Biphasic Effects of Imipramine in Experimental Models of Epilepsy

Abstract

In a variety of laboratory models of experimental epilepsy, imipramine exerts a biphasic action on the CNS as manifested by antiepileptic properties at low doses and convulsant effects at higher doses. In mice, imipramine (17.5-25 mg/kg, i.p.) blocks maximal electroshock seizures while exerting little or no effect on pentylenetetrazol-induced seizures. In cats, imipramine (2.5-15 mg/kg, i.v.) reduces penicillin and estrogen-induced epileptiform discharge, shortens afterdischarge duration and elevates afterdischarge threshold. Higher doses in mice induce neurotoxicity, including clonic seizures. In cats, doses above 20 mg/kg intensify chemically and electrically induced seizures and induce spontaneous epileptiform episodes. Such a biphasic action of imipramine may limit the drug's clinical utility as an antiepileptic agent and may provide an interesting tool for studies of catecholamines and brain excitability.

Antiepileptic Effects of Thyrotropin‐Releasing Hormone and Its New Derivative, DN‐1417, Examined in Feline Amygdaloid Kindling Preparation

“…The anticonvulsive profile of the agents obtained in this study, e.g., transient effectiveness with considerable interindividual variation, is quite different from those of phenytoin, phenobarbital, car-CONTROL bamazepine, ethosuximide, clorazepate (Wada et al, 1976a,b;Wada, 1980), as well as sodium valproate (Sato et al, 1977;Wada, 1980), all of which have been studied using the kindling model of epilepsy. The observed transient and non-dose-dependent anticonvulsive effect of these agents is shared by nomifensine (Sato et al, 1978), imipramine (Lange et al, 1976), and amphetamine (Riffee and Gerald, 1976). Since these three drugs are known to facilitate neurotransmission through interference with reuptake and/or the accentuated release of brain catecholamines, and since both TRH-t and DN-14 17 accelerate the release of catecholamines, the observed anticonvulsive effects in this study are likely mediated through catecholaminergic mechanisms.…”

Pharmacokinetic/pharmacodynamic considerations for epilepsy – depression comorbidities

“…Biphasic action of imipramine was observed in mice and cats. Imipramine at lower doses exhibited a protective action in penicillin and estrogen-induced seizures in cats [62], cocaine-induced seizures in mice [63] and MES, but it did not inhibit pentylenetetrazole (PTZ)-induced convulsions in mice [62]. This antidepressant at higher doses aggravated cocaine-induced seizures in mice [63], chemically-and electrically-induced seizures in cats [62], while at doses of above 20-25 mg/kg i.p.…”

Clinical Features, Pathogenesis and Management of Drug-Induced Seizures

“…Low dosages of imipramine or amitriptyline were found to raise the maximal electroshock and pentetrazol seizure thresholds in mice (Sigg 1959;Vernier 1961). Further studies in different experimental models of epilepsy showed that imipramine has a biphasic effect since at low dosages the drug blocks the maximal electroshock seizures in mice, but induces clonic seizures at high dosages (Lange et al 1976). Trimble and colleagues (1977) found that the intravenous administration of clomipramine or imipramine lowers the convulsive threshold in the photosensitive baboon Papio papio.…”