Antiepileptic drug pharmacokinetics and neuropharmacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid: milacemide.

1. The kinetics and metabolism of milacemide have been studied in an animal model which allows the simultaneous investigation of the temporal inter-relationships of drugs and metabolites in blood (pharmacokinetics) and cerebrospinal fluid (CSF, neuropharmacokinetics) in individual freely moving rats. 2. Milacemide dose-dependently increased CSF glycine and glycinamide (intermediary metabolite) concentrations. This confirms that milacemide is a CNS glycine prodrug. 3. Pretreatment with L-deprenyl (2 mg kg-1), a specific inhibitor of monoamine oxidase type B (MAO-B), almost completely prevented the formation of glycinamide and increased milacemide accumulation in CSF. Tmax and t1/2 were significantly increased and Cmax and AUC values were decreased for glycinamide compared to controls. Pretreatment with clorgyline (5 mg kg-1), a specific inhibitor of MAO-type A, only moderately decreased glycinamide Cmax and AUC values. 4. After milacemide administration (100, 200 and 400 mg kg-1, i.p.) serum and CSF milacemide concentrations rose linearly and dose-dependently. Serum glycinamide concentrations exhibited small dose-dependent rises but these were not linearly related. In contrast, CSF glycinamide concentrations rose linearly and dose-dependently with Cmax values 2.5, 3.2 and 4.1 times greater than the corresponding values for serum glycinamide after giving 100, 200 and 400 mg kg-1 respectively of milacemide. 5. Serum glycine concentrations were unaffected but CSF concentrations increased dose-dependently and these were significant at the higher milacemide doses (200 and 400 mg kg-1). Animals given 400 mg kg-1 milacemide had glycine values which were still significantly elevated 7 h later.(ABSTRACT TRUNCATED AT 250 WORDS)     

A microdialysis study of glycinamide, glycine and other amino acid neurotransmitters in rat frontal cortex and hippocampus after the administration of milacemide, a glycine pro-drug

Milacemide is a glycinamide derivative which readily enters the brain and is metabolised to glycine. As its mechanism of action as an anticonvulsant drug is unknown we used the technique of microdialysis to study the temporal inter-relationship of glycinamide, glycine and other amino acid neurotransmitters in the extracellular fluid of rat hippocampus and frontal cortex. After milacemide administration (400 or 800 mg/kg i.p.), glycinamide concentrations rose linearly and dose-dependently in both hippocampus and frontal cortex. In contrast, whilst glycine concentrations rose in the hippocampus, glycine was unaffected in the frontal cortex. Concomitant increases in taurine hippocampal concentrations were observed. An increase in serine and a decrease in alanine concentrations was only observed at the highest milacemide dose (800 mg/kg). Other amino acids were unaffected. Thus, while glycinamide appears to be universally distributed throughout the brain, its metabolism to glycine and its effects on brain amino acids appear to be region specific.     

Effect of milacemide on extracellular and tissue concentrations of dopamine and 5-hydroxytryptamine in rat frontal cortex.

1. Milacemide is a glycine prodrug which is both an inhibitor and a substrate for monoamine oxidase-type B (MAO-B) and also an inhibitor of MAO-type A (MAO-A). Its effects on dopamine and 5-hydroxytryptamine (5-HT) metabolism in rat frontal cortex tissue and dialysate were evaluated. 2. Dialysate dopamine concentrations increased linearly and dose-dependently after milacemide administration (100, 200, 400 mg kg-1, i.p.), peaking at 1 h. A concomitant dose-dependent decrease in dialysate 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations was observed but these changes were smaller (27% and 40% respectively) than the change in dopamine (125% after 400 mg kg-1 milacemide). 3. Dialysate 5-HT was significantly increased only at 1.5 h after giving milacemide 400 mg kg-1. Dialysate 5-hydroxyindoleacetic acid (5-HIAA) concentration was not affected. 4. Milacemide (400 mg kg-1) at 1.5 h post-administration significantly increased frontal cortex tissue concentrations of dopamine and 5-HT; the percentage increase in dopamine being about four times that of 5-HT. Metabolite concentrations, including 5-HIAA, decreased. Changes in tissue and dialysate dopamine, DOPAC and HVA were approximately proportionate to each other. 5. The results are explicable in terms of an inhibition by milacemide of MAO-A.     

The glycine-prodrug, milacemide, increases the seizure threshold due to hyperbaric oxygen; prevention by 1-deprenyl

The novel glycine-prodrug anticonvulsant, milacemide (2-N-pentylaminoacetamide) (500 mg/kg), significantly increased (>400% the seizure threshold induced by hyperbaric oxygen (4.5 atmosphere). This effect was significantly reduced by the selective inhibition of monoamine oxidase B by 1-deprenyl (2.0 mg/kg). 1-Deprenyl alone hardly affected the seizure threshold. These results suggest that, in the brain, milacemide is oxidized to glycine and that this reaction is mediated primarily by monoamine oxidase B. However, the interaction of milacemide metabolites (glycine amide, pentanoate and glycine) as antagonists of receptors of the glutamate NMDA (N-methyl-D-aspartate) subtype cannot be excluded.     

Microionophoretic study with milacemide, a glycine precursor, on mammalian central nervous system cells.

1. The effect of milacemide, a glycine percursor known to increase gamma-aminobutyric acid (GABA) and glycine content in the brain, and to have anticonvulsant properties, was tested by ionophoresis on 247 neurones situated in the cerebral cortex and in deeper structures of cats and rats anaesthetized with urethane. 2. Virtually all the neurones, either firing spontaneously or exogenously driven by the excitatory amino acids, glutamate, N-methyl-D-aspartate (NMDA), kainate and quisqualate or by acetylcholine, were reversibly depressed in a dose-dependent fashion. The same depressant effect was observed in animals pretreated with the monoamine oxidase B inhibitor (IMAO-B) deprenyl which is known to reduce milacemide metabolism into glycinamide and glycine. Intravenous administration of milacemide (10 to 100 mg kg-1) also depressed the firing induced by glutamate, NMDA and acetylcholine. 3. When compared to GABA, milacemide was a weaker depressant. However, its effect could still be observed in the presence of the reversible GABAA antagonist, SR 95531, and thus milacemide is unlikely to act through GABA receptors. In addition, on cells unaffected by glycine, milacemide also had a depressant effect, and on cells inhibited by glycine, it was still capable of depressing cell firing during reversible blockade by strychnine of the glycine inhibitory action; thus milacemide is unlikely to act through glycine receptors. Simultaneous release of milacemide and GABA or of milacemide and glycine, did not show potentiation of the inhibitory amino acid action. However, the depressant effect of milacemide was additive with that of GABA and glycine. 4. No consistent depression of glutamate-induced firing was obtained by ionophoresis of glycinamide, the first metabolite of milacemide.(ABSTRACT TRUNCATED AT 250 WORDS)     

淫羊藿苷对快速老化小鼠SAMP10脑组织单胺类及氨基酸类神经递质的影响

目的:探讨淫羊藿苷(ICA)对快速老化小鼠SAMP10脑组织单胺类及氨基酸类神经递质的影响。方法:本实验采取8月龄快速老化小鼠SAMP10为实验对象,随机分为模型SAMP10组、阳性药多奈哌齐组(1mg/kg)、ICA 3个剂量(50、100、200mg/kg)组,每组12只,以12只同月龄抗快速老化小鼠SAMR1为正常对照。灌胃给药30d,一天一次,高效液相-电化学法检测快速老化小鼠SAMP10大脑皮层的去甲肾上腺素(NE)、5-羟色胺(5-HT)、多巴胺(DA)及其代谢产物3,4-二羟苯乙酸(DOPAC)和高香草酸(HVA)的含量来探讨ICA对SAMP10脑组织单胺类神经递质的影响,通过检测谷氨酸(Glu)、谷氨酰胺(Gln)、天冬氨酸(Asp)、γ-氨基丁酸(GA-BA)、牛磺酸(Tau)、甘氨酸(Gly)的含量来探讨ICA对SAMP10脑组织氨基酸类神经递质的影响。结果:ICA可显著降低SAMP10大脑皮层内Glu、Gln、GABA含量(P<0.01),升高NE、DA、DOPAC、5-HT、HVA、Asp以及Tau的含量(P<0.01或P<0.05),但对SAMP10大脑皮层内Gly的含量并没有显著影响(P>0.05)。结论:ICA可能通过升高脑内单胺类神经递质的含量、调节兴奋性氨基酸类递质的代谢平衡以及调节抑制性氨基酸的代谢平衡达到改善SAMP10的学习记忆的作用。     

The effects of reserpine, L-dopa and 5-hydroxytryptophan on 5-hydroxyindoleacetic and homovanillic acids in cerebrospinal fluid, behaviour and EEG in cats.

Four hours after injection of reserpine (0.5 mg/kg). concentrations of 5-hydroxyindoleacetic acid and homovanillic acid in cerebrospinal fluid increased by 130 and 83% respectively. Eight hours after injection, the first periods of EEG synchronization appeared coinciding with a decrease in homovanillic acid concentration. Slow-wave sleep episodes appeared at 16 hr, at which time the concentration of homovanillic acid approached control levels while the 5-hydroxyindoleacetic acid concentration remained significantly elevated.Administration of l-dihydroxyphenylalanine (50 mg/kg) increased homovanillic acid above control levels through 21 hr with a peak increase of 2428% at 4 hr. 5-Hydroxyindoleacetic acid concentration did not change significantly. The animals were alert with mydriatic pupils. The 9 hr EEG record showed desynchronization in the cortical leads, increased dorsal neck muscle tone and active eye movements.Four hours following administration of 5-hydroxytryptophan (50 mg/kg) both 5-hydroxyindoleacetic acid and homovanillic acid increased by 1120 and 75% respectively. Synchronization with short periods of low amplitude appeared during 9 hr of EEG recording. During this time the animals were awake, but demonstrated miotic pupils and recurrent periods of drowsiness. These results suggest that behaviour and EEG can be related to changes in brain monoamine metabolism measured in cerebrospinal fluid. Increased metabolism of 5-hydroxytryptamine, as indicated by increased 5-hydroxyindoleacetic acid concentration, correlates with cortical synchronization. Homovanillic acid, the major metabolite of dopamine, was increased in waking behaviour and EEG desynchronization.     

Clinical measurements of central dopamine and 5-hydroxytryptamine metabolism: reliability and interpretation of cerebrospinal fluid acid monoamine metabolite measures

Concentrations of 5-hydroxyindoleacetic acid and homovanillic acid were measured with and without probenecid pretreatment in the lumbar cerebrospinal fluid of psychiatric patients and inmate controls. Values were obtained for the errors of the methods (both 5-hydroxyindoleacetic acid and homovanillic acid), and for intra-individual variation among some sequential samples. Baselines values for 5-hydroxyindoleacetic acid and homovanillic acid correlated positively with the increment after probenecid in individual subjects. Following the administration of probenecid, cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid showed a significant positive correlation. In clinical studies, not only absolute values for these cerebrospinal fluid acid amine metabolites but also their ratio must be considered in the interpretation of results. The use and interpretation of these measures in clinical studies is briefly reviewed.     

Effects of 2,4-dichlorophenoxyacetic acid (2,4-D) on biogenic amines and their acidic metabolites in brain and cerebrospinal fluid of rats

Effects of single subcutaneous doses of sodium 2,4-dichlorophenoxyacetate (2,4-D-Na) on biogenic amines and their acidic metabolites in rat brain and cerebrospinal fluid (CSF) were analyzed by high pressure liquid chromatography. After 200 mg/kg 2,4-D-Na, the cerebral concentration of 5-hydroxytryptamine (5-HT) was increased slightly and that of 5-hydroxyindoleacetic acid (5-HIAA) roughly 3-fold between 1 and 8 h after the administration. There was also a tendency towards slightly lowered dopamine (DA) levels. No statistically significant changes in brain concentrations of noradrenaline (NA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) or tryptophan (TRY) were found. At the same time, however, the maximal increase in DOPAC, HVA and 5-HIAA concentrations in the CSF was 2.3–5.8-fold. The dependency of biogenic amines and metabolites on 2,4-D-Na dose was studied by injecting s.c. 0, 10, 30 and 100 mg/kg and sacrificing the rats at 2 h. In the brain, there was a dose-dependent increase in concentrations of 5-HIAA (at the two highest doses) and HVA (at the highest dose) while in the CSF those of all three acidic metabolites increased at the two highest doses. The 10 mg/kg dose had no effect. The results agree with the hypothesis that 2,4-D inhibits the organic acid transport out of the brain, which should then result in increased cerebral levels of acidic metabolites of biogenic amines, but it may also have effects on the activity of serotoninergic and dopaminergic neurones.     

Effects of chlorpromazine on the metabolism of catecholamines in dog brain

1. The effect of chlorpromazine (CPZ) on the metabolism of dopamine and 5-hydroxytryptamine in dog brain was investigated by following the concentrations of the acid metabolites of these amines, homovanillic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid, in the ventricular cerebrospinal fluid (C.S.F.) of dogs over a period of 5 hr after intravenous administration of CPZ (2.5, 5, 10 and 15 mg/kg), using the technique of serial sampling of lateral ventricular C.S.F. "Low" doses (2.5-10 mg/kg) produced a rise in the concentration of homovanillic acid and smaller increases in the concentrations of 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid. "High" doses (10-15 mg/kg) had a lesser effect on the concentration of homovanillic acid and had no effect on, or decreased, the concentrations of 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid. The concentration of 3,4-dihydroxyphenylacetic acid was maximal in the ventricular C.S.F. 2 hr after CPZ 5 mg/kg and was unaltered from the control level 2 hr after 15 mg/kg.2. The effects on the metabolism of brain amines of CPZ (5 mg/kg), doses which the serial sampling of C.S.F. experiments had indicated as producing maximal and minimal effects on dopamine metabolism in brain tissue, were studied by estimating the concentrations of adrenaline, noradrenaline, dopamine, metanephrine, methoxydopamine, homovanillic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid in the hypothalamus, midbrain, thalamus, hindbrain, cortex, globus pallidus and caudate nucleus of control dogs and of dogs treated with CPZ intravenously 2 hr before killing. The concentrations of homovanillic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid were estimated in samples of ventricular C.S.F. withdrawn from these dogs 2 hr after the injection of CPZ (i.e., immediately before death).3. The following changes in concentrations were observed. Dopamine: CPZ 5 mg/kg produced no change in the concentration in the caudate nucleus, globus pallidus and midbrain and increased the concentration in the thalamus; CPZ 15 mg/kg appeared to cause a reduction in the concentration of this amine in the caudate nucleus and globus pallidus. Homovanillic acid and 3,4-dihydroxyphenylacetic acid: CPZ 5 mg/kg increased the concentrations of both acids in the caudate nucleus and had no effect on the concentrations of the acids in the globus pallidus, hypothalamus and thalamus; CPZ 15 mg/kg produced no change in the concentrations of the acids in any area of the brain. Methoxydopamine: CPZ 5 mg/kg and 15 mg/kg reduced the concentration in the caudate nucleus. Noradrenaline: The concentrations in the hypothalamus, midbrain, thalamus and hindbrain were slightly increased by CPZ 5 mg/kg and 15 mg/kg. Only in the thalamus was a statistically significant increase in noradrenaline observed.4. It was concluded that the actions of chlorpromazine on catecholamine synthesis and metabolism in the brain of the dog are dose dependent. A dose of CPZ 5 mg/kg was postulated to have the following actions: (i) to increase dopamine synthesis; (ii) to activate mitochondrial monoamine oxidase. A dose of CPZ 15 mg/kg was postulated to act as follows: (i) to decrease dopamine synthesis; or (ii) to release dopamine from its storage sites.5. The ratios of the concentrations of homovanillic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid in the caudate nucleus to the concentrations of these acids in the ventricular C.S.F. were the same in the control dogs as in the dogs treated with CPZ (5 mg/kg and 15 mg/kg). It was concluded that the levels of the acid metabolites of dopamine in lateral ventricular C.S.F. reflect the levels of these acids in the caudate nucleus.     

Differential effects of clorgyline on catecholamine and indoleamine metabolites in the cerebrospinal fluid of rhesus monkeys

The effects of acute and chronic administration of clorgyline, an irreversible inhibitor of monoamine oxidase type A (MAO-A), on the deaminated metabolites of norepinephrine, dopamine and serotonin were examined in rhesus monkey cerebrospinal fluid (CSF). Acute clorgyline treatment resulted in highly significant, dose-dependent reductions in 3-methoxy-4-hydroxyphenylglycol (MHPG) of 50% (1 mg/kg) and 68% (2 mg/kg) compared to pretreatment values. Chronic clorgyline administration (0.25 to 0.5 mg/kg X 24 days) resulted in a 67% reduction in CSF MHPG. In contrast, the concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were less affected by acute clorgyline administration, being reduced significantly only after the 2 mg/kg dose, which lowered 5-HIAA 27% and HVA 48%. Chronic clorgyline treatment had no significant effect on the CSF concentrations of HVA and 5-HIAA. These data, which suggest that MAO-A inhibition by clorgyline in vivo is more closely associated with changes in the noradrenergic than the serotonergic or dopaminergic systems in nonhuman primates, are in general agreement with the effects of clorgyline on CSF and urinary biogenic amine metabolites in man. They differ from several in vitro studies which indicate a primary role of MAO-A in the metabolism of serotonin and of MAO-B in norepinephrine degradation in primate brain. The discrepancies may reflect modulating effects of synaptic feedback mechanisms on the actions of clorgyline in vivo or perhaps a failure of CSF metabolites to adequately reflect brain amine metabolism changes. The lack of change in platelet MAO-B activity during clorgyline treatment together with the minimal changes in HVA concentrations indicate that the selective inhibitory effects of clorgyline on MAO-A were maintained during chronic administration of low drug doses.     

Effects of chronic fenfluramine on blood serotonin,cerebrospinal fluid metabolites,and behavior in monkeys

The effects of long term (70 days) fenfluramine treatment on selected physiological and behavioral measures were examined in four adult male vervet monkeys (Cercopithecus aethiops sabaeus). Relative to pretreatment baseline values, whole blood serotonin (WBS) and cerebrospinal fluid 5-hydroxyindole acetic acid (5-HIAA) were reduced, cerebrospinal fluid homovanillic acid (HVA) was unaltered, and aggressive and locomotor behavior were increased. Both physiological and behavioral effects were reversible: all measures returned to baseline values in the 35 day post-treatment period, with WBS resuming pretreatment values more rapidly than CSF 5-HIAA. At the relatively low doses (1–4 mg/kg/day) employed in the present study fenfluramine produced behavioral effects similar to those resulting from PCPA and opposite to those following tryptophan administration. Thus the behavioral effects of long-term fenfluramine may involve reductions in serotonergic transmission.     

Monoamine metabolites and amino acids in serum from schizophrenic patients before and during sulpiride treatment

Twenty-four acutely ill schizophrenic patients (DSM-III-R), 18–42 years old, were treated for 6 weeks with sulpiride. Sulpiride was administered in three different daily dosages (starting with 400, 800 or 1200 mg) according to a double blind randomized administration schedule. The monoamine metabolites (MAM) homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA), 4-hydroxy-3-methoxy-phenylglycol (HMPG) and the amino acids tyrosine, tryptophan, glutamate and glutamine were measured in serum before treatment and once a week during treatment. There were no significant differences between healthy controls and schizophrenic patients in serum levels of monoamine metabolites and amino acids before treatment. There was no dose-response effect of sulpiride on serum levels of the monoamine metabolites or the amino acids. The results are therefore based on the whole group of patients. During treatment the HMPG levels were reduced at all points in time. The serum level of HVA was significantly reduced after 6 weeks. The 5-HIAA and the amino acid levels were not changed during treatment. There were no significant correlations among the monoamine metabolites before treatment. During treatment, however, significant correlations were found among MAM and amino acids. Since the biochemical findings during the treatment were not related to the dose or the concentration of sulpiride the results may be related to secondary biochemical effects of sulpiride and/or to changes in the clinical state following treatment.     

Effect of probenecid on the concentration of the lumbar cerebrospinal fluid acidic metabolites of tyramine, octopamine, dopamine and norepinephrine.

Mass fragmentography was employed to measure the concentrations of the acidic metabolites of tyramine (p-hydroxyphenylacetic acid), octopamine (p-hydroxymandelic acid), dopamine (3,4-dihy-droxyphenylacetic and homovanillic acid) and norepinephrine (vanilmandelic acid) in lumbar cerebrospinal fluid (CSF) of schizophrenic patients. Treatment with oral probenecid (100 mg/kg) increased the concentrations o f p-hydroxyphenylacetic. 3,4-dihydroxyphenylacetic and homovanillic acid by over 3-fold compared to the baseline levels. The concentration of p-hydroxymandelic acid was also increased, but only moderately compared to the increase of homovanillic acid. Vanilmandelic acid showed a tendency toward being elevated by probenecid, but in our study, the elevation was not statistically significant, probably due to the large variance between subjects.     

Plasma and cerebrospinal fluid probenecid concentrations as related to accumulation of acidic biogenic amine metabolites in man

The oral administration of probenecid (100 mg/kg/18 h) to depressed patients results in marked increases in the acidic metabolites of biogenic amines in the cerebrospinal fluid (CSF). In contrast to previous reports (where lower dose rates of probenecid were employed) the increases in 5-hydroxyindoleacetic acid and homovanillic acid were independent of plasma or CSF probenecid concentrations. Higher plasma and CSF probenecid concentrations were found in this study. The binding of probenecid to plasma proteins for each patient was also determined to examine the pharmacodynamics of probenecid distribution. The ratio of probenecid in CSF to the calculated free probenecid in plasma was higher (0.4) and more constant than previously noted. At these higher dose levels, probenecid successfully competes with the active transport process for biogenic amine acidic metabolites and also appears to block its own removal from CSF.A preliminary report of this work was presented (Fed. Proc. 32, 696 (1973).     

The effect of chlorpromazine on homovanillic acid levels in cerebrospinal fluid of schizophrenic patients

A mass fragmentometric method was used for determination of homovanillic acid levels in cerebrospinal fluid of acutely admitted schizophrenic patients. Spinal puncture was performed before and 12 days following the beginning of chlorpromazine treatment (200–600 mg/day). The level of homovanillic acid in cerebrospinal fluid before treatment was significantly higher in women than in men. Chlorpromazine treatment resulted on the average in a more than 2-fold elevation of the homovanillic acid level in cerebrospinal fluid. There were marked individual differences in the effect. The results are compatible with the view that therapeutic doses of chlorpromazine accelerate brain dopamine synthesis in man.A close analysis of the relation between effects of chlorpromazine on brain dopamine synthesis and psychotic and motor behaviour in schizophrenic patients seems required.     

Effects of RS-2232, a potential antidepressant, on the levels of monoamines, precursor amino acids and their related metabolites in mouse brain

The effects of RS-2232, a new antidepressant, on the levels of monoamines, precursor amino acids and their related metabolites in mouse brain were investigated and compared with some clinically effective antidepressants. RS-2232 (3, 10 and 30 mg/kg, p.o.) increased the levels of norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) dose-dependently, 60 min after administration. Tyrosine (TYR) levels were not changed, but tryptophan (TRP) was significantly increased by 20% at 30 mg/kg of the compound. On the other hand, DA metabolites such as 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were significantly reduced at all doses. 5-Hydroxyindoleacetic acid (5-HIAA), a 5-HT metabolite, was decreased by 32% at 10 mg/kg. These changes caused by RS-2232 administration were similar to those of the classical inhibitor of monoamine oxidase (MAO), isocarboxazid (ISO), but rather different from those of imipramine (IMP) and mianserin (MIA). RS-2232 and ISO antagonized against reserpine (2 mg/kg, s.c.)-induced changes in the contents of monoamines and their metabolites. Furthermore, time-course experiments clearly showed that increase in the levels of monoamines by 10 mg/kg of RS-2232 was restored to the control levels within a few hours. These results suggest that RS-2232 has reversible MAO inhibiting properties in vivo in mouse brain.     

Effects of antihistaminic drugs on feline brain monoamine metabolism.

Diphenhydramine and phenindamine were administered in various doses to cats and the time course of changes in monoamine metabolite levels in cerebrospinal fluid was determined. Diphenhydramine at a sedative dose did not alter 5-hydroxytryptamine or dopamine metabolism. Excitant doses of diphenhydramine elevated 5-hydroxyindolacetic acid levels, while homovanillic acid levels remained unchanged. At a convulsant dose, diphenhydramine lowered rectal temperature while elevating both 5-hydroxyindolacetic acid and homovanillic acid levels. Phenindamine, which reportedly produces only central nervous system (CNS) excitation and convulsions, caused excitation, tremor and stereotypy, while elevating 5-hydroxyindolacetic acid and homovanillic acid levels in cerebrospinal fluid. These data suggest that antihistaminic-induced sedation is not due to an alteration in brain 5-hydroxytryptamine or dopamine metabolism and that only 5-hydroxytryptamine metabolism is increased during CNS excitation. Stereotypic behavior after phenindamine may occur through a dopaminergic system as reflected by elevated levels of homovanillic acid in cerebrospinal fluid.     

Lack of effect of a glycine(B) receptor partial agonist on amphetamine-induced sensitization in mice

Effects of 1-aminocyclopropanecarboxylic acid (ACPC), a partial agonist of glycine(B) receptors, on the expression and development of sensitization to the locomotor activity of amphetamine (AMPH, 2.5 mg/kg) were studied in mice. ACPC in doses of 100-400 mg/kg did not affect the expression of AMPH sensitization. Combined injections of ACPC (200-400 mg/kg) and AMPH during the development of sensitization did not change the expression of sensitization to the challenge dose of AMPH 3 days after the drug withdrawal. Acute administration of ACPC, 400 mg/kg, enhanced the locomotor hyperactivity induced by a single dose of AMPH, that effect being probably connected with its own stimulatory action of that dose of ACPC. Summing up, our results show that ACPC affects neither the development nor the expression of AMPH sensitization in mice.     

The partial dopamine receptor agonist terguride in the MPTP-induced hemiparkinsonian monkey model

The partial dopamine agonist terguride (transdihydrolisuride) administered to four 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned hemiparkinsonian monkeys (at a dose of 4 mg/kg orally) induced marked contralateral turning that lasted 3.5 h. The 6-n-propyl derivative of terguride (proterguride) given to two monkeys (at a dose of 0.4 mg/kg orally) caused contralateral turning which lasted for more than 24 h but produced side effects such as dyskinesia and stereotype. After terguride treatment, cerebrospinal fluid concentrations of 3-methoxy-4-hydroxy-phenylglycol (MHPG) were increased, whereas concentrations of the metabolites dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were not significantly altered.