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1. We have given an oral load of lithium carbonate to healthy volunteers in order to investigate the transport of lithium across the erythrocyte membrane in vivo and the effects of known inhibitors of that transport. 2. Using this technique we have shown that pretreatment with either digoxin, an inhibitor of the sodium/potassium pump, or dipyridamole, an inhibitor of the anion transporter, does not alter the plasma or erythrocyte lithium concentration profiles, nor any of the pharmacokinetic variables derived from these data, and we conclude that these two transport pathways do not contribute significantly to the in vivo handling of lithium by erythrocytes. 3. We have also shown that erythrocyte lithium concentrations measured directly differ significantly from the predicted concentrations calculated using the two-compartment pharmacokinetic model which has been used in some earlier comparisons of in vitro and in vivo lithium handling. 4. We suggest that the in vivo administration of lithium carbonate may permit a specific measure of the in vivo activity of the sodium/sodium countertransport pathway. [ABSTRACT FROM AUTHOR]

The effects of aspirin on the metabolism of phosphoinositides in human platelets were studied in vitro and in vivo. Eight volunteers received, at two-weekly intervals, a single dose of 10, 30, 100 or 600 mg aspirin. Before the first dose platelets were taken and incubated in vitro with a range of concentrations (10 nM-100 microM) of aspirin. Formation of inositol phosphates (IP) was measured in [3H]-inositol labelled platelets after incubation with collagen and thrombin for 30 min, a time at which a maximal increase in [3H]-IP was observed. The in vitro IC50 for inhibition of the response to collagen by aspirin was approximately 1 microM; the in vivo ID50 was 40-50 mg. Aspirin did not fully inhibit the collagen stimulated IP formation either in vitro or in vivo, and the response to thrombin was unaffected. The ID50 and IC50 of aspirin is thus in accord with the doses of aspirin associated with inhibition of platelet aggregation and thromboxane production in other studies. The possible relevance of these data to the clinical uses of aspirin is discussed. [ABSTRACT FROM AUTHOR]

We have quantified specific [3H]-ouabain binding sites in normal human lymphocytes, and have measured the changes in the numbers of those sites which occur in response to various stimuli. We have confirmed previous findings that incubation for 72 h in the presence of fetal calf serum causes an increase in [3H]-ouabain binding, and that this does not occur if the cells are incubated in fetal calf serum which has first been dialysed. During incubation of the lymphocytes for 3 days in the presence of dialysed fetal calf serum each of the following stimuli caused an increase in specific [3H]-ouabain binding: addition of ethacrynic acid (1 mumol l-1), addition of lithium (1 mmol l-1), and reduction of the external potassium concentration (to 0.75 mmol l-1). By analogy with the similar results in HeLa cells reported by others, we suggest that the increase in [3H]-ouabain binding may, in the case of ethacrynic acid and the reduction of the external potassium concentration, be initiated by an increase in the intracellular sodium concentration. The mechanisms whereby fetal calf serum and lithium cause an increase in [3H]-ouabain binding are not clear. [ABSTRACT FROM AUTHOR]

We have studied the effects of digoxin on cation transport in vivo by measuring the changes in plasma and red cell rubidium concentrations following an oral load of rubidium chloride. In eight patients who had been taking digoxin for 7 to 10 days (mean plasma digoxin concentration 1.3 ng ml-1) the rise in plasma rubidium concentrations was enhanced and the rise in red cell rubidium concentrations was attenuated following the oral load of rubidium chloride, by comparison with the changes in well-matched controls. In contrast, the disposition of rubidium was not altered in 12 patients who had been taking digoxin for more than 3 months (mean plasma digoxin concentration 1.1 ng ml-1). These results suggest that the inhibitory effects of digoxin on cation transport are detectable in vivo during short-term therapy, but not during long-term therapy, and confirm our previous in vitro findings. [ABSTRACT FROM AUTHOR]

Plasma melatonin was used to determine overall beta-adrenergic transmission through pineal neuro-effector junctions during desmethylimipramine (DMI) treatment in 10 normal subjects. Changes in plasma melatonin indicated that an initial increase in noradrenaline (NA) transmission produced by DMI was counteracted by adaptive changes which restored transmission to normal by the third week of treatment. A 'rebound' increase in NA transmission was seen on DMI withdrawal. The results suggest that the adaptive changes which occur in NA synapses during DMI treatment do not, as has been proposed, decrease NA transmission below normal levels, but instead restore homeostasis in the presence of the drug. [ABSTRACT FROM AUTHOR]

Using a [3H]-lysergic acid diethylamide [(3H]-LSD) binding technique, platelet 5-hydroxytryptamine (5-HT) receptor number and affinity were compared in schizophrenics treated with depot thioxanthenes and phenothiazines and controls. There was an approximately 30% increase in platelet receptor number (Bmax) in the patient group. There was a decrease in affinity (increase in Kd) of about 30% in the patient group. This was probably due to the persistence of the neuroleptic in the platelet membrane preparation. There was a weak positive correlation between receptor number and total neuroleptic dosage. The increased number of 5-HT receptors is consistent with the previously reported enhancement of 5-HT-induced platelet aggregation in patients treated with long-term phenothiazines and thioxanthenes. Our findings are compatible with 5-HT up-regulation in human platelets produced by depot neuroleptic therapy. It is not known whether parallel changes may be occurring in brain 5-HT receptors. [ABSTRACT FROM AUTHOR]

We have studied the specific binding of [3H]-ouabain to intact mononuclear leucocytes (82% lymphocytes) and polymorphonuclear leucocytes. In both types of cells [3H]-ouabain binding was saturable, confined to a single site of high affinity, slow to reach equilibrium, slow to reverse, temperature-dependent, competitively antagonized by potassium, and facilitated by the presence of divalent cations. The equilibrium dissociation constants were 2.4 +/- 0.7 nmol/l (polymorphs) and 2.4 +/- 0.4 nmol/l (mononuclear cells) (NS). The values of maximal specific ouabain binding, measured by Scatchard analysis of concentration vs binding curves (Bmax), were 33.9 +/- 6.0 fmol/10(6) cells (polymorphs) and 59.3 +/- 11.6 fmol/10(6) cells (mononuclear cells) (P less than 0.02). The corresponding numbers of sites per cell were 20415 +/- 3616 and 35712 +/- 6986 respectively (P less than 0.02). When the numbers of binding sites were expressed per square micron of cell surface area the difference between the two cell types was proportionately greater (83 and 186 sites per micron 2 respectively). We conclude that the [3H]-ouabain binding sites on mononuclear and polymorphonuclear leucocytes are similar in nature, but different in both number and density on the cell surface. Measurements of Bmax in mixed cell populations should therefore take account of cell type as well as cell size and number. [ABSTRACT FROM AUTHOR]

1 The effects of treatment with a range of neuroleptic drugs on 5- hydroxytryptamine (5-HT) induced platelet aggregation in vivo were examined in a group of recently admitted psychiatric patients and in a larger group of chronic schizophrenic patients. 2 Five of seven recently admitted patients treated with chlorpromazine showed enhanced aggregation. Four of seven patients treated with fluphenazine, flupenthixol, trifluoperazine and haloperidol showed enhancement. 3 Enhanced aggregation responses were observed in only 20% of chronic schizophrenic patients being treated with a neuroleptic drug. 4 The relationship between changes in platelet aggregation and clinical changes in recently admitted patients was variable and platelet aggregation responses were not predictive of response to treatment. 5 Chronic schizophrenic patients with enhanced aggregation showed significant week to week variation in platelet aggregation response. Variability of responses was not related to the drug used or to the dose administered. There was some evidence that higher plasma concentrations of neuroleptic drugs were associated with enhanced platelet aggregation responses. 6 Treatment with neuroleptic drugs leads to enhancement of platelet aggregation responses induced by 5-HT. The frequency and reliability with which such responses can be elicited is unpredictable and the value of platelet aggregation responses as an empirical guide to treatment with neuroleptic drugs is therefore open to question. [ABSTRACT FROM AUTHOR]

1 The aggregation response of platelets induced by 5-HT was greatly increased in psychiatric patients receiving chlorpromazine therapy when compared with normal volunteers and psychiatric patients not receiving chlorpromazine. 2 Platelet aggregation responses to ADP were normal during chlorpromazine therapy, but 5-HT induced aggregation was increased in rate and the typical transient reversible response was converted to an irreversible response in all subjects. This was usually indistinguishable from the ADP response. 3 When chlorpromazine therapy was stopped, plasma concentrations of chlorpromazine, monodesmethylchlorpromazine and chlorpromazine sulphoxide fell rapidly within one week, whereas 5-HT induced platelet aggregation responses became normal after three weeks. The enhanced responses returned when chlorpromazine therapy was re-instituted. 4 It is possible that platelet aggregation responses to 5-HT in vitro could prove to be a useful index of the pharmacological effect of chlorpromazine in vivo. [ABSTRACT FROM AUTHOR]

1 The reliability of 5-hydroxytryptamine induced platelet aggregation responses in psychiatric patients treated with neuroleptic drugs was investigated by examining the effects of a number of technical factors which could account for the variability of responses observed in some patients. 2 Variation in incubation time, temperature, aggregometer stirrer speed, and in the time interval between withdrawal of the blood sample and testing, had no significant effects on the consistency of responses. 3 Dilution of platelet rich plasma (PRP) led to enhanced platelet aggregation responses becoming non-enhanced. 4 Overcentrifugation of blood samples during the preparation of PRP caused a decrease in the incidence of enhanced platelet aggregation responses observed in chronic schizophrenic patients receiving chlorpromazine. 5 The reliability of platelet aggregation responses as indices of the action of neuroleptic drugs in psychiatric patients remains doubtful. [ABSTRACT FROM AUTHOR]

1 Previous work showed that platelets from patients receiving chlorpromazine (CPZ) have an enhanced aggregation response to 5-HT. This was caused by an action of CPZ on the platelets, a factor borne by the plasma, or both. 2 Therefore we studied 5-HT induced aggregation of platelets from CPZ treated patients resuspended in normal plasma and from normal subjects resuspended in CPZ plasma. 3 Aggregation responses of normal platelets to 5-HT were not enhanced by resuspension either in normal plasma or in CPZ plasma. In addition the enhanced responses of platelets from CPZ treated patients did not revert to normal after resuspension in normal plasma. 4 It is concluded that the enhanced aggregation response to 5-HT seen after CPZ treatment is due to a change in the properties of the platelets rather than a factor in the plasma. [ABSTRACT FROM AUTHOR]

It has recently been suggested that an increase in brain-derived neurotrophic factor (BDNF) expression may mediate some of the therapeutic effect of antidepressant drugs, via their effects on the neurotransmitter 5-hydroxytryptamine (5-HT). However, because it is unclear whether 5-HT manipulations directly affect BDNF expression, we examined BDNF mRNA levels in C6 glioma cells following incubation with 5-HT using reverse transcription polymerase chain reaction (RT-PCR) and Northern blot analysis. Incubation of C6 glioma cells with 5-HT increased the BDNF mRNA expression approx twofold. The effect of 5-HT (100 microM) was inhibited by a 5-HT2A receptor antagonist (ketanserin; 1 microM). The RNA synthesis inhibitor (actinomycin D; 10 microg/mL), but not a protein synthesis inhibitor (cycloheximide; 0.5 microg/mL) blocked the effect of 5-HT. Furthermore, incubation of C6 glioma cells with EGTA (1 mM), a protein kinase inhibitor (staurosporine; 1 microM), the Ca2+ ATPase inhibitor thapsigargin (1 microM), or a calcium/calmodulin-dependent kinase inhibitor (KN 62; 1 microM) inhibited the response to 5-HT. Our data show that 5-HT increases de novo BDNF mRNA synthesis following direct activation of the 5-HT2A receptor, via a calcium-dependent and protein kinase-dependent pathway.

We have used intracellular recording techniques to examine the effects of 5-hydroxytryptamine (5-HT, serotonin) on 5-HT-containing neurones of the guinea pig dorsal raphe nucleus in vitro. Bath-applied 5-HT (30-300 microM) had two opposing effects on the membrane excitability of these cells, reflecting the activation of distinct 5-HT receptor subtypes. As demonstrated previously in the rat, 5-HT evoked a hyperpolarization and inhibition of 5-HT neurones, which appeared to involve the activation of an inwardly rectifying K(+) conductance. This hyperpolarizing response was blocked by the 5-HT(1A) receptor-selective antagonist WAY-100635 (30-100 nM). In the presence of WAY-100635, 5-HT induced a previously unreported depolarizing, excitatory response of these cells, which was often associated with an increase in the apparent input resistance of the neurone, likely due to the suppression of a K(+) conductance. Like the hyperpolarizing response to 5-HT, this depolarization could be recorded in the presence of the Na(+) channel blocker tetrodotoxin. In addition, the response was not significantly attenuated by the alpha(1)-adrenoceptor antagonist prazosin (500 nM), indicating that it is not due to the release of noradrenaline, or to the direct activation of alpha(1)-adrenoceptors by 5-HT. The 5-HT(3) receptor antagonist granisetron (1 microM) and the 5-HT(4) receptor antagonist SB 204070 (100 nM) failed to reduce the depolarizing response to 5-HT; however, ketanserin (100 nM), mesulergine (100 nM) and lysergic acid diethylamide (1 microM) significantly reduced or abolished the depolarization, indicating that this effect of 5-HT is mediated by 5-HT(2) receptors.

The aim of the present study was to determine the influence of thyroid hormone, T3, on the regulation of hippocampal BDNF expression by 5-HT receptor agonists. Chronic T3 administration prior to treatment with the 5-HT(1A) agonist, 8-OH-DPAT, significantly decreased BDNF mRNA in the dentate gyrus region of the hippocampus. Administration of 8-OH-DPAT did not alter hippocampal BDNF mRNA expression in naive, euthyroid rats. Pretreatment with the 5-HT(1A) antagonist, WAY 100635, completely blocked the 8-OH-DPAT-induced down-regulation of BDNF mRNA in chronic T3-treated rats. Acute T3 administration prior to 8-OH-DPAT treatment led to a small, but significant, decrease in hippocampal dentate gyrus BDNF mRNA. Acute or chronic administration of T3 did not alter the decrease in hippocampal BDNF mRNA induced by the 5-HT(2A/2C) receptor agonist, DOI. The influence of 8-OH-DPAT and DOI on hippocampal BDNF mRNA was also unaltered in rats rendered hypothyroid by propylthiouracil administration. Chronic T3 treatment or hypothyroidism did not influence the basal expression of hippocampal BDNF mRNA. The affinity and density of 5-HT(1A) receptors, and the hippocampal expression of 5-HT(1A) mRNA were also not influenced by chronic T3 treatment. The results of this study clearly demonstrate a powerful interaction between thyroid hormone and the 5-HT(1A) receptor in the regulation of hippocampal BDNF expression. Crosstalk between signal transduction cascades influenced by T3 and 5-HT(1A) receptors may mediate the synergistic effects of these systems on hippocampal BDNF expression.

Arc (activity regulated, cytoskeleton associated protein) is an effector immediate early gene that is selectively localized in the neuronal dendrites. Elevation of brain 5-HT by the combined administration of the monoamine oxidase inhibitor, tranylcypromine (TCP, 5 mg/kg, i.p.), and the 5-HT precursor L-tryptophan (L-TP, 100 mg/kg, i.p.), increased Arc mRNA abundance in the cingulate, orbital, frontal and parietal cortices as well as in the striatum but a reduction was observed in the CA1 region of the hippocampus. The 5-HT releasing agent p-chloroamphetamine (PCA, 5 mg/kg, s.c.) also increased Arc mRNA in the cortical and striatal areas. Depleting brain 5-HT with the tryptophan hydroxylase inhibitor, p-chlorophenylalanine (pCPA, 300 mg/kg, i.p. for two days), on the other hand, significantly attenuated the increase in Arc mRNA induced by tranylcypromine and L-tryptophan (TCP/L-TP). Pretreatment with the 5-HT2 receptor antagonist ketanserin (2 mg/kg, i.p.) significantly attenuated the effect of TCP/L-TP in the cortex but only partially in striatum and did not affect the reduction in the CA1 region. The 5-HT2 agonist DOI (0.2, 1 and 2 mg/kg, i.p.) dose-dependently increased Arc mRNA abundance in cortical areas with a pattern similar to that of TCP/L-TP and PCA. DOI, however, had much weaker effects on Arc mRNA in the striatum and did not have any significant effect in the CA1, CA3 and the dentate gyms (DG) of the hippocampus. Pretreatment with ketanserin completely blocked the effect of DOI on Arc expression. These data suggest that Arc mRNA expression can be induced in the cortex by increases in extracellular 5-HT and that 5-HT2 receptors play a major part in mediating such effects. Additional 5-HT receptors as well as other neurotransmitters may also be involved, particularly in the striatum and in CA1 subfield of the hippocampus. Overall, our data suggest that expression of Arc mRNA is highly responsive to changes in brain 5-HT functions, and may provide a sensitive marker of postsynaptic 5-HT2(2A and 2C) receptor functions.

This study reports the effect of repeated electroconvulsive shock on the sprouting of 5-hydroxytryptamine neurons in the partly lesioned rat dorsal hippocampus. We have adopted a 5-hydroxytryptamine homotypic collateral sprouting model to examine whether electroconvulsive shock administration altered the rate of 5-hydroxytryptamine axonal reinnervation of the dorsal hippocampus. The 5-hydroxytryptamine innervation of hippocampus originates from the median raphe via the cingulum bundle and the fimbria-fornix. Lesioning of the cingulum bundle has previously been shown to cause sprouting of intact 5-hydroxytryptamine afferents originating from the unharmed fimbria-fornix. Rats were unilaterally injected with the 5-hydroxytryptamine neurotoxin, 5,7-dihydroxytryptamine, into the right cingulum bundle and 5-hydroxytryptamine immunoreactivity in the dorsal hippocampus was investigated 1, 3, 6 and 12weeks after the injection. The lowest level of 5-hydroxytryptamine-immunoreactivity in the hippocampus was detected at three weeks after the lesion. At six weeks, 5-hydroxytryptamine immunoreactive fibres started to reappear, and at 12weeks the level of 5-hydroxytryptamine immunoreactivity was similar to that observed on the unlesioned side. Based on this time-course, six weeks was chosen as the time-point to investigate the action of a course of repeated electroconvulsive shock administrations. Repeated electroconvulsive shock (five shocks over 10days) doubled the number of sprouting 5-hydroxytryptamine-immunoreactive fibres and significantly increased levels of the 5-hydroxytryptamine metabolite, 5-hydroxyindoleacetic acid. The present data provide the first direct evidence that electroconvulsive shock enhances 5-hydroxytryptamine axon sprouting in the partly lesioned hippocampus. This is an effect which may contribute to the therapeutic effect of electroconvulsive therapy in major depression.

The aim of the present study was to investigate whether changes in brain 5-HT concentrations affect the expression of BDNF mRNA in rat brain. Brain 5-HT concentration in the rat was elevated by combined treatment with tranylcypromine and L-tryptophan, tranylcypromine alone, by a single dose of the 5-HT releasing agent p-chloroamphetamine (PCA) or by the selective 5-HT reuptake inhibitor paroxetine. 5-HT was depleted by either multiple p-chlorophenylalanine (pCPA) or PCA injections. The extent of 5-HT depletion following pCPA or PCA was monitored using 5-HT immunocytochemistry. BDNF mRNA abundance in treated rats and the corresponding vehicle injected control rats was studied by in situ hybridization histochemistry (ISHH). Two hours after the combined administration of tranylcypromine and L-tryptophan BDNF mRNA abundance in the dentate gyrus was significantly decreased but increased in the frontal cortex. Tranylcypromine alone or a single injection of PCA had similar effects on BDNF mRNA expression to the combination of tranylcypromine and L-tryptophan, i.e. they caused significant reductions of BDNF mRNA expression in dentate gyrus and increased it in frontal cortex. Paroxetine also reduced BDNF mRNA in DG but was without effect in frontal cortex. Multiple injections of both pCPA or PCA resulted in marked reductions of 5-HT immunoreactive axons in the hippocampus, pCPA being more effective. Both drugs significantly increased BDNF mRNA abundances in the dentate gyrus. Multiple PCA injections also increased BDNF mRNA expression in parietal cortex, while pCPA induced 5-HT depletion was ineffective. These results suggests that 5-HT modulates BDNF mRNA levels in rat brain.

G-protein-activated inward rectifier potassium channels are coupled to a number of neurotransmitter receptors, including some monoamine receptors. In the present study we have investigated the effect of electroconvulsive shock on gene expression of the G-protein-activated inward rectifier potassium channel subunits G-protein-coupled inward rectifier K+-channel (GIRK1) and GIRK2 in the rat brain using in situ hybridization and immunocytochemistry. Acute electroconvulsive shock (a single shock) increased GIRK2 expression while causing a transient reduction of the messenger RNA abundance of GIRK1 in granule cells of the dentate gyrus. Chronic electroconvulsive shock (five shocks over 10 days) caused a larger increase in GIRK2 messenger RNA abundance, which was accompanied by an increase in GIRK2 immunoreactivity in the molecular layer of the dentate gyrus. Unlike for acute electroconvulsive shock, GIRK1 messenger RNA abundance in the dentate gyrus was significantly increased after chronic electroconvulsive shock. No significant alterations in GIRK1 and GIRK2 messenger RNA abundance were detected in the other brain regions studied, including the CA1 and CA3 subfields of the hippocampus, the frontal-parietal cortex and piriform cortex. The neuroanatomically specific changes in expression of the potassium channel subunits may directly influence neuronal excitability as well as the functions of G-protein-coupled neurotransmitter receptors.

Background: Reports of abnormalities of potassium-channel function in various cultured cells of Alzheimer's disease patients led us to attempt to characterise the pharmacological characteristics of the abnormal channel., Methods: We studied platelets from 14 patients with Alzheimer-type dementia and 14 non-demented controls matched for age and sex. The effects of specific inhibitors of K+ channels on the efflux of rubidium-86 ions, a radioactive analogue of K+, from the platelets were measured., Findings: Normal platelets contain three types of K+ channel, sensitive to the inhibitory actions of apamin (small-conductance calcium-dependent potassium channels), charybdotoxin (of less specificity, but probably intermediate-conductance calcium-dependent K+ channels), and alpha-dendrotoxin (voltage-sensitive K+ channels). However, 8Rb+ efflux from the platelets of patients with Alzheimer-type dementia was not inhibited by either apamin or charybdotoxin. By contrast, inhibition by alpha-dendrotoxin did occur., Interpretation: Our results suggest that calcium-dependent K+ channels in platelets are selectively impaired in Alzheimer's disease. A similar abnormality in neurons could contribute to the pathophysiology of the disorder.

Quinine and quinidine are reported to potentiate the behavioural effects of serotonergic agents and monoamine uptake inhibitors. We have therefore investigated the presynaptic actions of quinine and quinidine on monoamine uptake and release in rat brain tissue in vitro. Quinidine evoked the release of [3H]5-HT, [3H]noradrenaline and [3H]dopamine from pre-loaded rat brain slices in a concentration dependent manner with EC50 values of 175, 486 and 150 microM, respectively. Quinine induced [3H]monoamine release with similar potencies. Both quinine and quinidine also inhibited the active uptake of [3H]5-HT, [3H]noradrenaline and [3H]dopamine into rat brain synaptosomes with IC50 values in the range 0.13-12.4 microM. The potency of each drug to inhibit [3H]5-HT uptake was significantly higher than that for [3H]noradrenaline or [3H]dopamine. The relative potency of quinidine compared to quinine was more marked in the case of [3H]5-HT (58-fold) than for [3H]noradrenaline (3-fold) or [3H]dopamine (4-fold). The inhibition of [3H]5-HT uptake by quinine and quinidine was competitive in nature and corresponded with the potencies of these drugs to inhibit [3H]paroxetine binding. No correlation was observed between the potencies of quinine and quinidine to induce the release of [3H]monoamines and to inhibit their uptake, suggesting that these effects are mediated by two distinct mechanisms. We conclude that the presynaptic actions of quinine and quinidine on monoamine uptake and release may be implicated in their potentiation of the effects of serotonergic agents and uptake blockers.

Brain-derived neurotrophic factor (BDNF) is known to modulate synaptic function as well as to promote neuronal growth in the adult brain. The aim of the present study was to compare the duration of electroconvulsive shock (ECS)-induced BDNF gene expression following a single shock (acute ECS) to the more clinically relevant situation, where repeated shocks (chronic ECS) are administered. For this purpose, we have used quantitative in situ hybridisation with a 35S-labelled oligonucleotide probe complementary to mRNAs encoding genes for all forms of BDNF. The results confirm previous studies that the administration of ECS increases BDNF mRNA abundance in parts of rat brain with particularly marked changes in the granule cell layer of the dentate gyrus. We also for the first time show the long lasting nature of the increase in BDNF mRNA abundance measured after chronic ECS, i.e., significant increases in BDNF mRNA persisted up to 48 h after the last shock. Acute ECS at 6 h after the shock produced a slightly more pronounced effect on BDNF mRNA abundance than chronic ECS 6 h after the last shock. However, this change was not detectable already 24 h after a single ECS. These results indicate that repeated ECS induces adaptive changes in BDNF mRNA expression., (Copyright 1998 Elsevier Science B.V. All rights reserved.)