Minipump clorgyline administration and CSF amine metabolites in unrestrained monkeys.

The irreversible MAO-A inhibitor clorgyline was administered in doses of 0.5 mg/kg (N = 1), 1 mg/kg (N = 3), and 2 mg/kg (N = 1) to 5 young (age 5.5 to 23.9 months) pigtail (M. nemestrina) monkeys using a 28-day (Alza 2ML4) osmotic minipump. CSF MHPG, 5-HIAA, HVA, and plasma MHPG were measured before and at approximately weekly intervals after pump implantation. Implants were well tolerated. CSF MHPG decreased about 75%, 5-HIAA 30%, and HVA from 30-50% with a tendency to plateau by the second week. Plasma MHPG decreased to undetectable levels. The findings demonstrate that long-term inhibition of MAO-A can be produced in unrestrained monkeys by minipump administered clorgyline. There is an apparently greater effect on the norepinephrine system relative to the serotonin and dopamine systems.     

The effects of amiflamine on cerebrospinal fluid amine metabolites in the rhesus monkey

Amiflamine, a drug reported to be a reversible inhibitor of monoamine oxidase type A (MAO-A) selective for serotonergic neurons in rodents, was administered to rhesus monkeys over a 12-fold dosage range (0.5-6 mg/kg). Amiflamine produced small, essentially equivalent reductions in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA, 1-28%), 3-methoxy-4-hydroxyphenylglycol (MHPG, 4-26%), and homovanillic acid (HVA, 7-29%), suggesting that the effects of amiflamine are approximately equal on serotonin, norepinephrine and dopamine metabolism in nonhuman primates. Concentrations of amiflamine were very low in CSF 3-6 h after drug administration (less than 7 nmol/l), while those of its two major, biologically active metabolites were higher (22-150 nmol/l) and varied in relative proportions among the monkeys. Further investigation is required of some preliminary observations of a possible association between drug metabolite variations and the substantial individual differences in the amine metabolite changes following amiflamine treatment. MAO-B in platelets was not inhibited by 6 mg/kg amiflamine, indicating that MAO-A selectivity was maintained. At low amiflamine doses, early and transient increases in CSF 5-HIAA and HVA concentrations were observed, suggesting an amine-releasing effect of the drug within brain serotonergic and dopaminergic neurons.     

Rhesus monkey cerebrospinal fluid amine metabolite changes following treatment with the reversible monoamine oxidase type-A inhibitor cimoxatone

The effects of cimoxatone, a reversible inhibitor of monoamine oxidase type A (MAO-A), on the deaminated metabolites of norepinephrine, dopamine, and serotonin were examined in continuously collected rhesus monkey cerebrospinal fluid (CSF). Cimoxatone, 0.5–8 mg/kg given PO, produced dose-proportionate reductions of 24-h mean CSF 3-methoxy, 4-hydroxy phenylglycol (MHPG) concentrations of 21%–52%. Homovanillic acid (HVA) concentrations also decreased 27%–55%, while CSF 5-hydroxyindoleacetic acid (5-HIAA) decreases were somewhat smaller (7%–32% from baseline). All three metabolite concentrations reached a nadir approximately 6–10 h after drug administration, and required over 40 h to gradually return towards baseline following drug discontinuation. HVA concentration reductions in particular persisted during the entire 24-h period following treatment and were the slowest to return to baseline values. CSF concentrations of cimoxatone and its MAO-inhibiting O-demethyl metabolite showed a parallel time course peaking 6–10 h after treatment and persisting for up to 24 h in the case of cimoxatone and over 48 h for its metabolite. Single simultaneous time point determinations revealed 10-to 20-fold lower concentrations of cimoxatone and its metabolite in CSF compared to plasma 2 h after treatment. MAO-B activity in platelet-rich plasma was not inhibited by 8 mg/kg cimoxatone, indicating that this drug maintains MAO-A selectivity in vivo. As cimoxatone's preferential effects on catecholamine metabolites were similar to those previously observed with the irreversible MAO-A inhibiting antidepressant, clorgyline, our results are consistent with limited clinical trials data suggesting that cimoxatone may also prove to be an effective antidepressant.     

Neurochemical changes in pigeon cerebrospinal fluid during chronic administration of buspirone or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)

Cerebrospinal fluid (CSF), collected repeatedly from White Carneau pigeons chronically implanted with guide cannulae located in the lateral ventricles, was analyzed for metabolites of serotonin, dopamine and norepinephrine after acute and chronic administration of buspirone or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Following the acute administration of 3.0 mg/kg buspirone, levels of 5-hydroxyindoleacetic acid (5-HIAA) decreased, while increases occurred in the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC). Decreases in 5-HIAA persisted throughout the chronic dosing regimen (36 days), while dopamine metabolites returned to control levels within 8 days. When chronic buspirone was discontinued, levels of 5-HIAA were restored to predrug control levels, while levels of HVA, DOPAC and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) decreased. All metabolites returned to predrug control levels within one week following buspirone discontinuation except for MHPG, which remained depressed. When the acute effects of buspirone were reexamined, levels of 5-HIAA were again significantly decreased, while HVA and DOPAC levels, as well as those of MHPG, increased significantly. Acute administration of the 5-HT1A receptor ligand 8-OH-DPAT (3.0 mg/kg) resulted in large decreases in 5-HIAA levels that persisted throughout the period of chronic administration. Neither acute nor daily administration of 8-OH-DPAT changed levels of HVA, DOPAC or MHPG. Large increases in 5-HIAA occurred when chronic 8-OH-DPAT was discontinued but declined within one week to control levels. Following a two-week drug-free period, 8-OH-DPAT again caused a significant reduction in 5-HIAA levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Marked enhancement by clorgyline of nocturnal and daytime melatonin release in rhesus monkeys

The type A monoamine oxidase (MAO)-inhibiting antidepressant clorgyline (1 mg/kg/24 days) administered to rhesus monkeys increased night-time cerebrospinal fluid (CSF) melatonin concentrations 3-fold and day-time maltonin values 5-fold. Other circadian parameters of melatonin release, including the peak time and duration of nocturnal melatonin elevation measured during continuous CSF collection periods of 90 min duration over 24-h cycles, were unaffected by clorgyline. While pinealocytes are thought to contain only MAO-B, treatment with the selective MAO-B inhibitor deprenyl (2 mg/kg/24 days) did not alter day or night-time melatonin concentrations. These results are consistent with MAO-A and non-selective MAO inhibitors acting via blockade of degradation of the preferential substrates of MAO-A, serotonin and/or norepinephrine, in adrenergic neurons entering the pineal gland. Further study is needed to evaluate the relative contributions of an increased availability of the melatonin precursor, serotonin, or a sustained net increase in alpha₁-or beta adrenoceptor-mediated input on pinealocytes to these marked changes in melatonin production.     

Effects of monoamine oxidase inhibitors on levels of catechols and homovanillic acid in striatum and plasma

Levels of homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG) in plasma and the striatium were measured after inhibition of monoamine oxidase type A (MAO-A) by clorgyline (4 mg/kg i.p.), MAO-B by (-)deprenyl (1 mg/kg i.p.), both MAO-A and MAO-B by nialamide (75 mg/kg i.p.) or peripheral neuronal MAO by debrisoquin (40 mg/kg i.p.). Levels of HVA in plasma decreased by about 60% after single doses of nialamide or clorgyline, by about 80% after repeated doses of nialamide, by about 40% after a single dose of debrisoquin and by about 50% after repeated doses of debrisoquin. The administration of clorgyline, nialamide or debrisoquin significantly decreased concentrations of DOPAC and DHPG in plasma, whereas (-)deprenyl did not affect levels of DHPG or HVA. None of the MAO inhibitors produced more than about 80% depression of levels of any of the deaminated metabolites. The results suggest that most of the HVA in plasma is derived from deamination of DA by MAO-A in peripheral neurons; that DOPAC in plasma is derived from cells outside the central nervous system; that DHPG in plasma is derived virtually exclusively from the metabolism of norepinephrine in sympathetic nerve endings and that residual levels of HVA after treatment with debrisoquin provide an improved but limited indication of central dopaminergic activity.     

Dose-dependent effects of deprenyl on CSF monoamine metabolites in patients with Alzheimer's disease

Deprenyl, a monoamine oxidase (MAO) inhibitor with selective effects on MAO type-B at low doses, was administered to 13 patients with dementia of the Alzheimer type (DAT), a disorder reported to be associated with increased brain MAO-B activity. Cerebrospinal fluid was obtained for measurement of three monoamine metabolites, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), by high pressure liquid chromatography with electrochemical detection. Deprenyl treatment (10 mg/day) for 3–4 weeks was associated with small but statistically significant reductions in HVA (21%) and 5-HIAA (15%) compared to baseline values. Subsequent administration of deprenyl at the higher dose of 40 mg/day for 3–4 more weeks led to greater reductions in HVA (40%) and MHPG (43%) than 5-HIAA (20%). These dose-dependent reductions are consistent with in vitro biochemical and anatomical data from primate brain suggesting that at low doses of deprenyl, MAO-B inhibition might be expected to selectively affect dopamine and serotonin-containing neurons, while at higher doses (which lead to MAO-A as well as MAO-B inhibition), noradrenergic neurons may become relatively more affected by the drug.     

Tyramine infusions and selective monoamine oxidase inhibitor treatment

The relationship between changes in IV tyramine pressor sensitivity accompanying selective monoamine oxidase (MAO) inhibitor treatment and estimates of MAO-A and MAO-B inhibition in vivo were studied. Reductions in platelet MAO activity provided an index of MAO-B inhibition, while changes in plasma 3-methoxy-4-hydroxyphenethylene glycol (MHPG) were used as an hypothesized reflection of MAO-A inhibition. Chronic treatment with the MAO-A inhibitor clorgyline and the MAO-B inhibitor pargyline showed significant inhibition of the alternate MAO enzyme as well, although this crossover effect was greater for pargyline than clorgyline. The MAO-B inhibitor deprenyl appeared to maintain the greatest degree of MAO inhibition selectivity in vivo. Tyramine pressor sensitivity changes accompanying administration of the MAO inhibitors were highly correlated with decreases in plasma MHPG (r=0.92), supporting our previous data indicating the rank order of clorgyline > pargyline > deprenyl for enhancement of tyramine pressor sensitivity and, thus, suggesting that tyramin potentiation is primarily a function of MAO-A rather than MAO-B inhibition. Changes in plasma MHPG are suggested to provide a potentially useful clinical index of in vivo MAO-A inhibition.Presently with the Biological Psychiatry Branch, NIMH     

In vivo evidence for the reversible action of the monoamine oxidase inhibitor brofaromine on 5-hydroxytryptamine release in rat brain

We have used intracerebral microdialysis to examine the reversibility of the action of brofaromine, a selective inhibitor of monoamine oxidase-A (MAO, E.C. 1.4.3.4.), on 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) output in rat frontal cortex. Brofaromine significantly increased the 5-HT output to about 200% of basal values 4 h after the s.c. administration of 10 and 30 mg/kg (but not 3 mg/kg) and reduced the concentration of 5-HIAA in the dialysate dose-dependently (61%, 53% and 41% of basal value with doses of 3, 10 and 30 mg/kg, respectively). At this time, cortical 5-HT concentration was increased and cortical 5-HIAA concentration was decreased in a dose-dependent manner.Treatment of rats with 10 mg/kg brofaromine plus 2.5 mg/kg of the irreversible MAO-B inhibitor l-deprenyl increased the concentration of 5-HT in the dialysate more than did brofaromine alone (503% vs 206% of the basal value, 4 h after administration). Similarly, clorgyline (5 mg/kg) plus l-deprenyl (2.5 mg/kg) increased the concentration of 5-HT in the dialysate to 461 % of the control value. This indicates that the concurrent inhibition of both types of MAO increases 5-HT output more than the selective blockade of either enzyme subtype. We have used this characteristic to examine, in vivo, the reversibility of the interaction of brofaromine with MAO-A. The output of 5-HT and 5-HIAA was examined 19–21 h after treatment with l-deprenyl plus clorgyline or l-deprenyl plus brofaromine. At this time, the concentration of 5-HT in the dialysate was increased six-fold in the clorgyline plus l-deprenyl group, as compared to pre-treatment values, but did not differ significantly from these in the brofaromine plus L-deprenyl group. Also, 5-HIAA concentration in the dialyste was still reduced (48% of basal value) in the clorgyline plus l-deprenyl group but not in the brofaromine plus l-deprenyl group. Cortical 5-HT and 5-HIAA concentrations in these animals, measured at the end of the microdialysis experiments (21 h after treatment), displayed changes that paralleled those in the extracellular compartment.These results indicate that: (a) as with clorgyline, the inhibition of MAO-A with brofaromine has a more pronounced effect on tissue 5-HT concentrations than on extracellular 5-HT concentrations; (b) the simultaneous inhibition of both forms of MAO with l-deprenyl and either brofaromine or clorgyline increased the concentration of 5-HT in the dialysate shortly (1–4 h) after administration more than did treatment with either of the MAO-A inhibitors alone; (c) dialysate and tissue 5-HT concentrations were greatly increased one day after the irreversible inhibition of MAO by clorgyline plus l-deprenyl, whereas they had returned to pretreatment values in those animals treated with brofaromine plus l-deprenyl. These transient effects on 5-HT and 5-HIAA in vivo provide further support for the conclusion that the interaction of brofaromine with brain MAO-A is reversible.     

CSF monoamine metabolite concentrations vary according to age,rearing, and sex,and are influenced by the stressor of social separation in rhesus monkeys

In humans, CSF monoamine metabolite concentrations have been shown to vary as a complex function of age, sex, psychiatric diagnosis, and stress. To test for such relationships in rhesus monkeys, 28 subjects, reared either in anxiety producing peer-only groups or in mother-infant dyads, were studied at 6, 18 or 50 months of age. Each monkey underwent a series of four 4-day social separations, each followed by 3 days of reunion. Prior to and during the first and fourth separations, CSF was obtained from the cisterna magna and assayed for the serotonin metabolite 5-HIAA, the dopamine metabolite HVA, and the norepinephrine metabolite MHPG. CSF 5-HIAA showed an age-related decline which was greater in the mother-reared subjects. Peer-only-reared males had an increased 5-HIAA concentration relative to females, and higher 5-HIAA levels than mother-reared males. MHPG was also higher in peer-only-reared monkeys than in mother-reared subjects at all ages. In both groups HVA declined across the three ages, and MHPG increased from the 18- to the 50-month measurements. Both MHPG and 5-HIAA concentrations increased during the initial social separation, although only MHPG remained elevated across the repeated separations; HVA, on the other hand declined during social separation. These results are discussed in terms of established anxiety and aggression differences between peer-only and mother-reared monkeys.     

Correlative changes of serotonin and catecholamines with pharmacokinetic alterations of imipramine in rat brain

Rats were given i.p. imipramine (20 mg/kg), acutely or chronically, and the levels of serotonin (5-HT), norepinephrine (NE), dopamine (DA) and their metabolites in the brain at different times were compared with the concentrations of imipramine and desipramine. The levels of 5-HT, DA, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the brain did not appear to be affected by quantitative alterations in the concentrations of imipramine and desipramine. The level of 5-hydroxyindole acetic acid (5-HIAA) was reduced and the level of 3-methoxy-4-hydroxyphenylglycol (MHPG) tended to decrease 3 h after imipramine administration in acutely treated rats. The reduced level of 5-HIAA was maintained during the chronic treatment with imipramine, whereas the MHPG level increased and the NE level decreased. The decrease in 5-HIAA depended on the concentration of imipramine in the brain, whereas the changes in the levels of NE and MHPG appeared to be caused by desipramine. The present studies show that pharmacokinetic variations of imipramine in the brain might correlate with the altered levels of 5-HIAA, NE and MHPG.     

Monoamine metabolite levels in rat CSF: kinetic studies

The kinetics of monoamine metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), in cisternal CSF were determined after monoamine oxidase (MAO) inhibition (pargyline, 100 mg/kg) and tyrosine hydroxylase inhibition (alpha-methyl-p-tyrosine, alpha-MPT, 250 mg/kg) in awake rats. In addition, the possibility of a peripheral contribution to CSF MHPG levels was investigated by infusing large amounts of the metabolite into vena jugularis. Pargyline induced an exponential decrease of CSF MHPG, 5-HIAA and HVA, with respective half-lives of 51, 86 and 46 min. alpha-MPT caused a slower decline of MHPG and HVA, while 5-HIAA was unaffected. Results from the MHPG-infusion experiments indicate minor peripheral contribution to CSF MHPG levels in acute pharmacological studies. The present paper gives further support for the validity of our new animal model in detecting acute changes in central monoaminergic activity.     

Effect of probenecid on free 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and its sulphate in human cerebrospinal fluid

In a mixed group of 46 patients with affective disorder, or with various neurologic disorders, high doses of probenecid (100 mg/kg over 18 hr) produced a significant increase in lumbar cerebrospinal fluid (CSF) levels of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the major metabolite of norepinephrine centrally. This increase (averaging 60%) is modest in comparison to probenecid induced increases in homovanillic acid (HVA) or 5-hydroxyindo-leacetic acid (5-HIAA). Analysis for free MHPG and its sulfate showed no significant differences for either compound after nine hours. After 18 hours of treatment significant increases in free MHPG and small but not significant increases of MHPG.SO₄ were found. These results suggest that a probenecid sensitive active transport mechanism for MHPG.SO₄ of the degree demon-strated for HVA and 5-HIAA in humans, and for MHPG.SO₄ in rats, does not occur in human CSF.     

Monoamine oxidase type a: differences in selectivity towards l-norepinephrine compared to serotonin

l-Norepinephirine and serotonin have been regarded as preferential substrates for monoamine oxidase (MAO) type A. A close comparative examination of a number of tissues from different species, however, indicated the following differences. Serotonin was a more selective substrate for MAO-A, being inhibited by low concentrations (< 10^-7M) of the irreversible MAO-A inhibitor, clorgyline, more consistently and to a greater extent (80–100%) than was l-norepinephrine (30–85%). These serotonin-norepinephrine differences were greater in humans and other primates than in rodents. Serotonin also had a 2- to 4-fold smaller apparent K_m for MAO-A than l-norepinephrine and was deaminated 2- to 5-fold more readily by MAO in vitro in most tissues. In contrast, the MAO-B in human platelets deaminated l-norepinephrine more readily than serotonin. Thus, l-norepinephrine, like dopamine, should be regarded as a substrate for both MAO-A and MAO-B in vitro. The prominent role of MAO-B in norepinephrine degradation in primates may need to be considered in interpreting laboratory and clinical studies of clorgyline selective MAO-inhibiting drugs.     

The effects of selective and non-selective monoamine oxidase (MAO) inhibitors on conflict behavior in the rat

Conflict behavior in rats was examined over the course of several weeks of chronic treatment with selective and non-selective monoamine oxidase inhibitors (MAOIs). In daily 10min sessions, rats were trained to drink from a tube which was occasionally electrified (0.5mA). Electrification was signalled by the presence of a tone. Within 3-4 weeks, control (i.e. non-drug) conflict behavior had stabilized (30-40 shocks and 8-12ml water/session) and drug testing began. Chronic administration (two injections/day for 8 weeks) with a non-selective (i.e. MAO-A and MAO-B inhibiting) dose of pargyline (15mg/kg) resulted in a time-dependent increase in punished responding. In contrast, chronic administration of the MAO-A selective inhibitor (clorgyline; 1.0mg/kg, 2mg/kg), the MAO-B selective inhibitor deprenyl (5mg/kg) or MAO-B inhibiting doses of pargyline (1.0mg/kg, 5mg/kg) were without effect. Finally, chronic treatment with the combination of a low dose of clorgyline (1.0mg/kg) and a low dose of pargyline (1.0mg/kg) did result in a time-dependent increase in punished responding. These results suggest that inhibition of both MAO-A and MAO-B is required for the eventuation of the anxiolytic effect resulting from chronic MAOI treatment.     

Deamination of norepinephrine, dopamine, and serotonin by type A monoamine oxidase in discrete regions of the rat brain and inhibition by RS-8359

Levels of monoamines and their metabolites were determined in the cortex, hippocampus, and striatum of rats killed by microwave irradiation. Moclobemide (20 mg/kg, p.o.) and clorgyline (10 mg/kg, p.o.), type A monoamine oxidase (MAO-A) inhibitors, increased the levels of normetanephrine (NM) and 3-methoxytyramine (3MT) and decreased those of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA) in almost all three regions. Deprenyl (10 mg/kg, p.o.), a type B monoamine oxidase inhibitor, however, little affected monoamine and metabolite levels in all regions. The maximum effects of RS-8359 (10 mg/kg, p.o.) were obtained at 2 to 6 hr after administration, when the levels of norepinephrine (NE), NM, 3MT, and serotonin (5HT) in all regions and dopamine (DA) in the striatum increased, while DOPAC and HVA levels decreased. The levels of monoamines and metabolites had returned to normal by 20 hr after administration. Dose-dependency of the effects of RS-8359 on monoamine metabolites was observed at doses up to 30 mg/kg (p.o.) at 1 and 6 hr after administration. In conclusion, NE, DA, and 5HT are exclusively or preferentially deaminated by MAO-A in the cortex, hippocampus, and striatum of rats, and RS-8359 exhibits a reversible MAO-A inhibitory action in all three regions tested in vivo.     

Central nervous system monoamine correlates of social dominance in cynomolgus monkeys (Macaca fascicularis).

Social dominance is a fundamental component of both human and nonhuman primate sociality. However, its neurobiological correlates remain incompletely understood. We evaluated the association between dominance status and monoamine metabolite concentrations in cisternal cerebrospinal fluid (CSF) in adult male (n = 25) and female (n = 21) cynomolgus macaques (Macaca fascicularis) housed in unisexual social groups. Concentrations of the metabolites of dopamine (homovanillic acid [HVA]), norepinephrine (3-methoxy-4-hydroxyphenylglycol [MHPG]) and serotonin (5-hydroxyindoleacetic acid [5-HIAA]) were assayed. Dominant monkeys, both males and females, had significantly higher CSF HVA concentrations than did subordinates (p values <.05). Among males, but not females, dominants also had lower CSF 5-HIAA than subordinates (p <.05). The Dominance-HVA association observed here is consistent with recent speculation that social extraversion, a dominance-related personality trait in humans, may also reflect heightened central nervous system dopaminergic activity.     

Effect of co-administration of subchronic lithium pretreatment and acute MAO inhibitors on extracellular monoamine levels and the expression of contextual conditioned fear in rats

We investigated the effects of clorgyline [a selective MAO (monoamine oxidase inhibitor)-A inhibitor] and lazabemide (a selective MAO-B inhibitor) on extracellular serotonin, dopamine and noradrenaline concentrations in the medial prefrontal cortex after 1-week treatment with subchronic 0.2% or 0.05% Li2CO3 (p.o.) and the effects on expression of contextual conditioned fear, previously reported to be reduced by facilitation of serotonin neurotransmission. As compared to normal diet controls, the subchronic 0.2% Li2CO3 group showed significantly higher levels of extracellular serotonin, but not noradrenaline. No changes were observed in the 0.05% Li2CO3 group. Acute clorgyline (10 mg/kg) treatments combined with subchronic 0.2% Li2CO3 treatments showed significant increases in extracellular serotonin concentrations, but not in dopamine or noradrenaline, as compared with clorgyline treatment alone. There was an additive effect with combined treatment of subchronic 0.2% Li2CO3 and acute clorgyline on the reduction of conditioned freezing, an index of conditioned fear, and this was not observed with subchronic 0.05% Li2CO3. These behavioral data indicate the functional significance of increased extracellular serotonin concentrations due to combined use of a MAO-A inhibitor with subchronic lithium. Effects of lazabemide (10 mg/kg) on extracellular monoamine concentrations and conditioned fear were slight or negligible, and were not affected by subchronic lithium treatment. The present study suggests that lithium augmentation of the antidepressant effect of MAO inhibitors is mediated by additional increases in the extracellular serotonin concentrations induced by MAO-A inhibition and suggests that the anxiolytic action of MAO inhibitors may be enhanced by lithium.     

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.     

Changes of serotonin and catecholamines are related to pharmacokinetic alterations of clomipramine in rat brain.

When rats received a single i.p. injection of clomipramine (20 mg/kg), clomipramine and desmethylclomipramine were rapidly distributed into the brain and their concentrations were markedly higher in the brain than in the serum, while the concentration of the metabolite in the brain was much lower than that of clomipramine. Chronic administration of clomipramine gradually increased the concentrations of the metabolite in both serum and brain, but did not significantly change those of clomipramine. The levels of serotonin (5-HT), norepinephrine (NE), dopamine (DA) and their metabolites in the brain were compared with the concentrations of clomipramine and desmethylclomipramine at different times. The levels of 5-HT, NE, DA, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the brain did not appear to be affected by changes in the concentrations of the drug and metabolite. The level of 5-hydroxyindole acetic acid (5-HIAA) was reduced following clomipramine injection and the reduced level was maintained during chronic treatment. Chronic treatment for more than 7 days increased the 3-methoxy-4-hydroxyphenylglycol (MHPG) level with no alteration of NE level. This elevation appeared to be induced by desmethylclomipramine.