Tomoko Urano

Effects of central monoamine compounds on tranylcypromine-induced barbital-withdrawal convulsions

Challenge with tranylcypromine (Tcp) during barbital (B) withdrawal induces dose-related clonic-tonic convulsion (C-TC), which is also related to the severity of withdrawal signs and their changes with the passage of time. The effects of neuropharmacological agents on the Tcp-induced convulsions were observed. dl-Propranolol, phentolamine, phenoxybenzamine and methysergide had been administered intraperitoneally 20 approximately 30 minutes before Tcp challenge. B-withdrawn rats had been pretreated with alpha-methyl-p-tyrosine, 5-hydroxytryptophan, p-chlorophenylalanine or reserpine, or with the combination of iproniazid and reserpine (5 hrs after iproniazid administration) before Tcp challenge. alpha-MT and dl-propranolol inhibited B withdrawal convulsion markedly, though high doses of dl-propranolol rather tended to show a less effect on the convulsion. alpha-Adrenoceptor blockers scarcely inhibited the convulsion. Methysergide or 5-HTP failed to inhibit, but PCPA intensified the convulsion. Reserpine, when administered alone, aggravated the convulsion, but when administered after iproniazid, inhibited it significantly. These findings suggested that the balance between the activities of noradrenergic and serotonergic neurons might be of importance in the manifestation of B withdrawal convulsions, the former probably being excitatory and the latter, inhibitory.

Specific action of tranylcypromine to precipitate barbital withdrawal convulsions

This research was designed to determine whether the convulsion-eliciting action of tranylcypromine (TCP) during barbital (B) withdrawal was specific to physical dependence on B, and to compare the findings with the action of pentetrazol (PTZ). Challenge with 15–20 mg/kg IP TCP at 48 h of B withdrawal resulted in the elicitation of clonictonic convulsion (CTC) in all rats (N=6) within 10 min. Another challenge with 5–20 mg/kg TCP led to the doserelated precipitation and intensification of CTC. The CTC-inducing action of TCP was relatively reduced as the B withdrawal signs were gradually mitigated. In other words, when challenge with the drug was made at 72h of B withdrawal, the time of CTC onset was prolonged, and the incidence was reduced to 50% in parallel with abolition of the other withdrawal signs. A challenge at 120 h of B withdrawal when the vital signs had almost recovered to prewithdrawal level failed to induce even the prodromal signs of convulsion. In all rats exhibiting only mild to moderate withdrawal signs (such as hyperirritability, hyper-reflexia, anorexia, weight loss), 40 mg/kg TCP was required to induce CTC during B withdrawal, which was twice the dose required in severely dependent rats. Other monoamine oxidase inhibitors, i.e., pargyline, iproniazid, and clorgyline, elicited no CTC during B withdrawal. Methamphetamine was without effect on B withdrawal convulsions. From these findings, the convulsive threshold for TCP during B withdrawal proved well correlated to the grade of B-dependence and the duration of B-withdrawal signs.