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Dissertation
The effect of chronic lithium treatment on serotonergic neurotransmission
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania
Oct 1988
DOI:
https://doi.org/10.17918/00009931
Abstract
The effect of chronic lithium treatment on serotonergic neurotransmission was investigated in an attempt to define the molecular mechanisms of lithium's actions. The results illustrate that lithium affects serotonergic neurotransmission via multiple mechanisms of action which may not be directly related to each other. The effect of chronic lithium treatment on [³H]5-HT release and its regulation by presynaptic mechanisms was studied in [³H]5-HT preloaded superfused rat brain slices. The [³H]5-HT efflux evoked by a 30 second exposure to 65 mM K⁺ was increased following three weeks of lithium administration in the three brain regions examined. The K⁺-evoked overflow observed in both control and chronically lithium-treated animals was Ca²⁺-dependent. Chronic lithium treatment was also found to be associated with a decrease in spontaneous [³H]5-HT efflux in the cortex and hypothalamus and with an increase in basal hippocampal 5-HT efflux. The sensitivity of the inhibitory serotonin autoreceptors was assessed by the response to 5-HT agonists, 5-methoxytryptamine and LSD as well as to the 5-HT antagonist, methiothepin. The data indicate that long-term lithium administration depresses the maximal functional capacity of presynaptic serotonin autoreceptors. The presynaptic 5-HT autoreceptor was characterized pharmacologically using several 5-HT subtype selective agonists and antagonists which have previously been classified by radioligand binding assays. The results illustrate that presynaptic 5-HT autoreceptors appears to possess unique pharmacological properties. The functional down regulation of the presynaptic autoreceptor may be responsible, at least in part, for the facilitated K⁺-stimulated 5-HT release and the alterations in postsynaptic serotonin receptors observed in brain tissues of animals chronically treated with lithium. The [³H]5-HT preloaded superfusion system was also used to explore the regulation of 5-HT release by protein kinase C-related mechanisms and the effect of lithium on this regulatory mechanism. Introduction of active phorbol esters such as phorbol 12-myristate, 13-acetate (PMA) or phorbol 12, 13-dibutyrate (PDBu) but not inactive 4 -phorbol 12, 13-didecanoate (4[alpha]-PDD) resulted in dose-related and time-related potentiation of K⁺-evoked [³H]5-HT release. Active phorbol esters also increased the spontaneous [³H]5-HT efflux. However, the magnitude of facilitation induced by phorbol esters was far lesser than those of K⁺-stimulated release (66-103% and 12. 6-26% increase in K⁺-evoked and spontaneous serotonin release, respectively). The response to phorbol esters was reversible and Ca²⁺-dependent. The putative protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) inhibited K⁺-evoked [³H]5-HT release significantly (11%) without affecting the spontaneous release. The PMA-induced facilitation of serotonin release was, however, markedly prevented by the enzyme inhibitor. In addition, the PMA-induced potentiation of serotonin release was completely abolished by the pretreatment of microtubular inhibitor - colchicine. The effect of PMA on release was not found to be directly mediated through presynaptic serotonin autoreceptors. These results suggest an important role for protein kinase C in the regulation of central serotonin release. This protein kinase C-mediated regulatory mechanism was found to be profoundly abolished by long-term lithium treatment. To further investigate the mechanism underlying lithium's effect on protein kinase C-related function, (1) the activation of protein kinase C, (2) the protein kinase C activation-induced phosphorylation of neuronal protein substrates and (3) the effect of lithium on protein kinase C activation were assessed. The results indicate that PMA increased protein kinase C translocation from cytosol to membrane-bound fractions. The translocation of the enzyme could also be activated presynaptically by K⁺-evoked depolarization and postsynaptically by stimulation of 5-HT₂ receptors. This trans location process appears to be Ca²⁺-dependent. Following the activation of protein. kinase C by pretreatment with PMA, the levels of immunoprecipitated MAPs, TAU and [alpha]-tubulin, were found to be increased. The data presented indicate that lithium, at therapeutic concentrations, inhibits protein kinase C translocation specifically both presynaptically and postsynaptically. The results further indicate that lithium inhibits protein kinase c by interfering with Ca²⁺ mediation of the translocation process. It is asserted that the lithium-elicited attenuation of protein kinase C-mediated function may limit the ability of neurons to respond to external signals. The data presented here suggest specific biochemical mechanisms which may underlie lithium's diverse therapeutic actions. Future contributions to this body of knowledge will enhance understanding of the biochemical basis of certain affective disorders.
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Details
- Title
- The effect of chronic lithium treatment on serotonergic neurotransmission
- Creators
- Hoau-Yan Wang
- Contributors
- Eitan Friedman (Advisor) - Drexel University, Medical College of Pennsylvania (1970-1993)
- Awarding Institution
- Medical College of Pennsylvania
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Medical College of Pennsylvania; Philadelphia, Pennsylvania
- Number of pages
- xiii, 170 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Medical College of Pennsylvania (1970-1993)
- Other Identifier
- 991021888851004721