Chapter 38: Lithium selectively potentiates cholinergic activity in rat brain

A.C. Cuello (Editor)

Progress in Brain Research. Vol. 98

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0 1993 Elsevier Science Publishers B.V. All rights reserved.

CHAPTER 38

Lithium selectively potentiates cholinergic activity in rat brain Richard S. Jope Department of Psychiatry and Behavioral Neurology, University of Alabama at Birmingham, Birmingham, AL 35294-oO17, USA

Introduction Lithium is one of the most effective drugs available for the treatment of psychiatric disorders, as it is therapeutic in approximately 80% of manic-depressive patients and it reduces the manifestations of both phases of the illness. Thus. we have the intriguing conjugation of the simplest drug known to man effectively treating disorders of great complexity, those involving emotion and behavior. Lithium is a mood-stabilizer; it seems to support homeostatic mechanisms that strive to maintain a balance in the responses to stimuli which cause fluctuations in mood. Thus, learning the mechanism of action of lithium may increase our understanding of the neurochemical basis of emotion and of related disorders. This chapter describes experimental results which show that lithium selectively increases cholinergic activity in mammalian brain in vivo. Furthermore, at appropriate doses, the co-administration of lithium and cholinomimetics results in seizures which are generalized to all regions of the brain that have been examined and which are difficult to control pharmacologically, leading invariably to death. A tremendously large increase in the concentrations of acetylcholine and choline accompany the seizures, as do increases in the products of the phosphoinositide second messenger system. Potential mechanisms which might mediate the stimulatory effects of lithium on cholinergic function are discussed.

Lithium selectively potentiates cholinergic function This laboratory has been investigating the effects of lithium on cholinergic function and signal transduction mechanisms. The historical development of this line of research was reviewed previously (Jope, 1987). The initial stimulus was the proposal by Janowsky et al. (1972) that mania is associated with reduced cholinergic activity. Therefore,

lithium was hypothesized to increase cholinergic activity. Initial in vitro studies with lithiurn using rat brain (Jope, 1979) and human erythrocytes (Jope et al., 1978) supported this hypothesis. However, it is often difficult to translate effects of a drug that are observed with in vitro measurements to the in vivo situation. Therefore, in vivo interactions of lithium with cholinomimetics provided a means to directly examine these interactions (Jope, 1987). These experiments used EEG recordings and behavioral observations to document the in vivo responses of rats to cholinergic agonists given with or without acute or chronic lithium administration. Cholinergic drugs will cause seizures when administered in high doses to rats. Lithium administration reduced the convulsant dose of all cholinomimetics tested, including pilocarpine, arecoline and physostigmine (Jope et al., 1986; Morrisett et al., 1987). The importance of this observation is that it demonstrates that in vivo lithium potentiates the responses of stimulated muscarinic receptors. It is logical to assume that the response to endogenous acetylcholine will be enhanced in a similar manner. This is supported by the finding that lithium potentiated the response to physostigmine, an inhibitor of acetylcholinesterase, the effects of which are transmitted by endogenous acetylcholine. The interaction of lithium and pilocarpine has been studied in the greatest detail. N-Methylatropine (5 mgkg) is always administered with pilocarpine to block peripheral cholinergic stimulation. Administration of LiCl (3 mmoY kg) 20 h prior to pilocarpine (30 m a g ) results in paroxysmal spikes, spike trains and, after 20-25 min, generalized convulsive status epilepticus which consists of continuous seizure activity for several hours until death occurs. These responses are similar (but not identical; Ormandy et al., 1989) to those caused by a very high dose of pilocarpine (380 m a g ) in lithium-naive rats, indicating that lithiurn causes a greater than 10-fold potentiation of cholinergic responses. Also, these results indicate that lithium not only potentiates cholinergic stimulation but also apparently contributes to the induction of seizures that are not con-

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trolled by the normal endogenous mechanisms that usually terminate acute seizures. Lithium is effective at doses equal to and below those equated with therapeutic effects and chronic (4 weeks) lithium treatment is as effective as acute lithium (Momsett et al., 1987). Compared with many other convulsant treatments, the seizures produced in response to lithium plus pilocarpine show little interanimal variation, which facilitates biochemical and pharmacological studies. Potentiation by lithium of responses to cholinomimetics appears to be selective. For example, EEG recordings were used to monitor seizure activity in rats after administration of several doses of kainate, N-methyl-D-aspartate (NMDA), bicuculline and pentylenetetrazole, and lithium pretreatment did not alter the responses to these convulsants (Ormandy et al., 1991). Of course, the responses to other agents which have not yet been tested may also be potentiated by lithium. Such a finding may prove useful for identifying the mechanism of action of lithium. However, the findings to date indicate that lithium is not a general proconvulsant but instead selectively potentiates responses to cholinomimetics which, if the dose is great enough, can result in seizures.

Modulation of lithium-cholinomimetc interactions A number of drugs with different sites of action have been tested for modulatory effects on the response to lithium plus pilocarpine. Atropine, a muscarinic antagonist, blocked seizures when given before pilocarpine but had no effect when given after status epilepticus had developed (Jope et al., 1986). These results indicated that seizures were initiated by activation of muscarinic receptors but status epilepticus was maintained by other processes. MK-801,an NMDA receptor antagonist, did not impede the initial seizure activity induced by lithium plus pilocarpine, but blocked the deyelopment of status epilepticus (Ormandy et al., 1989). It was concluded that activation of NMDA receptors was not involved in initiation of seizures but that the muscarinic stimulation caused recruitment of NMDA receptor activation which was obligatory for maintenance of status epilepticus. This interaction was observed also when non-convulsive doses of pilocarpine (in the absence of lithium) and NMDA were found to act synergistically when given together, resulting in status epilepticus (Ormandy et al., 1989). These results raised the possibility that lithium enhances stimulatory interactions between cholinergic and excitatory amino acid systems (Ormandy et al., 1991). Because cholinergic and noradrenergic systems are well known to maintain balanced activities, and because this balance may be disturbed in manic-depressive illnesses, the influence of modulation of noradrenergic function on the

response to lithium plus pilocarpine was examined. Most interestingly, depletion of norepinephrine by pretreatment with DSP-4 greatly potentiated the response to pilocarpine (in the absence of lithium), although not to as great an extent as did lithium pretreatment (Ormandy et al., 1991). Also, the aZadrenergic receptor agonist. clonidine, prolonged latencies to seizure activity after lithium plus pilocarpine while the antagonist, idazoxan, reduced latencies. These results show that noradrenergic activity balances responses to cholinomimetics and indicated that lithium may potentiate cholinergic responses in part by impairing norepinephrine-stimulated second messenger systems (Ormandy et al., 1991). The effects of in vivo pertussis toxin administration, which inactivates specific G-proteins via ADP-ribosylation, were examined on the responses to pilocarpine because lithium has been suggested to impair G-protein function (Ormandy and Jope, 1991). The maximally effective dose of pertussis toxin mimicked the effect of lithium by causing a remarkably similar potentiation of pilocarpine-induced seizures. This does not prove that this is the mechanism of action of lithium, but the similarities in the effects of lithium and pertussis toxin were very striking. It was suggested that pertussis toxin may cause this response by suppressing inhibitory transmission mediated by adenosine or GABAs receptors, both of which are coupled to G-proteins sensitive to pertussis toxin (Ormandy and Jope, 1991).

Presynaptic cholinergic responses to lithium A presynaptic component to the enhancement by lithium of cholinergic activity was identified in an early study of acetylcholine turnover (Jope, 1979) and subsequently when the effect of hemicholinium-3 (HC-3) on seizures was examined (Jope et al., 1986). HC-3 impairs acetylcholine synthesis by blocking high affinity choline transport. Seizure activity induced by lithium plus pilocarpine was partially blocked by HC-3 pretreatment, indicating that enhanced release of endogenous acetylcholine contributed to the response. In support of this proposal, Evans et al. (1990) reported that lithium caused presynaptic facilitation, due at least in part to blockade of presynaptic auto-inhibition of acetylcholine release. Further presynaptic effects were found when the acetylcholine concentration was observed to increase 3- to Cfold in rat hippocampus and cerebral cortex during seizures induced by lithium plus pilocarpine (Jope et al., 1987). These are the highest in vivo concentrations of acetylcholine that have been found in rats after any treatment. Later studies showed that such large increases did not occur with other treatments that caused status epilepticus (Jope and Gu, 1991). The increased acetylcholine was retained in slices

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and excess acetylcholine was released by depolarization in a Ca2+-dependent manner (Jope et al., 1987). Increased in vivo release of acetylcholine was also observed. Yamada et al. (1991) found increased HC-3 binding sites after treatment with lithium and pilocarpine, suggesting that activation of high affinity choline transport contributed to the increased synthesis of acetylcholine. Thus, the data indicate that this treatment increases the synthesis and release of acetylcholine and that this accounts for a portion of the increased cholinergic activity. However, since HC-3 did not completely block seizures induced by lithium and pilocarpine although it depleted endogenous acetylcholine, it is evident that lithium must also potentiate postsynaptic muscarinic responses.

Receptor-coupled responses after lithium administration Investigations of postsynaptic responses after in vivo lithium treatment have often focused on the activity of the phosphoinositide second messenger system and have used two experimental approaches: (i) in vitro measurements using brain slices or membranes after in vivo lithium administration; or (ii) in vivo measurements of second messenger concentrations. Both methods have limitations. The in vitro approach introduces problems associated with disruption of the neuronal environment which may alter the response to lithium that was expressed in vivo. With the in vivo approach, it is difficult to selectively isolate responses associated with the cholinergic system. Unfortunately these two approaches seem to give different results. In vitro measurements after lithium treatment indicate that there is reduced phosphoinositide hydrolysis in response to muscarinic receptor stimulation (Kendall and Nahorski, 1987; Song and Jope, 1992). This may be due to impaired function of G-proteins which mediate this process and also to lithium-induced depletion of inositol and phosphoinositides, although this depletion may be artificially induced by incubation of brain slices in inositol-free media (Lee et al., 1992). In vivo measurements do not reveal inhibition of phosphoinositide hydrolysis by lithium treatment. Sherman et al. (1981) first provided evidence that lithium increased muscarinic receptor stimulated phosphoinositide hydrolysis and massive hydrolysis of phosphoinositides by seizures induced by lithium plus pilocarpine was reported later (Honchar et al., 1983). Both of these studies measured inositol monophosphate concentrations. More recent investigations have employed measurements of the primary second messenger, inositol trisphosphate (IP3). In mice, lithium treatment increased the IP3 concentration and coadministration of pilocarpine led to further increases

(Whitworth et al., 1990). In rats, although lithium alone did not increase the IP3 concentration, co-administration of pilocarpine caused large increases in IP3 (Jope et al., 1992) and the related second messenger inositol tetrakisphosphate (Smith et al., 1991). Only after prolonged seizure activity did the concentration of IP3 decline. Thus, under normal conditions there was no evidence from in vivo measurements that lithium impaired phosphoinositide hydrolysis, except after prolonged, massive stimulation which could be due to depletion of inositol and phosphoinositides or to other regulatory mechanisms. However, the primary conclusion that the in vivo data indicate is that lithium facilitates phosphoinositide hydrolysis. Further evidence that lithium enhances muscarinic receptor-induced signals in intact cells comes from investigations of immediate early gene (IEG) expression. IEGs constitute a family of genes that are rapidly activated in response to neuronal stimulation and which code proteins (e.g. Fos, Jun) that are transcription factors. Thus, activation IEGs can influence the transcription of many genes and subsequently the protein constituents of neurons. In cultured cells, lithium potentiated carbachol-induced accumulation of c-fos mRNA (Arenander et al., 1989; Kalasapudi et al., 1990) and in rat cortex lithium potentiated the in vivo stimulation by pilocarpine of c-fos mRNA (Weiner et al., 1991). In PC12 cells, this potentiation by lithium was demonstrated to occur at or distal to activation of protein kinase C, which is stimulated through the phosphoinositide system (Divish et al., 1991). Thus, these data indicate that lithium potentiates responses associated with cholinergic agonist-induced phosphoinositide hydrolysis in agreement with the in vivo measurements of inositol phosphate concentrations.

Conclusions The problem arises of how to reconcile the evidence from in vivo studies that lithium increases cholinergic activity, including second messenger production, with the in vitro evidence that lithium impairs cholinergic-linked phosphoinositide hydrolysis. It is evident that in vitro measurements with rat brain slices are influenced by impaired availability of inositol since both biochemical and electrophysiological methods show that inositol supplementation reverses inhibitory effects of lithium to some extent (Worley et al., 1988; Pontzer and Crews, 1990; Lee et al., 1992). Additionally, the reduced phosphoinositide turnover detected in vitro after lithium treatment may be due to a relatively small pool with a rapid turnover rate which makes it especially susceptible to lithium but not detectable by in vivo methods (Berridge, 1989). Acute in vivo effects of lithium may also be influenced by lowered inositol concen-

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trations, although this occurs only to a small extent below toxic doses of lithium, but with chronic lithium treatment normal inositol concentrations are retained (Sherman et al., 1985; Hirvonen and Savolainen, 1991). Another possibility which has not received much attention is that the enhanced in vivo activity may lead to feedback down-regulation of the system and this is what is observed by in vitro measurements of phosphoinositide hydrolysis after chronic lithium treatment (Fig. 1). This situation is similar to responses caused by tricyclic antidepressants which increase catecholaminergic activity and result in down-regulation of functional receptors. The evidence for the latter hypothesis and that G-proteins (Manji, 1992) may be the site of down-regulation include the following. Lithium treatment reduces G-protein concentrations and mRNA levels in rat brain in vivo (Li et al., 1991; Colin et al., 1991), although G,, which mediates pertussis toxin-insensitive phosphoinositide hydrolysis has not been studied. Measurements of phosphoinositide hydrolysis in brain membranes with exogenous phosphoinositides (thus excluding any changes in phosphoinositide concentrations) demonstrated reduced G-protein activatedphosphoinositide hydrolysis after chronic lithium treatment (Song and Jope, 1992). The reduced G-protein function may be the result of enhanced protein phosphorylation by protein kinase C after lithium treatment. It is well known

c+ Cholinergic Stimuiatlon

1 PI

Hydrolysis

Reduced

in vitro PI Responses

G-Protein Function

Fig. 1. Modulatory effects of lithium. Lithium administration potentiates responses to cholinergic agonists in vivo, but the specific sites of action, whether within the cholinergic response pathway or by way of external modulators, nre not clear. Evidence has been reported that lithium increases the production of diacylglycerol and the transcription of immediate early genes, the latter due at least in part to a site at or distal to protein kinase C. These stimulatory effects of lithium may result in down-regulation of the system, possibly by affecting G-proteins, leading to appnrent reductions in phosphoinositide mernbolism when assayed in vitro. PI, phosphoinositide;DAG, diacylglycerol; PKC, protein kinase C; IEG, immediate early genes.

that activation of protein kinase C reduces phosphoinositide hydrolysis induced by cholinergic agonists and lithium increases diacylglycerol concentrations (Brami et al., 19911, an activator of protein kinase C, and increases the phosphorylation of some protein substrates of protein kinase C (Casebolt and Jope, 1991; Lenox et al., 1992). Since lithium in vitro does not directly modify protein kinase C activity, these effects may be indirect through interactions with substrates or phosphatases. Especially provocative is the finding that lithium increases immediate early gene expression induced by activators of protein kinase C (Divish et al., 1991). Therefore, either transcriptional regulation or phosphorylation might lead to reduced G-protein function as a feedback inhibitory process activated in response to potentiation by lithium of cholinergic function. In vitro assays may then detect the results of inhibitory feedback as reduced responses. In other cell types, reduced active G-proteins have been shown to mediate desensitization of second messenger systems (Green et al., 1992). Of course, sites other than Gproteins may also mediate this regulatory response to lithium-potentiated cholinergic activity. A potential mechanism for these effects was raised by the finding of Godfrey (1 989) that CDP-DAG, a precursor of phosphatidylinositol, was increased by lithium treatment. The accumulation of CDP-DAG may directly, or indirectly through the actions of DAG, activate protein kinase C to produce the effects discussed above. In summary, this hypothesis suggests that the increased in vivo cholinergic activity which clearly is produced by lithium administration results in the down-regulation or desensitization of phosphoinositide hydrolysis which can be detected by in vitro measurements, possibly by altered Gprotein function and possibly through changes in the phosphorylation state of key proteins. This hypothesis is consistent with much of the experimental data as well as with clinical observations indicating that activation of cholinergic function should counter manic behavior and that chronic lithium administration is required for a therapeutic response. By functional down-regulation, but not blockade, lithium maintains cholinergic responses at enhanced levels and may stabilize mood without interfering with critical neuronal function. Thus, severe fluctuations in mood are limited in the presence of lithium, but there is little interference with normal neuronal function. This is certainly an oversimplification, necessary to some degree to formulate experimental strategies, which necessarily focussed on the cholinergic system for this chapter although it is obvious that modulation of other neurotransmitter systems by lithium are important and that it does not encompass all influential factors. For example, lithium also modulates cyclic AMP production, possibly by modulation of G-proteins, as elegantly discussed by Manji (1992). Also, the association of altered glucocorticoid hormone function in many rnanic-

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depressive patients must be considered. In this regard, it is interesting that both lithium treatment and adrenalectomy, which removes circulating glucocorticoids, potentiate immediate early gene expression in rat brain (Li et al., 1992). Clearly, further layers of complexity must be included in an integrated understanding of the therapeutic mechanism of action of lithium.

Acknowledgements I am grateful to my many skilled collaborators who have worked on this project, and especially Dr.George Ormandy for also providing comments on this manuscript. Supported by NIMH grant MH38752.

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