ROLE OF BRAIN AMINES IN THE FATAL HYPERPYREXIA CAUSED BY TRANYLCYPROMINE IN LiCl-PRETREATED RATS

Abstract

Tranylcypromine (TCP), a monoamine oxidase inhibitor, caused a fatal hyperpyrexia in rats pretreated with LiCl once a day for 4 days. Pretreatment with LiC1 alone did not alter the level of serotonin (5-HT). dopamine (DA) and norepin ephrine (NE) in the brain.In the fatal hyperpyrexia caused by LiCI plus TCP, the brain 5-HT and DA levels 'sere increased, whereas the brain NE level was decreased.Reserpine and a-methyl-p-tyrosine completely prevented the hyperpyrexia, but FLA-63 did not show any effect.The hyperpyrexia was completely prevented by p-chloro phenylalanine (PCPA) given 72 hours before TCP but not by PCPA given 24 hours before TCP.Haloperidol and chlorpromazine, DA receptor blockers, inhibited the fatal hyperpyrexia, while cyproheptadine and inethysergide, 5-HT receptor blockers, did not. These results suggest that DA plays an essential role in the hyperpyrexia induced by the combination of TCP and LiCI in rats, but the involvement of 5-HT is inconclusive.The use of lithium salts for the treatment of manic disorders and prophylaxis of affective disorders is well established.However, the mechanism of action of lithium salts has not been clarified. There are a number of reports concerning the effect of lithium on the be haviour of laboratory animals. Lithium decreased the spontaneous locomotor activity (1, 2, 3) and the drug-induced hyperactivity in animals (4,5,6,7). On the contrary, lithium, when combined with a monoamine oxidase inhibitor (MAOI), caused hyperactivity in rats (8,9,10), and this hyperactivity syndrome was assumed to be due to an effect of lithium on brain serotonergic and dopaminergic mechanisms.In studies on the pharmacological properties of lithium, we found that the adminis tration of tranylcypromine (TCP), a monoamine oxidase inhibitor, to rats pretreated with LiCI produced a marked and fatal hyperpyrexia in a large proportion of animals. Therefore, we attempted to clarify the possible relationship between the LiCI-'I CP induced hyperpyrexia and brain amines in rats. MATERIALS AND METHODSMale Sprague-Dawley rats, weighing 220-280 g, were used throughout the experiments. Statistical analysis: Calculations of p values according to Student's t-test or CochranCox test were performed using a computer program. RESULTSEffects of LiCI and TCP on the rectal temperature of normal rats Saline or 0.5 % MC given i.p. to rats produced no significant change in the rectal temper ature measured 0.5, 1, 2, 4, 6 and 24 hr after the injection. Injection of LiCI 125 (2.9 mEq/ kg) or 250 (5.9 mEq/kg) mg/kg, however, produced a rapid decrease in the rectal temper ature, the effect being dose dependent in both potency and duration. When LiCI 125 mg/kg was given, the rectal temperature decreased by about 2'C at 0.5 hr and then recovered in 4 hr. When LiCI 250 mg/kg was given, the maximum decrease in the rectal temperature was of 3 °C at 2 hr after dosing and recovery was attained in 6 hr ( Fig. 1 A). On the other hand, TCP 8 or 16 mg/kg given i.p. produced a slow decrease in the rectal temperature ...

The role of caudate nucleus dopamine and cyclic amp in the hyperpyrexia induced by licl plus tranylcypromine in rats

“…Serotonin receptor blockers, cyproheptadine and methysergide, did not prevent the hyper pyrexia as shown in our previous study (1). These results indicate that the hyperpyrexia induced by LiCI plus TCP depends specifically on the central DA mechanism.…”

“…In a previous study (1), we demonstrated that tranylcypromine (TCP) produced a fatal hyperpyrexia in rats pretreated with repeated doses of LiCI. In the hyperpyrexia produced by LiCI plus TCP, the brain dopamine (DA) was postulated to play an essential role, because the occurrence of the hyperpyrexia was dependent upon the presence of the brain DA and was suppressed almost completely by DA receptor blocking drugs.…”

Characteristic hyperpyrexia induced by LiCl and tranylcypromine in rats.

“…In one series of experiments, rats were given a drug or an alkali metal once daily for 4 days. Control animals were given LiCI at a dose of 250 mg/kg which was used in our previous experiments (1,2). The alkali metals other than LiCI were given in two doses which were equivalent to that of LiCI either on the weight or molar basis.…”

“…Our previous studies have shown that the dopamine (DA) in the caudate nucleus plays an important role in hyperpyrexia (1,2), as the occurrence of the hyperpyrexia was dependent on an increase in the brain DA and was suppressed by DA blockers. TCP increased the DA in the caudate nucleus, while pargyline was without effect (4).…”