The Role of Brain 5‐hydroxytryptamine in the Hyperactivity Produced in Rats by Lithium and Monoamine Oxidase Inhibition

Abstract

Administration to rats of LiCl (3 mEq/kg) subcutaneously twice daily for 3 days followed by monoamine oxidase inhibition with either tranylcypromine (TCP; 20 mg/kg) or pargyline (75 mg/kg) on the fourth day produces a syndrome of hyperactivity indistinguishable from that produced by monoamine oxidase inhibition and l‐tryptophan administration. At least 3 injections of LiCl (3 mEq/kg) are necessary before hyperactivity is seen but one dose of LiCl (10 mEq/kg) 5 h before TCP also caused hyperactivity. The hyperactivity is blocked by prior administration of p‐chlorophenylalanine, a tryptophan hydroxylase inhibitor. LiCl pretreatment does not alter the concentration of l‐tryptophan in the brain. However after monoamine oxidase inhibition the 5‐hydroxytryptamine (5‐HT) accumulation was significantly greater in animals given lithium indicating an increase in 5‐HT synthesis of 70%. This was confirmed by measuring 5‐hydroxyindoleacetic acid accumulation after probenecid (200 mg/kg). The hyperactivity produced by the 5‐HT analogue, 5‐methoxy N,N‐dimethyltryptamine was not potentiated by lithium pretreatment but one injection of LiCl (3 mEq/kg) which did not alter the rate of 5‐HT synthesis, did potentiate the hyperactivity following TCP (20 mg/kg) and l‐tryptophan (50 mg/kg). These results suggest that lithium administration may cause an initial alteration of the 5‐HT available for release at the nerve ending, which is followed after subsequent treatment by an increase in the rate of 5‐HT synthesis. The possible clinical significance of these findings is discussed.

Increased Tonic Activation of Rat Forebrain 5-HT1A Receptors by Lithium Addition to Antidepressant Treatments

“…Central 5-HT function has also been shown to be affected by lithium administration, although its effect on the 5-HT system differs according to the duration of treatment and the brain region studied (Goodwin 1989;Price et al 1990b). Accordingly, it has been shown that acute, but not chronic, lithium administration increases rat brain 5-HT turnover (Grahame-Smith and Green 1974;Minegishi et al 1981;Karoum et al 1986). Acute treatment with lithium potentiates the tranylcypromine-plus l-tryptophaninduced 5-HT syndrome in the rat, a syndrome sensitive to stimulation of 5-HT synthesis (Grahame-Smith and Green 1974).…”

“…Interestingly, lithium is also a useful augmentation strategy in the treatment of depression (de Montigny et al 1981;Rouillon and Gorwood 1998). Although the underlying neurobiological mechanism remains as yet not fully defined, there is a considerable body of preclinical evidence reporting an increase in 5-HT neurotransmission following lithium administration (Baptista et al 1990;Grahame-Smith and Green 1974;Treiser et al 1981;Blier and de Montigny 1985;Goodwin et al 1986;Goodwin 1989;Price et al 1990b;Sangdee and Franz 1980;Sharp et al 1991).…”

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

“…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.…”

“…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.…”

How Much Serotonin in the CNS is Too Much?

“…However, it should be kept in mind that the measures likely mirror intensity of serotonergic innervations (Schaefer et al, 2008), but not functional activity of neurotransmission. Nevertheless, the range of 5HT content in the homogenized brain is 1 to 2 nmol/g (Baumann et al, 2008a;Bhide et al, 2009;Grahame-Smith et al, 1974;Malberg et al, 1998). Moreover, raphe nuclei have relatively higher contents than other regions (Adell et al, 1991b).…”