistical significance. Subjects who received dextroamphetamine learned significantly more slowly than those who received placebo.

Magnesium pemoline: enhancement of brain RNA polymerases.

The stimulation by magnesium pemoline of systems that synthesize brain nucleic acid was studied in vivo and in vitro. There are differential effects between true RNA polymerase and pseudo-RNA polymerase. The selective stimulation of true RNA polymerase by magnesium pemoline was not observed with stimulants of the central nervous system and psychotropic agents.

Magnesium pemolone: lack of facilitation in human learning, memory, and performance tests.

Either a placebo or 25 or 37.5 milligrams of magnesium pemoline was administered on a doubleblind basis to three intelligencematched groups of normal, adult males. Learning and 24-hour retention tests included verbal learning, motor learning, and classical conditioning. Short-term memory tests were administered through both the visual and auditory modalities. Arm-hand steadiness and visual reaction time performance tests were included. The only measures revealing significant group differences showed the performance of subjects given pemoline was inferior to that of subjects given a placebo.

Magnesium pemoline: effect on avoidance conditioning in rats.

Rats administered 20 milligrams of magnesium pemoline per kilo gram of body weight learned to avoid shock in a jump-out apparatus in fewer trials than did controls. However, the results suggested that the principal effect of the drug was to facilitate the avoidance behavior of those animals that tended to "freeze" in response to electric grid shock. No differences in retention were observed between experimental and control animals that had achieved equal levels of learnine.

Magnesium pemoline: failure to affect in vivo synthesis of brain RNA.

The effect of magnesium pemoline on the synthesis of brain RNA in vivo was studied. No significant effect either on the concentration of RNA or on the uptake of H(3)-uridine into RNA was detected.

Pemoline and magnesium hydroxide: lack of effect on RNA and protein synthesis.

Brain RNA polymerase isolated from rats treated with pemoline and magnesium hydroxide (Cylert) was not more active than enzyme from control animals. The drug did not increase enzymic activity in vitro. Pemoline did not significantly affect either RNA or protein synthesis in suspensions of Ehrlich ascites carcinoma cells.

Activity and responsivity in rats after magnesium pemoline injections.

Rats injected intraperitoneally with magnesium pemoline avoided a buzzing sound (conditioned stimulus) associated with an electric shock to the feet (unconditioned stimulus) more frequently than controls. Drug-injected rats did not avoid the foot shock more frequently than controls, although the experi mental rats did have shorter response latencies fn the active avoidance task. In sub sequent experiments which measured activity changes and response to the buzzing sound alone, it was found that magnesium pemoline caused a lesser decrease in activity level and a more sustained responsivity to the buzzer's. sound than did control injections of tragacanth. This may account for the latency differences observed in the avoidance task.

Acceleration tolerance at night with acute fatigue and stimulants.

INTRODUCTION: The impact of pharmacological agents on aviators concerns all flight surgeons. This study tested the related hypotheses that acute fatigue reduces +Gz tolerance and endurance, and that stimulants can partially reverse this impact. Additionally, the researchers attempted to develop a test battery sensitive enough to detect subtle differences in aviator cognition and performance among conditions. METHODS: To determine the effect of fatigue on +Gz tolerance and the impact of stimulant use, 10 male centrifuge subjects, mean age 32, from Brooks City-Base, TX, were tested in a repeated measures study under five nighttime conditions following an average of 22 h of sustained wakefulness during their circadian nadir. Using a within-subject design, subjects received placebo, dextroamphetamine 10 mg, modafinil 200 mg, methylphenidate 10 mg, and pemoline 37.5 mg at night, and were tested during a daytime control session. Cognitive/performance tests were administered before each centrifuge run. RESULTS: No difference in +Gz tolerance or endurance was detected among conditions. The cognitive/performance tests also did not detect any differences. Subject perception that anti-G straining maneuver (AGSM) difficulty was greater during the night placebo condition than during the daytime control, methylphenidate and modafinil night conditions reached statistical significance (P = 0.005, 0.012, 0.022, respectively). DISCUSSION: Physiological changes during the circadian nadir following acute sleep deprivation do not appear to negatively impact +Gz tolerance. A standardized protocol sufficiently sensitive to detect subtle behavioral and performance effects would be useful to test and compare the effect of other pharmacological agents on aviators.

Delusional parasitosis and the dopamine transporter. A new insight of etiology?

Delusional parasitosis (DP) is a psychotic condition in which a person has the unshakeable and mistaken belief (delusion) and/or aberrant perception (hallucination) of being infested with parasites. The disorder will be usually classified in a primary DP-group without a detectable cause (so-called pure forms), while secondary DP-groups are associated with general organic conditions, psychiatric illnesses and drugs (substance induced). Etiology and pathophysiology of DP remain however unknown. In the present paper we hypothesize for the first time a decreased striatal dopamine transporter (DAT)-functioning (corresponding with an increased extracellular dopamine-level) as etiologic condition for DP (primary and secondary groups). The DAT as key regulator of the dopamine-reuptake in the human brain is well known (regulation of the extracellular dopamine concentration). It is a presynaptic plasma membrane protein highly dense represented in the striatum. The hypothesis of a decreased DAT-functioning as etiologic condition by DP is revealed in case reports which show that DAT-inhibitors, such as cocaine, pemoline, methylphenidate and other amphetamine-derivatives can induce the clinical expression of DP. Several other associated causes of secondary DP-groups (medications, parkinson, chorea huntington, multiple system atrophy, diabetes, cerebrovascular diseases, alcoholism, traumatic brain injury, hyperuricemia, human immunodeficiency virus, iron deficiency, schizophrenia, depression) suggest that the clinical expression of DP may be related to a decreased striatal DAT-functioning (blocking, reduced ligand binding, reduced density, reduced activity). Our examined DP-cases (2-females) show means of magnetic resonance imaging a structurally damaged striatum. Furthermore, we presume that by the primary DP-group, the physiologically age-related decline of the DAT-density is pathologically elevated. Based on this hypothesis we show in the present paper the relation between DP and decreased striatal DAT-functioning, trying to give a new insight into the pathophysiologically mechanism involved. The hypothesis provides supporting evidence that increased levels of extracellular dopamine in the striatum of DP-patients is likely to be the result of decreased DAT-functioning and not increased rates of release. The hypothesis can be investigated simply by dopamine transporter imaging in patients with DP.

Cerebral functional magnetic resonance imaging activation modulated by a single dose of the monoamine neurotransmission enhancers fluoxetine and fenozolone during hand sensorimotor tasks.

Fluoxetine inhibits the reuptake of serotonin, and dextroamphetamine enhances presynaptic release of monoamines. Although the excitatory effect of both noradrenaline and dopamine on motor behavior generally is accepted, the role of serotonin on motor output is under debate. In the current investigation, the authors evidenced a putative role of monoamines and, more specifically, of serotonin in the regulation of cerebral motor activity in healthy subjects. The effects on cerebral motor activity of a single dose of fluoxetine (20 mg), an inhibitor of serotonin reuptake, and fenozolone (20 mg/50 kg), an amphetamine-like drug, were assessed by functional magnetic resonance imaging. Subjects performed sensorimotor tasks with the right hand. Functional magnetic resonance imaging studies were performed in two sessions on two different days. The first session, with two scan experiments separated by 5 hours without any drug administration, served as time-effect control. A second, similar session but with drug administration after the first scan assessed drug effects. A large increase in evoked signal intensity occurred in the ipsilateral cerebellum, and a parallel, large reduction occurred in primary and secondary motor cortices (P < 10(-3)). These results are consistent with the known effects of habituation. Both drugs elicited comparable effects, that is, a more focused activation in the contralateral sensorimotor area, a greater involvement of posterior supplementary motor area, and a widespread decrease of bilateral cerebellar activation (P < 10(-3)). The authors demonstrated for the first time that cerebral motor activity can be modulated by a single dose of fluoxetine or fenozolone in healthy subjects. Drug effects demonstrated a direct or indirect involvement of monoamines and serotonin in the facilitation of cerebral motor activity.

Modulation of rapid eye movement sleep in humans by drugs that modify monoaminergic and purinergic transmission.

Modulation of rapid eye movement (REM) sleep is a well-established effect of many centrally acting drugs. However, there is uncertainty concerning the nature of the changes and their significance, and it is in this context that we have analyzed the effects of several groups of drugs that alter monoaminergic or purinergic transmission on sleep in humans. The analysis shows that drugs that modulate noradrenergic and serotonergic transmission lead to marked suppression of REM sleep, irrespective of any increase or decrease in sleep duration. There is no evidence that the timing of the ultradian cycle of REM sleep relative to sleep onset is altered by these drugs. On the other hand, reduced REM sleep with dopamimetic drugs is due solely to increased wakefulness. However, there can be more subtle effects of some drugs on REM sleep. Benzodiazepine receptor agonists and drugs that modify purinergic transmission modulate the appearance of early REM activity. There may, therefore, be two discrete systems that control entry into REM sleep, and that are responsive to drugs. The exact appearance and timing of REM periods may be modulated by a feedback mechanism involving GABAergic, or possibly purinergic, transmission, while monoaminergic and cholinergic influences exert a reciprocal and overriding control of REM sleep.

Dopaminergic transmission and the sleep-wakefulness continuum in man.

Modulation of dopaminergic transmission on daytime alertness and performance and on nocturnal sleep were studied in man using 30, 60 and 90 mg pemoline, a dopamimetic drug, and 2, 4 and 6 mg pimozide, a dopamine receptor antagonist. Pemoline lengthened daytime sleep latencies and improved attention, and increased wakefulness during nocturnal sleep. Rapid eye movement (REM) sleep was reduced with 90 mg pemoline, but this was due entirely to increased wakefulness. Pimozide had little effect on overnight sleep, but increased the tendency to fall asleep and impaired performance during the day. These studies suggest that the effects of certain drugs which modulate the activity of neurotransmitters, involved in the control of sleep and wakefulness, may be related to the inherent level of activity of the central nervous system. Modulation of the dopaminergic system can have a profound influence on the manifestation of wakefulness and vigilance, but is unlikely to modify directly the elaboration of REM sleep in man.

Antidepressant and anticonvulsant activity of 1-(5-phenyl-4-oxazolin-2-yl)-4-substituted piperazines.

1-(5-Phenyl-4-oxo-2-oxazolin-2-yl)-4-substituted cinnamoylpiperazines and 1-(5-phenyl-4-oxo-2-oxazolin-2-yl)-4-carbamoylpiperazine and derivatives were synthesized and evaluated for antidepressant activity in the mouse Dopa potentiation test. 1-(5-Phenyl-4-oxo-2-oxazolin-2-yl)-4-carbamoylpiperazine and derivatives were further evaluated for anticonvulsant activity in the audiogenic seizure test in mice.

Dopaminergic agents and stimulants as antidepressant augmentation strategies.

Dopaminergic agents and stimulants have been used to manage depression when conventional antidepressant treatments fail. We reviewed evidence for the role of dopaminergic dysfunction in depression, the use of dopaminergic agents as antidepressants, and the use of dopaminergic agents and stimulants as antidepressant adjuncts. Dopamine may be part of the pathophysiology of depression for a subset of patients. When used with caution and an appreciation of the potential risk of abuse, dopaminergic agents and stimulants may be useful for patients refractory to antidepressants alone.

The hyperkinetic child syndrome and brain monoamines: pharmacology and therapeutic implications.

Decreased catecholaminergic activity within the central nervous system has been associated with altered arousal, attention, learning, and kinetic function in animals and humans. The hyperkinetic child syndrome (HCS) involves dysfunction in all these spheres and may thus reflect diminished catecholamine activity, particularly as related to brain dopamine. Accordingly, the efficacy of catecholaminergic agents in treating the HCS is a predictable rather than a paradoxical effect of these agents. Sufficient evidence is now available to strongly implicate catecholamine hypoactivity in the pathopharmacology of the HCS.

Four stimulants of the central nervous system: effects on short-term memory in young versus aged monkeys.

Aged Rhesus monkeys and young control monkeys were tested in a delayed-response procedure to assess the effects of central-nervous-system (CNS) stimulants on short-term memory (STM). Previous research had established that the aged monkeys showed specific impairments of STM in this procedure. Four different CNS stimulants (methylphenidate, magnesium pemoline, a pentylenetetrazole/niacin mixture, and caffeine) were chosen for evaluation on the basis of their relevancy to current geriatric-psychopharmacologic research. Four different doses of each of the four CNS stimulants were given to each monkey, counter-balanced for possible order effects. Methylphenidate and caffeine impaired the performance of both age groups in this non-human primate cognitive task, even at relatively low dose levels. Magnesium pemoline produced fewer adverse effects and some evidence of improving STM in the aged monkeys, although not within the levels of statistical significance. The pentylenetetrazole/niacin mixture produced a three-way interaction involving age, dose and retention interval. This reflected the fact that although no definite effects were noted under the zero-sec control condition, statistically significant age-related deficits did occur in the STM-dependent retention interval as the dose varied. The data demonstrate that, of these four CNS stimulants, none radily improves (and often may impair) performance of tasks requiring STM. Thus the results of this study offer little support for the hypothesis that general CNS stimulation may constitute significant therapy for cognitive impairments associated with advanced age.

Tape test as a simple new method for the study of compounds increasing the problem-solving ability of the rat.

A simple new method, the "tape test" has been developed for studying the enhancement of learning by drugs in "learning-dull" rats. A piece of adhesive tape is pressed on the left front pad of the rats. The time of tape removal by the animal, i.e., the problem-solving time is measured. In our experiments the selected learning-dull rats were used which were unable to remove the tape within 60 s observed on 3 consecutive days. The problem-solving ability of the rats was studied on 4 consecutive days, by posttrial administration. The problem-solving ability was found to be increased after treatment with different drugs such as para-chlorphenylalanine (PCPA), pemolin, orotic acid, vitamin B12. The stimulatory effect of vitamin B12 could be inhibited by vincristine.