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Journal ArticleDOI

Chronic lithium administration enhances serotonin release in the lateral hypothalamus but not in the hippocampus in rats. A microdialysis study.

01 Jan 1990-Journal of Neural Transmission (J Neural Transm Gen Sect)-Vol. 82, Iss: 1, pp 31-41
TL;DR: The effect of lithium on the PFH could be related to the improvement of the autonomic and cyclic symptoms of patients with manic depressive disorders undergoing lithium therapy.
Abstract: Chronic administration of lithium displays therapeutic and prophylactic effects in bipolar affective disorders, but its mechanism of action remains unknown. Several studies in animals and humans strongly suggest that central serotonergic neurons might be involved in lithium effects. In the experiments reported here microdialysis with removable probes and high pressure liquid chromatography and electrochemical detection were used to assess the amphetamine-induced release of serotonin (5-HT) and the 5-hydroxy-indoleacetic acid (5-HIAA) levels in the perifornical hypothalamus (PFH) and hippocampus (HP) of freely moving rats before and after chronic lithium chloride administration (2 meq/kg, as intragastric daily injections for 14 days). The serum lithium levels were 0.66 ± 0.08 meq/1. After lithium treatment, the amphetamine-induced 5-HT release was significantly enhanced in the PFH but not so in the HP. Basal levels of 5-HIAA in the control group decreased but remained unchanged in the lithium group in the PFH. No change of basal levels of 5-HIAA was observed in the HP. The effect of lithium on the PFH could be related to the improvement of the autonomic and cyclic symptoms of patients with manic depressive disorders undergoing lithium therapy.
Citations
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Journal ArticleDOI
TL;DR: 5-HTTLPR variants may be a possible influencing factor for the prophylactic efficacy of lithium in mood disorders and subjects with the s/s variant showed a worse response compared to both l/s and l/l variants.
Abstract: The aim of this study was to investigate the possible association between the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) and the prophylactic efficacy of lithium in mood disorders. Two hundred and one subjects affected by bipolar (n = 167) and major depressive (n = 34) disorder were followed prospectively for an average of 58.2 months and were typed for their 5-HTTLPR variant using polymerase chain reaction techniques. 5-HTTLPR variants were associated with lithium outcome (F = 5.35; df = 2,198; P = 0.005). Subjects with the s/s variant showed a worse response compared to both l/s and l/l variants. Consideration of possible stratification effects such as sex, polarity, age at onset, duration of lithium treatment and previous episodes did not influence the observed association. 5-HTTLPR variants may be a possible influencing factor for the prophylactic efficacy of lithium in mood disorders.

105 citations

Journal ArticleDOI
TL;DR: Preclinical research is discussed suggesting mechanisms likely to underlie lithium's therapeutic actions including direct targets inositol monophosphatase and glycogen synthase kinase-3 among others, as well as indirect actions including modulation of neurotrophic and neurotransmitter systems and circadian function.
Abstract: Mood disorders, including bipolar disorder and depression, are relatively common human diseases for which pharmacological treatment options are often not optimal. Among existing pharmacological agents and mood stabilizers used for the treatment of mood disorders, lithium has a unique clinical profile. Lithium has efficacy in the treatment of bipolar disorder generally, and in particular mania, while also being useful in the adjunct treatment of refractory depression. In addition to antimanic and adjunct antidepressant efficacy, lithium is also proven effective in the reduction of suicide and suicidal behaviors. However, only a subset of patients manifests beneficial responses to lithium therapy and the underlying genetic factors of response are not exactly known. Here we discuss preclinical research suggesting mechanisms likely to underlie lithium's therapeutic actions including direct targets inositol monophosphatase and glycogen synthase kinase-3 (GSK-3) among others, as well as indirect actions including modulation of neurotrophic and neurotransmitter systems and circadian function. We follow with a discussion of current knowledge related to the pharmacogenetic underpinnings of effective lithium therapy in patients within this context. Progress in elucidation of genetic factors that may be involved in human response to lithium pharmacology has been slow, and there is still limited conclusive evidence for the role of a particular genetic factor. However, the development of new approaches such as genome-wide association studies (GWAS), and increased use of genetic testing and improved identification of mood disorder patients sub-groups will lead to improved elucidation of relevant genetic factors in the future.

97 citations

Journal ArticleDOI
TL;DR: In this article, the authors investigated the possible association between the tryptophan hydroxylase (TPH) gene and prophylactic efficacy of lithium in mood disorders.

81 citations

Journal ArticleDOI
TL;DR: 5-HT2A and 2C variants are not, therefore, associated with lithium prophylactic efficacy in mood disorders and are not connected with lithium treatment.

66 citations

Journal ArticleDOI
TL;DR: The present results support the assumption that increases in hippocampal 5-HT neurotransmission may be important in the augmentatory effect of lithium.
Abstract: A substantial number of patients do not respond sufficiently to antidepressant drugs and are therefore often co-medicated with lithium as an augmentation strategy. However, the neurochemical rationale behind this strategy needs to be further clarified. We examined the effect of chronic citalopram and subchronic lithium, alone or in combination, on (a) serum levels of citalopram and lithium, (b) animal behaviour and (c) hippocampal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels. Furthermore, we examined the serum level of citalopram and hippocampal 5-HT following one acute citalopram injection. Microdialysis in the freely moving animals was used to determine hippocampal 5-HT and 5-HIAA. The animal behaviour was examined in the open field and forced swim test. We found that chronic administration of citalopram (20 mg/kg/24 h s.c.) significantly increased the 5-HT baseline relative to vehicle-treated rats. Addition of subchronic lithium (60 mmol/kg chow pellet p.o.) to chronic citalopram therapy further elevated the 5-HT levels. Moreover, we found acute citalopram (5 mg/kg s.c.) to increase the 5-HT level. The immobility time in the FST and the locomotion in the OF were unaffected by any treatments. The present results support the assumption that increases in hippocampal 5-HT neurotransmission may be important in the augmentatory effect of lithium.

64 citations


Cites background from "Chronic lithium administration enha..."

  • ...Moreover, studies based on the microdialysis technique have shown that lithium increases 5-HT release in some areas of the brain but not in others (Baptista et al. 1990; West et al. 1991; Mork 1998; Wegener et al. 2000; Muraki et al. 2001)....

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References
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Journal ArticleDOI
TL;DR: The purpose of the present study has been to try out the lithium treatment of manic psychoses in such a way that sources of error and uncertainty were reduced as much as possible.
Abstract: The treatment of manic psychoses with lithium salts was introduced by Cade in 1949, following an accidental observation of a sedative-like action of lithium ions when administered to guinea-pigs. Beneficial effects of this treatment in cases of mania have also been reported by Ashburner (1950) and by Noack and Trautner (1951). According to these reports the effects of lithium treatment are striking, and it is rather astonishing that this observation has failed to arouse greater general interest among psychiatrists. One possible reason may be that the doses reported necessary for a clinical effect are close to those giving rise to toxic symptoms. Another explanation may possibly be found in the difficulties encountered in attempts to convey to others in a quantitative manner the clinical impressions of the effect of a new psychiatric therapy. The proper evaluation of a psychiatric therapy is a matter of considerable difficulty for the following reasons: (1) An objective, quantitative assessment of the degree of the psychosis is often difficult or impossible, and usually the evaluation of the effect of a new therapy has to be based on a clinical estimate. (2) Unless special precautions are taken, the therapeutic effect and its evaluation are liable to gross distortions due to suggestibility, negative or positive, in the patients as well as in the observers. (3) Most psychoses, and notably manias and depressions, show spontaneous variations in duration and intensity. For this reason it is not always evident whether an improvement occurring concomitantly with the administration of a certain therapy is spontaneous or due to the therapy given. The purpose of the present study has been to try out the lithium treatment of manic psychoses in such a way that these sources of error and uncertainty were reduced as much as possible.

477 citations

Journal ArticleDOI
21 Jul 1978-Science
TL;DR: Silicone pellets containing d-amphetamine base were implanted subcutaneously in rats and swollen dopamine axons concomitant with large decreases in tyrosine hydroxylase activity were observed in the caudate nucleus, implying that continuous amphetamine administration has a selective neurotoxic effect on dopamine terminals in the Caudate.
Abstract: Silicone pellets containing d-amphetamine base were implanted subcutaneously in rats. These pellets release amphetamine continuously for at least 10 days. Several days after implantation, swollen dopamine axons concomitant with large decreases in tyrosine hydroxylase activity were observed in the caudate nucleus. Decreased tyrosine hydroxylase activity was still present 110 days after pellet removal in the caudate but not in several other brain regions, nor in the caudate of rats injected with an equivalent amount of amphetamine in daily injections. This implies that continuous amphetamine administration has a selective neurotoxic effect on dopamine terminals in the caudate.

316 citations

Journal ArticleDOI
25 Sep 1981-Science
TL;DR: Results suggest a mechanism by which lithium may stabilize serotonin neurotransmission, and increase both basal and potassium chloride-stimulated release of endogenous serotonin from the hippocampus but not from the cortex.
Abstract: The effects of long-term lithium administration on pre- and postsynaptic processes involved in serotonergic neurotransmission were measured in rat hippocampus and cerebral cortex Long-term lithium administration increased both basal and potassium chloride-stimulated release of endogenous serotonin from the hippocampus but not from the cortex Serotonergic receptor binding was reduced in the hippocampus but not in the cortex These results suggest a mechanism by which lithium may stabilize serotonin neurotransmission

221 citations

Journal ArticleDOI
TL;DR: Tests in awake rats with probes in the nucleus accumbens showed stable amounts of catecholamines and metabolites collected during repeated 20 min samples, and absolute recovery measured in picograms was independent of the perfusate flow rate inside the probe.

212 citations


"Chronic lithium administration enha..." refers background in this paper

  • ...Technical details of the probe are given elsewhere (Hernfindez et al., 1986)....

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  • ...Assuming that amphetamine diffused out of the probe at about the same rate that monoamines diffuse in (Hernfindez et al., 1986), roughly 10% (20 gg) of the drug diffused out of the microdialysis probe in 20 min....

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