Effect of melatonin on L-tryptophan- and apomorphine-stimulated growth hormone secretion in man.

The effect of subacute melatonin (250 mg every 8 h over a period of 40 h) and placebo treatment on L-tryptophan- and apomorphine-stimulated GH secretion was tested in 13 volunteers. Melatonin premedication significantly reduced the GH response to peroral L-tryptophan loading, suggesting that melatonin affects GH secretion in man by interfering with serotonergic transmission. In the apomorphine test, no significant difference in GH response was observed after melatonin when compared to placebo treatment. This suggests that dopaminergic mechanisms do not have a central role in mediating actions of melatonin on the hypothalamic-pituitary axis. It is further proposed that melatonin influences GH secretion at a suprahypophyseal level.

Stimulatory effect of acute baclofen administration on human growth hormone secretion.

The effect of acute administration of the gamma-amino-butyric acid (GABA) derivative, baclofen, on human GH secretion was tested. In eight of the nine volunteers, both 5 and 10 mg baclofen (Lioresal) significantly basal GH secretion. Previoulsy, it has been reported that subacute baclofen treatment inhibits the GH response to insulin hypoglycemia and arginine. Thus, the present study shows that baclofen is able to modify GH secretion via different mechanisms, depending on the test situation and duration of treatment. As a putative GABA agonist, the effect of baclofen may be mediated via GABA-ergic pathways. Because of variable results, the evaluation of a possible physiological role of GABA in GH secretion requires further study.

The effect of methysergide, pimozide, and sodium valproate on the diazepam-stimulated growth hormone secretion in man.

Diazepam-induced GH secretion was tested on 28 male volunteers before and after a 3-day treatment with methysergide, pimozide, or sodium valproate. Serum GH, diazepam, and blood glucose levels were determined. Without prior medication, the mean serum GH level increased 336% 1 h after diazepam administration. Treatment with the serotonin antagonist, methysergide, had no effect on the diazepam-stimulated GH secretion, whereas pimozide, the selective dopamine receptor-blocking agent, reduced the GH response to diazepam by 50% (P less than 0.05). Sodium valproate, a gamma-aminobutyric acid transaminase inhibitor, also inhibited diazepam-induced GH secretion; stimulated GH levels were 51% at 30 min (P less than 0.025), 39% at 60 min (P less than 0.025), and 46% at 90 min (P less than 0.025) relative to the stimulated levels without medication. No difference was found in blood glucose or serum diazepam levels after the drug treatments relative to the values obtained under basal conditions. It is suggested that diazepam-induced GH secretion is at least partly mediated via dopaminergic mechanisms. Serotonin does not seem to be involved. It is further proposed that gamma-aminobutyric acid plays an inhibitory role in GH secretion.

Human growth hormone and dopaminergic drugs, with special reference to deprenyl (selegiline): a summary of studies on volunteers.

The tubero-infundibular dopaminergic tract of the hypothalamus has a stimulatory effect on growth hormone (GH) secretion. In healthy volunteers levodopa, through the released dopamine and direct dopamine receptor agonists, therefore induces transient GH secretion. The indirect effect of levodopa at the presynaptic level can be modulated by inhibitory GABAergic drugs and by the potentiating deprenyl, for example. The GH response to direct postsynaptic dopamine receptor agonists like apomorphine is unaffected by these modulators. Below the dopamine level, the inhibitory effect of somatostatin and the negative feedback of the GH itself come into play. These regulatory mechanisms place limitations on dopamine-GH studies in man.

A review of the pharmacology of selegiline.

Selegiline (1-deprenyl) is an irreversible inhibitor of monoamine oxidase (MAO) type B. Because in the human brain, dopamine is metabolised mainly by MAO-B, selegiline increases dopamine content in the central nervous system. Besides the inhibition of MAO-B, selegiline also inhibits the uptake of dopamine and noradrenaline into presynaptic nerve and increases the turnover of dopamine. Thanks to these properties, selegiline significantly potentiates the pharmacological effects of levodopa. These favourable characteristics have been applied in the treatment of Parkinson's disease using selegiline both with levodopa and alone. Unlike earlier MAO-inhibitors, selegiline does not potentiate the hypertensive effects of tyramine. This is due to the selectivity to MAO-B, leaving intestinal MAO-A intact, and also due to the fact that selegiline inhibits the uptake of tyramine into neurons. Selegiline can prevent the parkinsonism caused by MPTP in animals; similar findings have been reported with other toxins like 6-OHDA and DSP-4, that destroys noradrenergic nuclei. Furthermore, selegiline reduces oxidative stress caused by degradation of dopamine and increases free radical elimination by enhancing superoxide dismutase and catalase activity. These findings may be important when considering the possible neuroprotective effects of selegiline. Besides the basic pharmacology also the interactions and pharmacokinetics of selegiline are reviewed in this article.

Pharmacokinetic aspects of l-deprenyl (selegiline) and its metabolites.

l-Deprenyl (selegiline), an irreversible and selective inhibitor of monoamine oxidase type B (MAO-B), is rapidly absorbed from the gastrointestinal tract and distributed into tissues. The reaction between MAO and selegiline takes place in two steps. The initial reversible reaction is followed by an irreversible reaction in which selegiline is bound covalently to the flavin part of the enzyme. Studies with positron emission tomography have shown retention of selegiline in brain areas with high MAO-B activity, including striatal structures, hippocampus, thalamus, and substantia nigra. Inhibition of MAO-B in vivo takes place rapidly; for example, platelet MAO is inhibited almost totally within the first 60 minutes after a single 10 mg oral dose of the drug. The recovery of MAO after inhibition depends on the organ and species in question. In rat brain the half-life of recovery in the brain is approximately 8 to 12 days; in rat liver it is shorter, 1 to 3 days. Selegiline is metabolized into l-(-)-desmethylselegiline, l-(-)-methamphetamine, and l-(-)-amphetamine mainly in the liver through the microsomal P-450 system. The stereoselectivity of the metabolites is maintained; no racemic transformation takes place. All three main metabolites are found in human serum, cerebrospinal fluid, and urine, and l-(-)-methamphetamine accounts for most of the metabolite pool. The metabolites are excreted mainly via urine l-(-)-Desmethylselegiline has been shown to be an irreversible inhibitor of MAO-B in the rat and in humans.

Effect of selegiline on mortality in patients with Parkinson's disease: a meta-analysis.

INTRODUCTION: The Parkinson's Disease Research Group of the United Kingdom (PDRG-UK) reported increased mortality in PD patients treated with levodopa plus selegiline compared with those treated with levodopa alone. METHODS: We performed a meta-analysis on five long-term, prospective, randomized trials of selegiline in patients with untreated PD. Included in the analysis were four randomized, double-blind, placebo-controlled studies and one randomized, double-blind, placebo-controlled study of 2 years' duration followed by long-term, open follow-up. RESULTS: The mean duration of follow-up was 4.1 +/- 1.8 years. There were 14 deaths in 297 selegiline-treated patients (4.7%) and 17 deaths in 292 non-selegiline-treated patients (5.8%). The hazard ratio for mortality was 1.02 (95% CI 0.44 to 2.37; p = 0.96). An analysis restricted to patients receiving only levodopa with or without selegiline noted 11 deaths in 257 levodopa/selegiline-treated patients (4.3%) and 11 deaths in 254 patients treated with levodopa alone (4.3%). The hazard ratio was 1.06 (95% CI 0.44 to 2.55; p = 0.90). Death rate per 1,000 patient years was 11.4 in the selegiline group and 14.2 in the nonselegiline group. Kaplan-Meier survival curves reflecting pooled survival data showed no significant difference in duration of survival. The hazard ratio was 0.84 (95% CI 0.41 to 1.70; p = 0.63) for selegiline- versus non-selegiline-treated patients and 1.05 (95% CI 0.46 to 2.43; p = 0.91) for selegiline/levodopa- versus levodopa-treated patients. CONCLUSION: These results contrast with those of the PDRG-UK study and demonstrate no increase in mortality associated with selegiline treatment whether or not patients also received levodopa.

The effects of dexmedetomidine, an alpha 2 agonist, on learning and memory, assessed using passive avoidance and water maze tasks in rats.

The effects of dexmedetomidine, a specific and potent alpha 2 agonist, on the performance of rats in passive avoidance and water maze tasks were studied. Pre-training administration of subanaesthetic dose (9.0 micrograms/kg) of dexmedetomidine impaired the retention of the passive avoidance task (assessed 24 hr after training) but it did not affect the training of this task. Smaller doses (0.3, 0.9 and 3.0 micrograms/kg) did not affect the training or retention of this aversively motivated task. On the other hand, pre-training administration of 0.3 and 0.9 microgram/kg dexmedetomidine impaired the acquisition of the water maze task, whereas larger doses (3.0 and 9.0 micrograms/kg) had no significant effect on spatial learning. Pre-training administration of dexmedetomidine (0.3-9.0 micrograms/kg) increased swimming speed in rats. Only a large dose (300 micrograms/kg) of dexmedetomidine, administered immediately after training, impaired the retention of the passive avoidance task and the acquisition of the water maze task. These data agree with previous findings that pharmacological manipulation of the noradrenergic system affects the retention of aversively-motivated (passive avoidance) tasks. The present results suggest that the dose-response curve of dexmedetomidine for impairment of learning/memory differs between the passive avoidance and water maze tasks.

Effect of alpha2 antagonists and an agonist on EEG slowing induced by scopolamine and lesion of the nucleus basalis.

In the present study, the effects of an alpha 2 agonist (clonidine, 1.0 mg/kg i.p.) and two antagonists (atipamezole, 1 and 10 mg/kg s.c. and yohimbine, 3.0 mg/kg i.p.) were studied on the EEG activity of naive rats, pretreated with either saline or scopolamine (0.8 mg/kg), or rats receiving lesioning of the nucleus basalis. The alpha 2 antagonists increased fast activity (alpha and beta). Clonidine increased slow wave activity (increased in spectral amplitudes) during periods of immobility and mobility. The EEG slowing, induced by scopolamine, was not alleviated by antipamezole or yohimbine, but in immobile rats, an increase in the delta and theta amplitudes was augmented by clonidine. In nucleus basalis-lesioned rats, the increase in delta activity was partially normalised by the alpha 2 antagonists. The decrease in the beta amplitude, induced by lesioning of the nucleus basalis, was not alleviated with either atipamezole or yohimbine. Clonidine increased the slow wave activity in nucleus basalis-lesioned rats and induced an increase in delta and theta bands during immobility. No changes were induced by clonidine in the EEG recorded from rats with lesions of the nucleus basalis.

Inhibition of platelet monoamine oxidase type B by selegiline.

Selegiline is an irreversible inhibitor of monoamine oxidase type B (MAO-B). No comparative data are available on the MAO-B inhibition caused by orally and intravenously administered selegiline. This study aimed to clarify this matter and to investigate the dose-response of MAO inhibition caused by orally administered selegiline. Sixteen healthy volunteers were given selegiline as a single intravenous dose (0.5 mg) and in three low oral doses (0.5 mg, 1.0 mg, and 1.5 mg) in an open-label randomized crossover trial. The MAO-B inhibition after the 0.5-mg intravenous dose was 79.6 +/- 15.1%. The dose-response of the three oral doses causing MAO-B inhibition was logistic. To check whether this equation could be applied to higher doses, eight of the volunteers were given 5-mg and 10-mg oral doses. The MAO-B inhibition after these doses (84.9 +/- 11.9% and 95.6 +/- 4.5, respectively) fitted well with the logistic model. With this equation obtained, it was calculated that a 3.4-mg oral dose of selegiline would be needed to obtain the same degree of MAO-B inhibition as after the intravenous dose of 0.5 mg. Therefore, the ratio of MAO-B inhibitory potential of intravenously and orally given selegiline is approximately 7 to 1, which fits well with the low bioavailability of the drug after oral administration.

Desmethylselegiline, a metabolite of selegiline, is an irreversible inhibitor of monoamine oxidase type B in humans.

Selegiline, an irreversible and selective inhibitor of monoamine oxidase type B (MAO-B), is metabolized into desmethylselegiline, levomethamphetamine, and levoamphetamine. In animal experiments, desmethylselegiline also has been shown to be an irreversible inhibitor of MAO-B. This study investigated the inhibitory potential of MAO-B and the pharmacokinetics of desmethylselegiline in humans. A double-blind, crossover trial was performed to compare the effects of a single dose (10 mg) of selegiline or desmethylselegiline on MAO-B platelet activity. The urinary excretion of phenylethylamine, which is considered to be a parameter of MAO-B inhibition, also was measured. The concentrations of selegiline, desmethylselegiline, and their metabolites were measured in plasma after administration of the two compounds. Ten healthy volunteers participated in the study. There was a clear inhibition of platelet MAO-B by both compounds. Desmethylselegiline caused a 63.7 +/- 12.7% inhibition of platelet MAO-B compared with 96.4 +/- 3.9% caused by selegiline. The maximal inhibition by desmethylselegiline was reached significantly later after desmethylselegiline (time to reach maximal inhibition [tmax], 27 +/- 20 hours) than after selegiline administration (tmax, 1.4 +/- 1.4 hours). The platelet MAO-B activity returned to baseline levels within 2 weeks, thus reflecting the irreversible nature of the inhibition by both compounds. The cumulative 48-hour excretion of phenylethylamine was 33% lower after desmethylselegiline than after selegiline administration. All three major metabolites of selegiline could be detected in plasma after selegiline administration. Levoamphetamine was the only metabolite of desmethylselegiline. The area under the concentration-time curve from time 0 to 24 hours (AUC0-24) of desmethylselegiline was 33 times higher than that of selegiline, suggesting a better bioavailability of desmethylselegiline. Desmethylselegiline is an orally active, irreversible inhibitor of MAO-B and could possibly be used to treat Parkinson's disease in the same way as selegiline.

Endocrine mechanism of action of toremifene at the level of the central nervous system in advanced breast cancer patients.

PURPOSE: To differentiate the antagonistic and agonistic effect of toremifene at the level of the hypothalamus-hypophysis axis a leutinizing hormone-releasing hormone (LHRH) test was performed during a phase II clinical trial. METHODS: In 15 postmenopausal patients with advanced breast cancer, follicle-stimulating hormone (FSH) and LH release--induced by an LHRH agonist (Suprefact injection, 0.5 mg s.c.)--was monitored during a 16-week period of toremifene treatment (60 mg/day p.o.). Prolactin, estradiol, and sex hormone-binding globulin (SHBG) levels were also measured. The functional test was carried out prior to toremifene therapy and then 4, 8, 12, and 16 weeks afterward. RESULTS: The drug sensitized the pituitary to the action of the gonadotrophins; the LHRH-induced FSH and LH release showed a considerably increasing tendency during the toremifene therapy. Estradiol levels decreased statistically significantly and SHBG levels showed a statistically significant increase. A decreased level of prolactin is the sign of an antiestrogenic effect of toremifene on the hypophysis and, as a result, provides evidence for a direct influence of toremifene upon the pituitary. An increase in LH and prolactin release in response to the LHRH test was characteristic in the responders. CONCLUSION: According to the LHRH test, the antagonistic effect of toremifene seems to be more dominant than the concomitantly existing agonistic property. Neither clinical nor endocrinological side effects could be observed at the level of the CNS during a prolonged period of toremifene administration.

Facilitation of cognitive functions by a specific alpha2-adrenoceptor antagonist, atipamezole.

The present experiments investigated the effects of a specific and potent alpha2-adrenoceptor antagonist, atipamezole (as a stimulator of the noradrenergic system) on cognitive performance in rats. Atipamezole enhanced the acquisition of a linear-arm maze test and also improved the choice accuracy of poorly performing rats in a delayed (20 min) three-choice maze test. Furthermore, atipamezole improved the achievement of a one-trial appetite-maze when injected immediately after teaching, thus having an effect on consolidation. Atipamezole clearly impaired the acquisition of the active avoidance test. The present results indicate that stimulation of noradrenergic system by atipamezole improves the performance of animals in tasks assessing relational learning and memory, possibly affecting attention, short-term memory and the speed of information processing. It has also an effect on a consolidation process unrelated to attentional or motivational mechanisms. In a stressful test. stimulation of noradrenaline release leads to impairment of performance.

The effects of alpha 2-adrenoceptor stimulation on neocortical EEG activity in control and 6-hydroxydopamine dorsal noradrenergic bundle-lesioned rats.

The present study investigated the effects of a alpha 2-adrenoceptor agonist, D-medetomidine (0.3, 3.0, 30.0 and 300.0 micrograms/kg, s.c.), on neocortical EEG activity in control and 6-hydroxydopamine dorsal noradrenergic bundle-lesioned rats. D-Medetomidine at 0.3, 3.0, and 30.0 micrograms/kg dose dependently increased waking-immobility-related high-voltage spike and wave spindles. Movement and waking-immobility-related slow wave activity was increased at doses of 3.0, 30.0 and 300.0 micrograms/kg. D-Medetomidine at 300.0 micrograms/kg produced continuous 1-2 Hz slow wave activity and the animals were markedly sedated. In rats injected with D-medetomidine at 0.3, 3.0 and 30.0, micrograms/kg EEG activity could be desynchronized (block of high-voltage spindles and slow waves) by pinching the tail. However, rats injected with D-medetomidine at 300.0 micrograms/kg showed no change in EEG activity or behavior following tail pinching. D-Medetomidine induced similar EEG activity (high-voltage spindles and slow waves) and behavioral changes (sedation) in 6-hydroxydopamine dorsal noradrenergic bundle-lesioned rats. Atipamezole, an alpha 2-adrenoceptor antagonist, blocked D-medetomidine-induced EEG and behavioral changes in control and 6-hydroxydopamine dorsal noradrenergic bundle-lesioned rats. Based on the present results we suggest that stimulation of presynaptic noradrenergic fibers is not a prerequisite for the increase of high-voltage spindle and slow wave activity induced by an alpha 2-adrenoceptor agonist and that the magnitude of EEG slowing induced by D-medetomidine correlates with the decreased behavioral response to sensory stimulation.

Alpha 1-adrenoceptor antagonist decreases alpha 2-adrenoceptor antagonist-induced high voltage spindle suppression in adult and aged rats.

The present experiments were undertaken to study whether blockade of alpha 1-adrenoceptors would prevent the high-voltage spindle suppressing effect of atipamezole, an alpha 2-adrenoceptor antagonist. In adult rats, an alpha 1-adrenoceptor antagonist, prazosin, increased dose dependently the high voltage spindles in saline and atipamezole-pretreated rats. In addition, in aged rats prazosin blocked the high-voltage spindle suppressing action of atipamezole. Prazosin produced a smaller increase in high-voltage spindle values in aged than in adult rats. According to the present results, alpha 2-adrenoceptor antagonists may suppress high-voltage spindles indirectly by activating alpha 1-adrenoceptors in young and aged rats.

Medetomidine--a novel alpha 2-adrenoceptor agonist: a review of its pharmacodynamic effects.

1. The pharmacodynamic effects of medetomidine, a novel alpha 2-adrenoceptor agonist, are reviewed. 2. In receptor binding experiments, and in isolated organ preparations medetomidine shows high specificity and selectivity to alpha 2-adrenoceptors. Its alpha 2/alpha 1 selectivity ratio is 1620 compared to 220 of clonidine. It is a highly potent full agonist at alpha 2-adrenoceptors, a fact that also distinguishes it from clonidine. 3. Medetomidine induces a dose-dependent decrease in the central release and turnover of norepinephrine (NE) measured as changes in metabolite concentrations or using pharmacological intervention techniques. 4. The selectivity, specificity and potency of medetomidine is further supported by various in vivo experiments showing dose-dependent hypotensive, bradycardic, sedative, anxiolytic mydriatic, hypothermic and analgesic effects. 5. The pharmacological, neurochemical and behavioral effects of medetomidine can be inhibited by prior, simultaneous or subsequent administration of selective and specific alpha 2-antagonists. 6. In humans medetomidine is well-tolerated and pharmacodynamic effects including e.g. dose-dependent decrease of vigilance, blood pressure, heart rate, salivary secretion and plasma NE are compatible with an agonistic action at alpha 2-adrenoceptors.

Interaction between the alpha 2-noradrenergic and muscarinic systems in the regulation of neocortical high voltage spindles.

The present experiments were carried out in order to study the interaction between alpha 2-noradrenergic and muscarinic systems in regulating high voltage spindle (HVS) activity in neocortex. Alpha 2-antagonist (atipamezole 1 and 10 mg/kg) blocked HVS activity. Atipamezole at 0.1 mg/kg dose had no effect on HVS activity. Alpha 2-agonist (guanfacine 0.004, 0.02 and 0.1 mg/kg) increased dose dependently HVSs. Guanfacine-induced HVSs were blocked by nucleus reticularis (NRT) lesions and by stimulation of either noradrenergic or cholinergic (pilocarpine) systems. Moreover, combined injections of atipamezole 1 mg/kg and pilocarpine 3 mg blocked HVSs more effectively than either of the drugs alone. Our results suggest that the NRT is jointly modulated by the noradrenergic and cholinergic afferents.

Effects of atipamezole and tetrahydroaminoacridine on nucleus basalis lesion-induced EEG changes.

In the present study the effect of combined anticholinesterase [tetrahydroaminoacridine (THA)] and alpha2-antagonist (antipamezole) treatment were evaluated on nucleus basalis (NB, quisqualic acid) lesion-induced EEG activity changes. THA (1, 3 and 6 mg/kg; an anticholinesterase) and atipamezole (Ati: 3 and 10 mg/kg; an alpha2-antagonist) suppressed dose-dependently NB lesion-induced high-voltage spindle activity and increase in slow/fast activity ratio. A combination of THA (3 mg/kg) and Ati (3 or 10 mg/kg) more effectively suppressed NB lesion-induced HVS activity than either of the drugs alone did. The present results suggest that alpha2-noradrenergic and NB cholinergic systems interact in the regulation of slow wave and HVS activity and that combined stimulation of these systems more effectively stabilize NB lesion-induced EEG changes.

Combination of atipamezole and tetrahydroaminoacridine/pilocarpine treatment suppresses high voltage spindle activity in aged rats.

The present study evaluated the effects of combined alpha2-antagonist (atipamezole) and anticholinesterase (tetrahydroaminoacridine, THA) or muscarinic agonist (pilocarpine) treatments on the high voltage spindle (HVS) activity in aged rats. On their own, high doses of THA (3 mg/kg), pilocarpine (3 mg/kg) and atipamezole (3 mg/kg) suppressed HVS activity. Low doses of THA (1 mg/kg), pilocarpine (1 mg/kg) and atipamezole (1 mg/kg) did not suppress HVS activity. Combinations of low doses of atipamezole and THA or pilocarpine suppressed HVS activity. Our results suggest that 1) the administration of alpha2-antagonist blocked the age-related deficit of thalamocortical activation, 2) a combination of alpha2-antagonist and a cholinergic drug may more effectively stabilize age-related HVS activity than either of the treatments alone.

Evoked field responses, recurrent inhibition, long-term potentiation and immobility-related nonrhythmical EEG in the dentate gyrus of fimbria-fornix-lesioned and control rats.

The effects of complete fimbria-fornix (FF) lesioning, bilateral medial-FF lesioning and systemic administration of a novel noradrenergic alpha 2-antagonist, atipamezole, on electrophysiological properties of the hippocampal formation were studied in the rat. In the hilus of the dentate gyrus (DG) complete FF lesioning abolished the long-term potentiation (LTP) of the population spike (PS), which in control rats could be induced by the application of high-frequency stimulus trains on the medial perforant pathway (PP). Several other electrophysiological properties examined in the medial-FF-lesioned rats changed as well. These changes included a decrease in the efficacy of recurrent inhibition and slight differences in granular cell population response evoked by perforant path stimulation. Also, in the DG the power of awake immobility-related nonrhythmical electroencephalogram (EEG) was significantly lower in FF-lesioned rats than in controls. In the DG of control rats systemic administration of atipamezole (1 mg/kg) shifted the population spike-field postsynaptic potential response curve towards the left. In FF-lesioned rats this drug had no effects. The slight effects of atipamezole would be in line with earlier studies, which have shown that noradrenergic activation facilitates neuronal transmission in the DG. Possible explanations for the changes seen in FF-lesioned rats include deafferentation of different subcortical projections and increased epileptic activity. These established changes in synaptic plasticity, recurrent inhibition, nonrhythmical EEG and evoked responses would indicate that information processing is severely hampered in the first stage of the hippocampal trisynaptic circuit after fimbria-fornix lesioning. Thus, the results show that aminergic/cholinergic projections have a significant role in information processing in the dentate gyrus of hippocampal formation.