The neuropharmacologic profile of intraperitoneally injected
harmala alkaloids and related
beta-carbolines was evaluated in the rat. All drugs induced central effects (convulsions,
catalepsy, or altered startle), but only
harmaline and
harmine were tremorogenic at low doses. Methoxylation of the
carboline 7 position was requisite for this effect. Coadministration of
harmaline (but not
harmine) and
5-hydroxytryptophan (
tryptamine or m-chlorophenyl-
piperazine) induced a lethal convulsive myoclonic syndrome which could not be evoked by either
drug separately. Compared with the myoclonic-serotonergic syndrome evoked by
5-hydroxytryptophan in rats with 5.7-dihydroxytryptamine lesions, harmaline+5-
hydroxytryptophan-treated rats displayed more continuous and greater axial
myoclonic jerks and some postural differences.
Clorgyline or
tranylcypromine but not
pargyline could be substituted for
harmaline. The
harmaline syndrome was blocked by the
benzodiazepine agonists,
physostigmine and
verapamil. The harmaline+5-
hydroxytryptophan syndrome was blocked by drugs acting at
benzodiazepine receptors (
CL 218,872 greater than ethyl-
beta-carboline-3-carboxylate,
clonazepam,
diazepam,
Ro 15-1788,
pentobarbital), and
baclofen.
Naloxone,
benztropine,
quipazine, and
apomorphine had partial effects, and
calcium channel blockers prevented death but did not prevent convulsions.
5-Hydroxytryptamine antagonists were poor blockers, although
cyproheptadine and
ketanserin significantly reduced mortality.
Phenobarbital was more effective than other
anticonvulsants. Lesion studies suggested a role for monoaminergic neurons and the inferior olive in the expression of the harmaline+5-
hydroxytryptophan syndrome. These data describe a complex convulsive myoclonic syndrome that is behaviorally related to but pharmacologically distinct from the
serotonin syndrome, which may be useful in studying serotonergic-
benzodiazepine interactions in the pathophysiology of
myoclonus.