harman and Seizures

The study investigated the activity of harmane on maximal electroshock seizures (MES) and seizures induced by pentilentetrazole (PTZ) in mice. Initial studies established convulsive current 50 (CC(50)) values or MES and effective dose 50 (ED(50)) for PTZ to produce seizures. Harmane (2.5, 5.0, or 10 mg/kg intraperitoneally) increased the threshold of seizures in MES dose-dependently. The convulsions produced by PTZ were decreased by the low dose of harmane (2.5 mg/kg), but the high dose of harmane (10 mg/kg) resulted in worse grade V convulsions followed by more lethality compared with PTZ alone. Therefore, harmane seems to be protective against grand mal seizures in the MES model but not against a petit mal seizure model (PTZ) in mice.

Topics: Animals; Convulsants; Disease Models, Animal; Electroshock; Epilepsy; Female; Harmine; Male; Mice; Pentylenetetrazole; Seizures

Tofizopam, an anxiolytic 3,4-benzodiazepine, increases the affinity of benzodiazepine receptors for 1,4-benzodiazepines. In this study we investigated whether this increased affinity of the receptors alters the sensitivity of mice to tremor and to convulsions. Convulsions induced by harmane were not affected by tofizopam (50-300 mg/kg), but diazepam (15 mg/kg) increased the ED50 of harmane from 9.9 to 25.1 mg/kg. Tofizopam did not alter the threshold for electroshock-induced convulsions, while a dose of 10 mg/kg diazepam protected mice from convulsions. Low doses of tofizopam (12.5-25 mg/kg) sensitized mice to the tremorogenic effect of harmaline. Diazepam inhibited tremor: the ED50 of harmaline increased by 153% after 50 mg/kg of diazepam. In contrast to 1,4-benzodiazepines, tofizopam has no anticonvulsive effect. It sensitises mice to the tremor induced by harmaline. In combination with diazepam, however, tofizopam enhanced the anticonvulsive and antitremorogenic actions of this 1,4-benzodiazepine by 12-65%. This effect probably results from a tofizopam-induced increase in the occupation of benzodiazepine receptors.

Topics: Animals; Anti-Anxiety Agents; Benzodiazepines; Diazepam; Drug Interactions; Electroshock; Harmine; Male; Mice; Seizures; Tremor

Cholecystokinin octapeptide (CCK-8), caerulein and diazepam inhibited exploratory rearing activity and harman-induced convulsions in mice. Pretreatment with the selective benzodiazepine receptor antagonist Ro 15-1788, reduced or abolished the sedative and anticonvulsive effects of diazepam, but left the same effects of both peptides unaffected. The peptide-induced ptosis was even increased by Ro 15-1788. The results suggest that the CCK-like peptides do not directly interact with the benzodiazepine receptor.

Topics: Animals; Anticonvulsants; Benzodiazepinones; Blepharoptosis; Body Temperature; Ceruletide; Cholecystokinin; Diazepam; Flumazenil; Harmine; Hypnotics and Sedatives; Male; Mice; Peptide Fragments; Seizures; Sincalide

Compounds from both the beta-carboline (BC) and xanthine groups have been suggested to be the natural ligands for benzodiazepine (BZ) receptors. In this study we examined the effects of several BC's and caffeine, 1,3,7-trimethylxanthine, on the binding of 3H-flunitrazepam (3H-FZ) and beta-3H-carboline-3-carboxylic acid ethyl ester (3H-BCCE) to the BZ receptors of rat and mouse brain. In mice, convulsion-producing doses of caffeine (120 mg/kg intravenously) and harmane (30 mg/kg intravenously) lowered the specific binding of 3H-FZ in vivo by 12-31%. A tremorogenic dose of harmaline (30 mg/kg intravenously) increased binding by 31%. Caffeine and harmane also slightly decreased the in vivo binding of 3H-BCCE, a compound that binds preferentially to the cerebellar type of BZ receptors. Harmaline stimulated the binding of 3H-BCCE only in the forebrain. Both harmaline and harmane increased by 41-111% the amount of 3H-BCCE that was distributed to the brain. In vitro BC's and caffeine displaced 3H-FZ from receptors in the rat brain with various Ki values (4.7 to 206.9 microM). The antagonism for BZ binding was competitive and in Scatchard analysis produced linear plots. Exceptions were harmaline and caffeine in the forebrain: both exhibited curvilinear plots for 3H-FZ binding. Harmaline increased the binding, and caffeine decreased it by altering the affinity of a subgroup of BZ receptors. In the hindbrain both harmaline and caffeine inhibited binding and produced linear plots. BC-induced tremor and convulsions unveil a large number of spare receptors in the brain, and these seem to be of the cerebellar type of BZ receptors. In addition, our results show that tremorogenic and convulsive BC's act differently on BZ receptors: during harmaline-induced tremor the affinity of some BZ receptors is increased, while harmane-induced convulsions are connected to direct occupation of BZ receptors.

Topics: Animals; Brain; Caffeine; Carbolines; Flunitrazepam; Harmaline; Harmine; Indoles; Male; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, GABA-A; Seizures; Tremor

Harmane and other related beta-carbolines are putative endogenous ligands of the benzodiazepine receptor. Since the compounds are potent convulsants they may have agonist activities at the benzodiazepine receptor while the benzodiazepines may be antagonists. This hypothesis was proved by comparing the in vivo and in vitro antagonism of benzodiazepines by harmane and other beta-carbolines. Harmane is clearly a competitive inhibitor of benzodiazepine receptor binding in vitro. Moreover, harmane-induced convulsions can be inhibited reversibly by diazepam in a manner which is consistent with the assumption of competitive antagonism in vivo. For some beta-carboline derivatives a correlation was found between the affinity for the benzodiazepine receptor in vitro and the convulsive potency in vivo. Thus, the data reported suggest that harmane or other related beta-carbolines are putative endogenous agonists of the benzodiazepine receptor. This suggestion is further supported by the observation that diazepam is equally potent in inhibiting harmane- or picrotoxin-induced convulsions, indicating a convulsive mechanism within the GABA receptor-benzodiazepine receptor system.

Topics: Alkaloids; Animals; Anti-Anxiety Agents; Benzodiazepines; Brain; Carbolines; Female; gamma-Aminobutyric Acid; Glycine; Harmine; In Vitro Techniques; Indoles; Rats; Receptors, Cell Surface; Receptors, Drug; Seizures; Spinal Cord; Strychnine

Caerulein, cholecystokinin octapeptide (CCK-8) and diazepam delayed the onset of seizures produced by harman and thiosemicarbazide (TSC). Caerulein had the potency of diazepam, whereas CCK-8 was less active by a factor of four. The convulsions induced by isoniazid (INH) were very resistant to both caerulein and diazepam; CCK-8 was not tested against isoniazid. Haloperidol did not influence the effect of TSC; it enhanced isoniazid-induced seizures, and antagonized the convulsant effect of harman.

Topics: Animals; Anticonvulsants; Ceruletide; Cholecystokinin; Diazepam; Haloperidol; Harmine; Isoniazid; Male; Mice; Mice, Inbred Strains; Seizures; Semicarbazides; Sincalide