Characterization of phenytoin, carbamazepine, vinpocetine and clorgyline simultaneous effects on sodium channels and catecholamine metabolism in rat striatal nerve endings.

The effects of two classic antiepileptic drugs (carbamazepine and phenytoin), a potential antiepileptic (vinpocetine) and a monoamine-oxidase inhibitor (clorgyline) on the simultaneous changes (detected by HPLC) on Glu, Asp, dopamine and DOPAC inside and outside striatal isolated nerve endings were investigated. Under resting conditions phenytoin, carbamazepine and clorgyline increased dopamine release. Phenytoin and clorgyline increased internal dopamine and decreased DOPAC formation. Carbamazepine decreased internal dopamine and practically did not change DOPAC formation. Glu and Asp release was unchanged. Neurotransmitter release induced by the Na+ channel opener veratridine was reduced by all the antiepileptic drugs tested, except phenytoin which, like clorgyline, facilitated veratridine-induced dopamine release. We conclude that besides the antagonism exerted by carbamazepine, phenytoin and vinpocetine on excitatory neurotransmitters release triggered by Na+ channel activation, that might importantly contribute to their anticonvulsant action, they exert different actions on striatal dopamine distribution, that might explain their different side effect profiles.

Selective and nonselective monoamine oxidase inhibitors: behavioral disturbances during their administration to depressed patients.

The occurrence of behavioral disturbances during four-week treatment of depressed patients with the nonselective monoamine oxidase (MAO) inhibitor, phenelzine sulfate (N = 14), the selective MAO-type A inhibitor, clorgyline (N = 12), and the partially selective MAO-type B inhibitor, pargyline hydrochloride (N = 13), was studied. Behavioral disturbances were encountered during treatment with each of the MAO-inhibiting drugs, with an overall incidence of 15% (six of 39 patients). All but one episode met criteria for mania or hypomania. Patients with bipolar illness experienced significantly greater incidences of behavioral disturbances in comparison with patients with unipolar illness (35.3% v 4.5%, respectively). The earliest latency to onset of a behavioral disturbances was 18 days, whereas the mean latencies were 22 to 26 days. Episodes of hypomania were observed after discontinuation of drug treatment in individual patients with unipolar and bipolar illness. Repeated MAO-inhibitor treatment, as part of a crossover study of clorgyline and pargyline, produced an increased severity of behavioral disturbances and a significantly shortened latency to onset.

Comparative behavioral effects of clorgyline and pargyline in man: a preliminary evaluation.

The antidepressant and other behavioral effects of clorgyline, a preferential inhibitor of monoamine oxidase (MAO) type A, were compared with those of pargyline, a preferential inhibitor of MAO type B, in 16 depressed patients. In a subgroup of more severely depressed patients, clorgyline treatment for 4 weeks resulted in significant improvement on both observer-rated and self-rated scales, while minimal changes occurred during pargyline treatment. Similarly, in a crossover study that included 8 patients examined with multiple scales, clorgyline had generally greater antidepressant and antianxiety effects than did pargyline, although pargyline had some activating effects and also tended to produce more side effects. MAO type A inhibition may be more important than MAO type B inhibition for antidepressant efficacy.

Risperidone counteracts lethality in an animal model of the serotonin syndrome.

RATIONALE: The serotonin (5-HT) syndrome is the most serious side effect of antidepressants, and pharmacologic treatment should be offered in severe cases. OBJECTIVE: In the present study, the effects of risperidone, ketanserin, and haloperidol on an animal model of the serotonin (5-HT) syndrome were evaluated. METHODS: Intraperitoneal administration of 100 mg/kg 5-hydroxy-L-tryptophan (5-HTP) (a precursor of 5-HT) and 2 mg/kg clorgyline (a monoamine oxidase type-A inhibiting antidepressant) induced the 5-HT syndrome in rats. The rectal temperature of the rats was measured, and the microdialysis method was used to measure noradrenaline (NA) levels in the anterior hypothalamus. RESULTS: In the group pre-treated with saline, the NA concentration increased to 13 times the pre-administration level, rectal temperature increased to more than 40 degrees C, and all of the animals died 75 min later. In the group pre-treated with risperidone (0.5 mg/kg), the 5-HT syndrome was completely inhibited, and the NA level increased to 6.5 times the pre-administration level. Ketanserin, a selective 5-HT2A antagonist (5 mg/kg) also inhibited the 5-HT syndrome. In contrast, all of the rats in the group pre-treated with haloperidol (0.5 mg/kg) died earlier than in the saline group. CONCLUSIONS: These results suggest that strong 5-HT2A antagonists such as risperidone, but not dopamine D2 antagonists, counteract lethality due to 5-HT syndrome, and that not only does enhancement of 5-HT activity occur in the 5-HT syndrome, but NA activity also increases.

Neuromuscular effects of monoamine oxidase inhibitors.

The MAOI class of drugs is known to produce neuromuscular effects at therapeutic and toxic doses when given alone or in combination with other drugs. These effects range from muscle tension and twitches in their mild form to forceful myoclonic jerks. These effects may also be part of a more pervasive toxic syndrome that includes autonomic and mental symptoms as well. There is meager direct and substantial indirect evidence that serotonergic mechanisms play a role in mediating the neuromuscular effects of MAOIs. We have hypothesized that MAOIs produce a condition of heightened neuromuscular excitability due to a combination of increased serotonergic tone and central disinhibition of alpha-motor neuron-mediated spinal activity. Further study is needed utilizing objective pharmacologic and neurophysiologic measures.

Cardiovascular baroreceptor activity and selective inhibition of monoamine oxidase.

Cardiovascular baroreceptor responsiveness of conscious rats treated with selective inhibitors of monoamine oxidase (MAO) types A and B was determined by measurement of blood pressure (BP) and heart rate (HR) responses to intravenous injection of phenylephrine and sodium nitroprusside. Treatment with selegiline (1 or 5 mg/kg p.o. daily for 7 days) did not significantly modify resting levels of BP and HR, lower or upper HR plateau levels, or HR/BP gain. Treatment with clorgyline (2 mg/kg p.o. daily for 7 days) increased HR/BP gain but also did not modify resting BP or HR, or lower and upper plateau levels of HR. The results are compatible with an effect of MAO-A inhibition to modify monoamine levels in medullary areas participating in CNS control of blood pressure.

Impact of 2 doses of clorgyline on the rat preimplantation embryo development and the monoamine levels in urine.

We have evaluated the impact of chronic administration of clorgyline, a potent monoamine oxidase A inhibitor and a former antidepressant, on the preimplantation embryo development in Wistar rats. Females were injected intraperitoneally daily for 30 days with saline (control animals), or with a low-dose clorgyline (LDC, 0.1 mg/kg per d) or with a high-dose clorgyline (HDC, 1 mg/kg per d). Embryos were isolated on day 5 of pregnancy and urine was collected by puncture of the urinary bladder. The number of embryos per female did not differ between experimental groups and control, but we have recorded a decreased number of embryos in HDC group compared to LDC (P < .05). We have found that LDC significantly reduced the presence of healthy embryos and increased the presence of the degenerated embryos (P < .001). The administration of the LDC resulted in the lowest cell number in blastocysts. We have observed significantly increased serotonin levels in HDC group compared to both control (P < .05) and LDC animals (P < .01). Norepinephrine (NE) levels in both experimental groups were significantly elevated compared to controls. Dopamine levels did not differ between groups (P > .05). We speculate that lesser negative effect of HDC compared to LDC on the preimplantation embryo development could be the consequence of the lower NE levels and/or elevated serotonin levels. Potential mechanisms mediating clorgyline-induced impaired preimplantation embryo development are proposed.