Effects of chronic lithium treatment on serotonin binding sites in rat brain

The effects of lithium treatment on serotonin (5-HT) binding sites in the rat brain were investigated. Oral administration of lithium carbonate for 3 weeks did not influence 5-HT2 binding sites in the cerebral cortex. On the other hand, the number of 5-HT1 binding sites labeled with [3H]5-HT was decreased significantly in the hippocampus, but not in the cerebral cortex. While non-5-HT1A sites, defined as specific [3H]5-HT binding in the presence of 100 nM 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), were not affected by lithium treatment in either brain region, chronic lithium administration reduced significantly the density of 5-HT1A sites labeled with [3H]8-OH-DPAT only in the hippocampus, but not in the cerebral cortex. These results suggest that 5-HT1A components are responsible for lithium-induced down-regulation of 5-HT1 binding sites in the hippocampus and that 5-HT1A sites in the hippocampus might be connected with the therapeutic efficacy of lithium.     

Long-term lithium treatment selectively reduces receptor-coupled inositol phospholipid hydrolysis in rat brain

Rats were treated with dietary lithium for 30 days, followed by assessment of the activity of the receptor-coupled inositol phospholipid second messenger-producing system in three brain regions. The major effect of long-term lithium treatment was a significant reduction of the response to norepinephrine in all three brain regions that were examined: the cerebral cortex, the hippocampus, and the striatum. After long-term lithium treatment, the response to serotonin was reduced in the hippocampus and striatum, but not the cortex, and the carbachol-induced response was only reduced in the striatum. Lithium treatment did not alter the incorporation of [3H]inositol into phospholipids, the in vitro lithium concentration-dependent accumulation of [3H]inositol monophosphate, or the stimulation by NaF of inositol phospholipid hydrolysis. These results indicate that the decreased responses to agonists after long-term lithium treatment are not likely to be due to depletion of inositol phospholipids or to altered activity of myo-inositol-1-phosphatase, phospholipase C, or the guanine nucleotide-binding protein. It is suggested that long-term lithium treatment may alter receptor number or receptor coupling, perhaps by phosphorylation, thereby selectively lowering the agonist-induced generation of second messengers by the inositol phospholipid system.     

Inhibitory effect of lithium on neuroleptic and serotonin receptors in rat brain

We investigated the effect of acute and chronic administration of lithium on neuroleptic receptors ([³H]spiroperidol binding sites) and serotonin receptors ([³H]serotonin binding sites) in rat brain. In the limbic-forebrain, both acute and chronic lithium treatment significantly reduced the density (B_max) of neuroleptic receptors, without affecting the affinity (K_d) of those receptors. However, lithium treatment had no apparent effect on neuroleptic receptors in the caudate-putamen and frontal cortex in either acute or chronic administrations. On the other hand, acute lithium administration markedly decreased the K_d and B_max of serotonin receptors in the hippocampus, but not in the cerebral cortez; this distinct observation was also found in animals chronically treated with lithium.These results indicate that lithium has an inhibitory effect on neuroleptic receptors in the limbic-forebrain and on serotonin receptors in the hippocampus. Therefore, it is possible to postulate that these effects of lithium in specific brain regions may be related to the therapeutic mechanism of this drug in affective disorders.     

Long-term lithium carbonate therapy causes hyperparathyroidism

Twelve patients taking lithium carbonate for two to 13 years were compared with age- and sex-matched controls to determine whether long-term lithium carbonate therapy is associated with alterations in calcium metabolism. As a group and individually, patients had significantly higher levels of serum total calcium, ionized calcium, and parathyroid hormone. When compared with serum calcium levels, patients' parathyroid hormone levels were significantly more likely than those of controls to indicate hyperparathyroidism. Lithium carbonate-induced mild hyperparathyroidism appears to be more common than had previously been suspected.     

Orally administered MDMA causes a long-term depletion of serotonin in rat brain

Recent studies suggest that 3,4-methylenedioxymethylamphetamine (MDMA), when administered subcutaneously, is toxic to central serotonergic neurons in rats. Because humans typically self-administer this drug orally, we compared this route to the s.c. route of administration. Orally administered MDMA produced a dose-related depletion of serotonin comparable to that produced by the s.c. route. These findings suggest that MDMA, when given orally, retains it neurotoxic activity and that humans using MDMA may be at risk for developing a persistent depletion of brain serotonin.     

Effects of muscarinic receptor agonists and antagonists on rat brain serotonergic activity

Summary The effects of some muscarinic M₁ and M₂ receptor agonists and antagonists on rat brain serotonergic activity was assessed by noting their effects on the levels of 5-hydroxytryptamine (5-HT) and its major metabolite, 5-hydroxyindole acetic acid (5-HIAA), estimated by a high pressure-liquid Chromatographie (HPLC) technique. The muscarinic M₁ receptor agonists, arecholine and McN-A-343, and the M₂ receptor agonists, gallamine and AF-DX 116, induced a dose-related decrease in the concentrations of both 5-HT and 5-HIAA. On the contrary, scopolamine and the selective M₁ receptor antagonist, pirenzepine, increased the levels of the amine and its metabolite. The anticholinesterase agent, physostigmine, and the putative M₂ receptor agonist, carbachol, induced a dose-related dual effect, with the smaller doses decreasing and the higher doses increasing 5-HT and 5-HIAA concentrations. The results indicate that an inverse relationship exists between the cholinergic and serotonergic neurotransmitter systems in the rat brain due to the likely presence of muscarinic heteroreceptors on serotonergic neurones. The data also indicates that though physostigmine and carbachol may function as M₂ receptor agonists, they lose their receptor specificity on dose increment.     

Long-term haloperidol treatment decreases somatostatin binding in rat brain

The effects of short and long-term haloperidol treatment on somatostatin concentration and specific binding in rat cerebral cortex and hippocampus were examined using the binding ligand 125I-Tyr1-somatostatin. Haloperidol treatment did not affect the concentration of somatostatin-like immunoreactivity in the two brain areas. Nevertheless, long-term, and not short-term, haloperidol treatment decreased the number of somatostatin receptors in the cerebral cortex and hippocampus. No significant differences in the apparent binding affinity values were seen after haloperidol treatment. When added at the time of the binding assay haloperidol 34.2 microM produced a 42% and 27% decrease in cerebrocortical and hippocampal membrane somatostatin receptors respectively.     

Changes in dopamine2 and serotonin2 receptors in rat brain after long-term verapamil treatment: comparison of verapamil and lithium.

Rat brain 5-HT2 and dopamine2 receptors were assessed following a chronic (3 weeks) administration of verapamil, lithium, and a combination of these two drugs. A significant increase in the number of 5-HT2 receptors was observed in the frontal cortex after the verapamil treatment, but the lithium and combined treatment had no effect on the densities of either binding sites. These data suggest that one or more of the mechanisms of the antimanic effect of verapamil may be involved in the change in 5-HT2 binding sites in a manner that is different from that of lithium.     

Combined lithium and valproate treatment and subsequent withdrawal: serotonergic mechanism of their interaction in discrete brain regions

Rats were administered with lithium carbonate (1 mmole/kg), valproate (300 mg/kg) and their combination for 12 days. Rats in the withdrawal group were treated for 10 days, followed by saline for 2 days. Mid-brain tryptophan levels increased in all the groups except lithium-treated rats. The administration of lithium together with valproate decreased tryptophan hydroxylase activity and 5-hydroxytryptamine levels in certain brain regions compared to either treatment alone. Also, the magnitude of valproate-induced 5-hydroxyindoleacetic acid elevation was decreased after combined treatment. Most of the changes observed after combined exposure persisted even after 2 days of treatment withdrawal. It appears from the data that combined administration of the two drugs produces persistent decrease in 5-hydroxytryptamine synthesis and turnover in the brain.     

Long-term lithium treatment and psychological functions

A group of 50 long-term lithium-treated outpatients were investigated with psychological examinations in order to study cognitive and emotional functions (memory, attention, speed, loss of effort, level of processing, productivity, and reactivity). The test results were compared with the general norms for the test applied. In average the test results were within the normal range. The inter-test variations which quantitatively and qualitatively characterize the performance of the lithium-treated patients indicate a relative lowering of the level of memory and perceptual processing as well as loss of effort when compared to the level of attention, productivity, and emotional reactivity. These findings support the hypothesis of a lithium-determined delay of the rate of information processing, a hypothesis which may be related to neuropsychological model of the level of arousal.     

The serotonin transporter and 5HT2A receptor in rat brain after localized lesions

OBJECTIVES: Post-stroke depression and depression after traumatic brain lesion are most often seen when the lesion includes frontal areas. The development of depression may include the serotonergic system because selective serotonin reuptake inhibitors (SSRIs) can be used to treat the depression. The purpose of the present study was to examine whether serotonin transporter density or 5HT2A serotonin receptor density is changed in specific brain areas following anterior or posterior lesions in the two hemispheres. METHODS: Localized heat-induced brain lesions were induced in rats, and the densities of the serotonin transporter and 5HT2A receptor were measured by quantitative autoradiography in eight and 15 different brain areas, respectively. RESULTS: A decrease in serotonin transporter density was detected in some frontal rat brain areas, and an increase in serotonin transporter density was detected in the right median raphe nucleus. No change was detected for 5HT2A receptor density.     

Chronic lithium treatment decreases [3H]-imipramine binding in rat brain

The effect of a chronic lithium treatment on the [3H]-imipramine binding in rat brain regions was investigated. In the striatum, an oral administration of lithium for 30 days induced a decrease in the [3H]-imipramine binding at the concentration of [3H]-imipramine, 1.0 nM, compared to the control. Lithium did not affect the [3H]-imipramine binding in the cerebral cortex and hypothalamus. A Scatchard analysis in the striatum revealed a decrease in the number of [3H]-imipramine binding sites with no changes in the binding affinity. These results suggest that the chronic lithium treatment may produce subsensitivity of the [3H]-imipramine binding in man and that this effect of the ion may be closely related to the established effect of lithium in the treatment of affective disorders.     

Changes in 5-HT(7) serotonin receptor mRNA expression with aging in rat brain

We examined 5-HT(7) receptor mRNA expression with in situ hybridization histochemistry in the brains of young (3 months), middle-aged (12 months) and old rats (24 months). In the ventral CA3 area of the hippocampus 5-HT(7) mRNA expression is reduced by approximately 30% between young and middle age without further decline between middle and old age. In other brain areas 5-HT(7) mRNA expression is unaffected by age.     

Effects of lithium carbonate on serotonin uptake in rat blood platelets

1. Lithium carbonate administration to male rats for 1 to 4 weeks increased the affinity of platelet serotonin (5-HT) uptake (decreased Km) and decreased the rate of 5-HT uptake (Vmax) when the serum lithium levels were 0.5 meq/1 to 0.65 meq/l. When the serum levels were increased further to 1 meq/1, Vmax decreased further, without additional change in Km. 2. No effect on the kinetics of 5-HT uptake was observed when serum lithium levels were at 0.4 meq/1 or below. 3. Addition of lithium carbonate in vitro (1 meq/1) had no effect on the Km and Vmax of rat platelet 5-HT uptake. 4. The possible mechanism of the inhibitory effect of lithium treatment on platelet 5-HT uptake is discussed.