Electrophysiological effects of monoamine oxidase inhibition on rat midbrain dopaminergic neurones: an in vitro study.

1 The effects of the inhibition of monoamine oxidase (MAO) type A and B have been evaluated on the spontaneous firing activity of the dopaminergic (principal) neurones of the rat midbrain intracellularly recorded from a slice preparation. 2 The non-specific MAO inhibitor, pargyline, superfused at a concentration of 10-100 microM, decreased or abolished the spontaneous firing discharge of the principal neurons in the subtantia nigra pars compacta and ventral tegmental area. This effect had a slow onset and appeared to be sustained. 3 The administration of the dopamine D2/3 receptor antagonist, sulpiride (100-300 nM), antagonized the pargyline-induced effect, while the superfusion of the dopamine D1 receptor antagonist, SCH 23390 (1-3 microM) did not counteract the induced inhibition of the firing rate. 4 The inhibitor for the MAO A, clorgyline (30-100 microM), reduced the firing rate of the dopaminergic neurones. A similar depressant effect was also observed when a MAO B inhibitor, deprenyl (30-100 microM), was applied. Lower concentrations of both drugs (300 nM-10 microM) did not produce consistent effects on neuronal discharge. 5 Our data suggest that only the blockade of both types of MAO enzymes favours the inhibitory action of endogenous dopamine on somato-dendritic D2/3 autoreceptors.

Inhibition of types A and B monoamine oxidase by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was studied as an inhibitor of type A monoamine oxidase (MAO) acting on [14C]serotonin as substrate and of type B MAO acting on [14C]phenylethylamine as substrate. MPTP was a reasonably potent (Ki = 9 microM), competitive, reversible inhibitor of MAO-A from rat brain in vitro. MPTP given at a 30-mg/kg i.p. dose antagonized the irreversible inactivation of MAO-A in rat brain by pargyline, indicating that it inhibited MAO-A in vivo. At that same dose, MPTP prevented the conversion of dopamine released by Ro 4-1284 to 3,4-dihydroxyphenylacetic acid and attenuated its conversion to homovanillic acid. Because dopamine is mainly deaminated by MAO-A, at least in rodent brain, inhibition of MAO-A by MPTP might play some part in its production of persistent effects on striatal dopamine neurons such as protection of intraneuronal, extragranular dopamine from deamination. MPTP was less potent as an inhibitor of MAO-B from rat brain in vitro (Ki = 106 microM). In contrast to the inhibition of MAO-A, the inhibition of MAO-B by MPTP showed noncompetitive kinetics, was not fully reversible by dialysis and was time dependent. The characteristics of MAO-B inhibition are like those of a kcat inhibitor, which is acted upon by an enzyme to produce a reactive product that can covalently attach to the enzyme or other macromolecules.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of tricyclic antidepressants on tetrabenazine-induced depletion of brain monoamines in rats. 1. Norepinephrine.

We studied the effects of tricyclic antidepressants on the tetrabenazine (TB)-induced depletion of brain norepinephrine (NE) using rats. The test drugs were generally administered orally 3 hr before and 2 mg/kg of TB or reserpine (RES) administered subcutaneously 2 hr before sacrifice. The TB-induced NE depletion was enhanced by pretreatment with desmethylimipramine (DMI, 25--100 mg/kg), imipramine (IM, 25--100 mg/kg), chlorimipramine (100 mg/kg), maprotyrine (50 mg/kg), amitriptyrine (50--100 mg/kg), chlorpromazine (CPZ, 5--20 mg/kg i.p.,) and amphetamine sulfate (10 mg/kg). DMI partially suppressed TB-induced NE depletion at 0.5 hr after TB administration. The RES-induced NE depletion was not enhanced with these drugs except for amphetamine. DMI, IM, and CPZ suppressed it instead. DMI also enhanced the yohimbine (2 mg/kg)-induced decrease. The brain NE content showed a tendency toward recovery 2 hr after TB administration, but approached the minimal level at 0.5 hr after TB administration or at 2 hr after RES administration in non-treated rats. In pargyline-pretreated rats, TB produced a decrease of brain NE with an increase of normetanephrine, while the action of RES was weaker than that of TB, up to 2 hr. These results suggest that enhancement of the TB-induced brain NE depletion by tricyclic antidepressants reflects the blockage of NE reuptake from the synaptic cleft.

Inability of imipramine to protect against type A or type B monoamine oxidase inhibition by pargyline.

Imipramine (30 mg/kg i.p.) did not antagonize the inhibition of either type A or type B MAO by pargyline in brain, heart or liver of rats. Occupancy of active sites on mitochondrial MAO by imipramine probably does not occur at doses of imipramine adequate to inhibit monoamine uptake.

Role of liver cytosolic aldehyde dehydrogenase isozymes in control of blood acetaldehyde concentrations.

The role of various cytosolic aldehyde dehydrogenase (ALDH) isozymes in acetaldehyde metabolism was determined. Rats of known genotype (RR, reactor; rr, nonreactor) with respect to induction of a cytosolic enzyme by phenobarbital were used. Animals were treated with either phenobarbital (1.0 mg/ml in drinking water for 3 days) or 75 microng/kg (i.p.) of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prior to ethanol treatment (2.5 g/kg). TCDD treatment is known to induce a second cytosolic ALDH isozyme in both RR and rr animals. Phenobarbital increased cytosolic ALDH activity 23-fold only in the RR animals, while TCDD increased activity 155-fold in both groups. Phenobarbital-treated RR rats maintained significantly lower blood acetaldehyde levels at 30, 90 and 150 minutes after ethanol injection compared to control RR animals. Blood acetaldehyde levels in phenobarbital-treated rr rats were not significantly different from rr controls. Administration of TCDD to RR or rr rats did not significantly alter blood acetaldehyde levels at 30, 90 or 150 minutes after ethanol treatment compared to appropriate controls. Similarly, phenobarbital significantly increased blood ethanol elimination rate (1.5 times greater than control) only in RR rats. Ethanol elimination rate was not significantly altered by TCDD in either group. Pargyline (100 mg/kg i.p.) did not significantly inhibit cytosolic ALDH activity, while total mitochondrial ALDH activity was inhibited by 28 and 57% in RR animals receiving TCDD and phenobarbital, respectively. Pargyline significantly increased blood acetaldehyde levels after ethanol administration. However, pretreatment with phenobarbital or TCDD significantly decreased elevated blood acetaldehyde levels resulting from pargyline treatment, with the greatest reduction in the phenobarbital-treated RR animals.

The use of antiserotonin-cyproheptadine HCL in pregnancy: an experimental and clinical study.

PIP: Habitual abortion of psychogenic origin may be associated with increased serotonin production. Serotonin is metabolized by monoamin oxidase (MAO) to hydroxyindole acetic acid (5-HIAA) which is excreted in the urine. When this metabolic system is inadequate excess serotonin may cause contractions of the estrogen-sensitized myometrium and, thus, abortion. In normal pregnancy and in nonpregnant women urinary 5-HIAA is 5.6 mg/day. Women suffering from habitual abortion os psychogenic origin showed 5-HIAA excretion of 10.6 mg/day during pregnancy with high amounts of nonmetabolized serotonin. In rats injection of pargyline HC1, a MAO inhibitor, produced abortion in 84%; a serotonin antagonist, cyproheptadine HC1, injected sc 4-8 hours prior to MAO inhibitor treatment preserved 42% of fetuses. No toxicity was shown in 92.8% of rat fetuses in a teratogenic study. Later 29 women with a total of 31 pregnancies were given 4 to 16 mg/day cyproheptadine HC1 for several months starting early in pregnancy. Previous study had revealed no other causes to explain their spontaneous abortions and treatments with progesterone, antibiotics, and vitamins in earlier pregnancies had been unsuccessful. After cyproheptadine HC1 treatment there were 3 spontaneous abortions, 23 normal infants delivered at term, and 5 premature deliveries of which 1 was a stillbirth. No teratogenic effects were observed. Reports by others in similar cases and results in a control group of 19 women in this study all give much higher rates of spontaneous abortion. Side effects were few and yielded to reduced dosage. It is recommended that patients suffering habitual abortion be examined for serotonin and 5-HIAA excretion. When indicated, treatment with antiserotonin drugs should be given. Observations indicate serotonin production or metabolism may be the decisive factor relating emotional stress to abortion.^ieng