Arne Geisler

Effects of GTP on hormone-stimulated adenylate cyclase activity in cerebral cortex, striatum, and hippocampus from rats treated chronically with lithium

The effects of lithium on guanosine triphosphate (GTP) stimulated adenylate cyclase activity and hormone-induced GTP activation of the enzyme have been studied in three regions of the rat brain. Chronic treatment with lithium, giving a serum lithium level of 0.71 +/- 24 mmol/L, reduced isoprenaline-induced GTP stimulation of adenylate cyclase activity in cortical membranes at concentrations of GTP up to 2 microM. No effect of lithium was observed at higher concentrations of GTP. The enzyme activity stimulated by GTP alone was unaltered by lithium ex vivo. In striatal membranes, lithium ex vivo decreased both dopamine-induced GTP activation of adenylate cyclase and GTP-stimulated adenylate cyclase activity at concentrations of GTP below 2 microM. No effects of lithium ex vivo were found in striatum at 2 microM GTP and above. In hippocampal membranes, lithium ex vivo did not influence either serotonin-induced GTP stimulation of the adenylate cyclase or GTP-stimulated enzyme activity at low levels of GTP. However, at 50 microM GTP, lithium ex vivo enhanced serotonin-stimulated enzyme activity. The present results suggest that lithium ex vivo decreases neurotransmitter activation of the cortical beta-adrenergic adenylate cyclase by influencing the mechanisms by which receptor agonists enhance the GTP stimulation of the adenylate cyclase. Furthermore, lithium ex vivo exerts a region-specific action on the brain adenylate cyclases, but in the brain regions studied, an effect of lithium on N-protein level might be of significance for the action of lithium ex vivo on neurotransmitter activation.

The effects of lithium in vitro and ex vivo on adenylate cyclase in brain are exerted by distinct mechanisms.

The effects of lithium on basal and forskolin-stimulated activity of adenylate cyclase in membrane preparations from cerebral cortex of the rat have been studied. Chronic treatment with lithium, yielding a level of lithium in serum of 0.71 +/- 0.18 mmol/l, reduced forskolin-stimulated activity in total homogenates but exerted no effect on the basal activity. Lithium in vitro, at 2 and 10 mM, did not influence the basal enzyme activity in membranes from either control or lithium-treated animals. The sensitivity of forskolin-stimulated adenylate cyclase to lithium in vitro was unaltered after chronic treatment and the in vitro and ex vivo effects of lithium on this parameter were additive. The inhibitory ex vivo effect of lithium was not antagonized by increasing concentrations of magnesium and the inhibitory effect of lithium ex vivo was still persistent after washing of the membranes. The present results indicate that lithium exerts its ex vivo effect on the activated cyclase, independently of the in vitro effect. Both effects may, however, contribute to the in vivo effect of lithium during chronic treatment.

Effects of lithium ex vivo on the GTP-mediated inhibition of calcium-stimulated adenylate cyclase activity in rat brain

The aim of this study was to investigate the effects of chronic lithium treatment on calcium (Ca2+)-stimulated adenylate cyclase activity in rat striatum and hippocampus, and to elucidate the effect of lithium treatment on the neurotransmitter/GTP-mediated inhibition of Ca2+-stimulated enzyme activity in the two brain areas. Lithium treatment, which gave a serum-lithium concentration of 0.9 +/- 0.16 mmol/l, enhanced Ca2+-stimulated enzyme activity in the hippocampus but reduced this activity in the striatum. Serotonin (5-HT) dose dependently reduced Ca2+-stimulated adenylate cyclase activity in the hippocampus, and chronic lithium administration reduced the ability of 1 microM 5-HT to inhibit Ca2+-stimulated enzyme activity. Furthermore, the 5-HT-induced GTP-mediated inhibition of Ca2+-stimulated adenylate cyclase activity in the hippocampus was markedly decreased by lithium. Increasing concentrations of dopamine in the striatum did not, however, affect Ca2+-stimulated adenylate cyclase activity and the inhibition of enzyme activity observed with increasing concentrations of GTP was not influenced by chronic lithium treatment. These results demonstrate that lithium ex vivo exerts dual and region-specific effects on Ca2+-stimulated adenylate cyclase in the brain. Furthermore, long-term administration of lithium could reduce the inhibitory effect of 5-HT on adenylate cyclase in the hippocampus, by influencing the inhibitory GTP-binding protein. The effects of lithium on serotonergic and dopaminergic neurotransmission could be involved in the therapeutic actions of lithium in manic-depressive illness.

Effects of Chronic Lithium Treatment on Agonist‐Enhanced Extracellular Concentrations of Cyclic AMP in the Dorsal Hippocampus of Freely Moving Rats

Abstract: Studies on brain slices and homogenates suggest that chronic lithium treatment affects the activity of adenylate cyclases in the brain. To investigate whether chronic lithium administration influences the cyclic AMP (cAMP) synthesis in vivo, we have used microdialysis to assess lithium‐induced alterations in extracellular concentrations of cAMP in the dorsal hippocampus of freely moving rats. Local infusion of noradrenaline or forskolin through the microdialysis probes produced rapid increases in the extracellular concentrations of cAMP in the dorsal hippocampus. Lithium administration for 4 weeks (serum lithium concentration of 0.8 ± 0.11 mmol/L) did not affect the baseline levels of cAMP. However, in rats fed a lithium‐supplemented diet, noradrenaline‐ and forskolin‐induced enhancement of cAMP levels was decreased in the dorsal hippocampus. The rats were videotaped 18 min before and 27 min after initiating the introduction of noradrenaline and forskolin into the dorsal hippocampus. The infusion of agonists induced a moderate behavioral excitation. Rats treated with lithium were less active compared with the control rats. Taken together, these data confirm that chronic lithium administration affects the cAMP signaling system in the brain of living animals, presumably by interfering with a site beyond the receptor level.

Lithium Inhibition of Forskolin-Stimulated Adenylate Cyclase

The lithium sensitivity of forskolin- and fluoride-stimulated adenylate cyclase activity was investigated in rat brain homogenates in vivo and in vitro. The unstimulated and fluoride-stimulated activity was not affected by lithium, while the forskolin stimulation exhibited a pronounced inhibition by this cation. Furthermore, if Mn2+ was substituted for Mg2+ in the assay media, the forskolin-stimulated activity was even more sensitive to lithium. The results indicate an action of lithium mainly on the catalytic moiety in the adenylate cyclase system. However, the effect cannot be direct on this protein, since the unstimulated activity was unaffected. The action is rather on the microenvironment surrounding this protein, thereby interfering with a possible conformational change of the adenylate cyclase of importance for the activation of this enzyme.

Characterization of human platelet beta-adrenoceptors

The widespread use of beta-adrenoceptor antagonists against hypertension, angina pectoris and migraine or as a preventive treatment after myocardial infarction has encouraged us to investigate the effects of these drugs on platelet function. The aim of this study was to examine whether beta-blocking drugs interfere with platelet beta- adrenoceptors and whether this dependency is related to their selectivity for beta-adrenoceptor subtypes. Beta-adrenoceptor stimulation of human platelets with isoprenaline increased cyclic AMP (cAMP), which is known to inhibit platelet aggregation. Furthermore, our studies showed that cAMP formation in vitro was stimulated by non-selective and beta 2-selective agonists, but not by the predominant beta 1-agonist prenalterol. Isoprenaline- stimulated cAMP formation was blocked by the non- selective beta-adrenoceptor antagonists propranolol, timolol, and alprenolol, while the beta 1-selective antagonists atenolol and metoprolol had no influence on an isoprenaline-induced cAMP formation. Receptor binding studies using (3H)-dihydroalprenolol revealed an IC50 value for propranolol of 85 nM, while metoprolol only displaced the bound (3H)-dihydroalprenolol at far higher concentrations (IC50, 20 microM). We conclude that the human platelet beta-adrenoceptors are mainly of the beta 2- subtype and that beta-adrenoceptor antagonists, especially the non-selective antagonists interfere with platelet function assessed as platelet cAMP formation.

5-Hydroxytryptamine receptor agonists influence calcium-stimulated adenylate cyclase activity in the cerebral cortex and hippocampus of the rat

The effects of 5-hydroxytryptamine (5-HT) receptor agonists on calcium (Ca2+)-stimulated adenylate cyclase activity in the hippocampus and cerebral cortex of the rat were studied. In the presence of Ca2+ (1.5 microM), 5-HT dose dependently inhibited adenylate cyclase activity (EC50 = 10 +/- 2 nM). The inhibitory effect of 5-HT on Ca2(+)-stimulated adenylate cyclase was antagonized by spiperone (KB = 2 +/- 0.8 nM). The rank order of potency of 5-HT agonists to inhibit Ca2(+)-stimulated adenylate cyclase in the hippocampus was: 5-carboxamidotryptamine (5-CT) greater than 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) greater than 5-hydroxytryptamine (5-HT) = 5-methoxytryptamine (5-OCH3-T) greater than trifluoromethylphenylpiperazine (TFMPP) greater than m-chlorophenylpiperazine (mCPP). 2-Methyl-5-hydroxytryptamine (2-CH3-5-HT) did not exert an effect on Ca2(+)-stimulated enzyme activity. In the cerebral cortex 5-HT exerted a biphasic stimulatory effect on adenylate cyclase activity in the absence of Ca2+ (EC50 = 0.2 +/- 0.04 nM and 10 +/- 3 microM), whereas 8-OH-DPAT, 5-CT and 2-CH3-5-HT exerted a monophasic effect. In the presence of Ca2+ (1.5 microM), low concentrations of 5-HT, 8-OH-DPAT, 5-CT and 2-CH3-5-HT potentiated adenylate cyclase activity, whereas higher concentrations, except 2-CH3-5-HT, inhibited the enzyme activity. We propose that the 5-HT receptor mediating inhibition of Ca2(+)-stimulated adenylate cyclase in the rat hippocampus corresponds to the 5-HT1A subtype.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced histamine- and β-adrenoceptor-mediated cyclic AMP formation in leukocytes from patients with endogenous depression

Beta-adrenoceptor-mediated cyclic AMP formation was found to be increased in leukocytes from manic-depressive patients during untreated depression when compared with euthymic patients treated with antidepressants. The difference was dependent on the stimulation used (isoprenaline or a combination of noradrenaline and phentolamine) and was only significant when the combination was used. Histamine-stimulated cyclic AMP formation in leukocytes was enhanced in patients with untreated depression, both when compared with euthymic patients suffering from manic-depressive illness, with or without treatment with antidepressant drugs, and also when compared with control persons without any known psychiatric disease. Although at variance with the results of some other studies on the same topic, the results of the present study indicate that changes in receptor function in leukocytes may be a state-dependent marker in depressive illness.

Lithium ved tvangsneuroser En dobbelt-blind terapeutisk undersøgelse

Lithium and obsessive-compulsive neurosis. A double-blind therapeutic trialIn a double-blind therapeutic cross-over trial on six patients suffering from severe obsessive-compulsive symptoms lithium was as ineffective as placebo.Lithium and obsessive-compulsive neurosis. A double-blind therapeutic trialIn a double-blind therapeutic cross-over trial on six patients suffering from severe obsessive-compulsive symptoms lithium was as ineffective as placebo.

A comparative study on the effects of tetracyclines and lithium on the cyclic AMP second messenger system in rat brain

1. This study was aimed at investigating the effects of demeclocycline (DMC), minocycline (MC), and lithium (Li) in vitro on cyclic AMP (cAMP) accumulation in rat cerebral cortex stimulated by noradrenaline, forskolin, and ouabain. 2. DMC, MC, and Li dose-dependently reduced noradrenaline-stimulated cAMP formation in cortical slices, but only Li inhibited the cAMP formation induced by forskolin. 3. In contrast to Li, DMC and MC did not affect noradrenaline-stimulated adenylate cyclase activity in cortical membranes. 4. In cortical slices, ouabain stimulated the cAMP production (required the presence of extracellular Ca2+ and was blocked by verapamil). Ouabain-stimulated cAMP accumulation in cortical slices was inhibited by DMC, MC, and Li. 5. DMC and MC do not seem to interact directly with the adenylate cyclase as reported for Li. It is concluded that the tetracyclines, DMC and MC, affect the cAMP signaling system in rat brain by mechanisms that differ from that of Li. The decreased receptor agonist-stimulated cAMP production in cortical slices in the presence of DMC and MC may be due to the Ca(2+)-chelating ability of these tetracyclines.