Alterations in serum and brain trace element levels after antidepressant treatment

We have studied the effect of chronic treatment with imipramine, citalopram and electroconvulsive shock (ECS) on serum and brain zinc levels in rats. Chronic treatment with citalopram (but not with imipramine or ECS) significantly (approx 20%) increased the serum zinc level. Chronic treatment with both drugs slightly (by approx 10%) increase the zinc level in the hippocampus and slightly decreased it in the cortex, cerebellum and basal forebrain. Calculation of the ratio hippocampus/brain region within each group demonstrated a significantly (approx 20%) higher value after treatment with either imipramine or citalopram. Moreover, chronic ECS induced a significant increase (by 30%) in the zinc level in the hippocampus and also a slight increase (by 11–15%) in the other brain regions. Thus, these different antidepressant therapies induced an elevation of the hippocampal zinc concentration, which indicates a significant role of zinc in the mechanism of antidepressant therapy.     

Chronic treatment with zinc and antidepressants induces enhancement of presynaptic/extracellular zinc concentration in the rat prefrontal cortex

Zinc exhibits antidepressant-like activity in preclinical tests/models. Moreover, zinc homeostasis is implicated in the pathophysiology of affective disorders. The aim of the present study was to examine the effect of chronic zinc, citalopram and imipramine intraperitoneal administration on the presynaptic and extracellular zinc concentration in the rat prefrontal cortex and hippocampus. We used two methods: zinc–selenium histochemistry (which images the pool of presynaptic-vesicle zinc) and anodic stripping voltammetry (ASV) for zinc determination in microdialysate (which assays the extracellular zinc concentration). We report that chronic (14×) zinc (hydroaspartate, 10 and 65 mg/kg) and citalopram (20 mg/kg) administration increased the pool of presynaptic zinc (by 34, 50 and 37%, respectively) in the rat prefrontal cortex. The 21% increase induced by imipramine (20 mg/kg) was marginally significant. Likewise, zinc (hydroaspartate, 65 mg/kg), citalopram and imipramine increased the extracellular zinc (although with a different pattern: time point, area under the curve and/or basal level) in this brain region. Furthermore, zinc induced an increase in presynaptic (by 65%) and extracellular zinc (by 90%) in the hippocampus, while both citalopram and imipramine did not. These results indicate that all of the treatments increase presynaptic/extracellular zinc concentrations in the rat prefrontal cortex, which may then contribute to their antidepressant mechanisms. Alterations induced by zinc (but not antidepressants) administration in the hippocampus may be related to specific zinc mechanisms. All the data (previous and present) on the effect of antidepressant treatments on the presynaptic/extracellular zinc concentrations suggest the involvement of this biometal presynaptic/synaptic homeostasis in the antidepressant mechanism(s).     

G(olf) protein levels in rat striatum are increased by chronic antidepressant administration and decreased by olfactory bulbectomy

There are many studies of the mechanisms of antidepressants; however, most of these studies were conducted on the hippocampus or frontal cortex. In the present study, we hypothesized that the nucleus accumbens and caudate/putamen might be major targets for antidepressant effects. Thus, we focused on G(olf) protein, a stimulant alpha-subunit of G protein that is coupled with the dopamine D1 receptor and specifically expressed in the striatum (nucleus accumbens, caudate/putamen and olfactory tubercle) in the rat brain. We examined the effects of chronic administration of imipramine, fluvoxamine, maprotiline and, as a negative control, cocaine on the level of G(olf) protein in the rat striatum. We also examined the effect of olfactory bulbectomy. Chronic imipramine treatment (10 mg/kg for 2 or 4 weeks) significantly increased the level of G(olf) in the striatum (by 17% or 18%, respectively), although this increase was not apparent after only 1 week of treatment. The time course of these changes corresponded well to that of the clinical efficacy of imipramine. Chronic fluvoxamine and maprotiline treatment (20 mg/kg for 2 weeks) also significantly increased the level of G(olf) (by 9% and 25%, respectively), but cocaine did not alter it significantly. Bulbectomy decreased the G(olf) protein level by 9%. The increases in G(olf) protein after chronic administration of these three different classes of antidepressants and the decrease after bulbectomy suggest that G(olf) protein may play an important role in the antidepressant effect.     

Chronic electroconvulsive shock decreases (+/-) 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI)-induced wet-dog shake behaviors of dexamethasone-treated rats

Electroconvulsive shock (ECS) therapy is considered to be an effective treatment for depression, but its mechanism of action is still unknown. We investigated the effect of chronic ECS in rats treated for 14 days with dexamethasone (Dex), a glucocorticoid receptor agonist. Chronic injection of sesame oil decreased body weight change and increased serotonin (5-HT)-2A receptor number and DOI (5-HT-2A, 2C receptor agonist)-induced wet-dog shake (WDS) behaviors. Dex treatment for 14 days decreased body weight of rats, but repeated ECS did not reverse this decrease. Dex also abolished plasma corticosterone levels, and ECS failed to restore these levels. These results indicate that chronic ECS does not antagonize the effect of Dex. The treatment with Dex increased 5-HT-2A receptor binding density of rat frontal cortex and the number of DOI-induced WDS behaviors. Chronic ECS reduced the enhanced WDS behaviors by Dex but had little effect on receptor density. These results suggest that chronic ECS might suppress 5-HT-2A receptor function at the postreceptor signaling level rather than at the receptor itself, without changing HPA axis function in Dex-treated rats.     

Pharmacokinetics of imipramine are affected by age and sex in rats

Chronic treatment with the antidepressant imipramine (IMI) leads to accumulation of imipramine's major metabolite desmethylimipramine (DMI) in the brain. Juvenile, young and middle-aged female rats, as well as juvenile and young male rats were treated chronically with imipramine (14 days) and analyzed 24 hours later for levels of IMI and DMI in the hypothalamus-preoptic area (HPA) and serum. Older animals of both sexes showed higher levels of DMI than juvenile animals, in both the HPA and serum. Females also had higher DMI levels than males at comparable ages. Analysis of IMI and DMI levels at intervals after a single imipramine injection suggested that the initial metabolism of imipramine is slower in older animals and in females (compared to males). The results indicate that age and gender alter the initial metabolism of imipramine, leading to enhanced accumulation of metabolites during chronic treatment in older animals and in female rats, compared to younger rats and males, respectively.     

Chronic Antidepressant Administration Alters the Subcellular Distribution of Cyclic AMP-Dependent Protein Kinase in Rat Frontal Cortex

The influence of chronic administration of antidepressants on cyclic AMP-dependent protein kinase activity was examined in rat frontal cortex. Chronic administration of imipramine, tranylcypromine, or electroconvulsive seizures decreased cyclic AMP-dependent protein kinase activity in soluble fractions by approximately 25%, whereas enzyme activity was increased in the particulate fractions by approximately 20%. In contrast, enzyme activity in crude homogenates was not altered. This effect appears to be specific to antidepressant drugs, because representatives of several other classes of psychotropic drugs-namely, haloperidol, morphine, and diazepam--failed to alter either soluble or particulate levels of cyclic AMP-dependent protein kinase activity in this brain region following chronic administration. When the total particulate fraction was subfractionated, it was found that chronic imipramine treatment significantly increased the activity of cyclic AMP-dependent protein kinase in crude nuclear fractions but not in crude synaptosomal or microsomal fractions. Taken together, the data raise the possibility that chronic antidepressant treatments may stimulate the translocation of cyclic AMP-dependent protein kinase from the cytosol to the nucleus. This effect would represent a novel action of antidepressants that could contribute to the long-term adaptive changes in brain thought to be essential for the clinical actions of these treatments.     

Repeated treatment with mirtazepine induces brain-derived neurotrophic factor gene expression in rats.

Recent studies indicate a role of the brain-derived neurotrophic factor (BDNF) in the pathophysiology of depression, as well as in the mechanism of action of antidepressant drugs (ADs). It has been shown that serum BDNF levels are decreased in depressed patients. Moreover, antidepressant treatment increases serum BDNF levels and it is positively correlated with medication response. In addition, repeated administration of ADs induces an increase in rat hippocampal or cortical BDNF gene expression. Since the most potent effect of ADs on BDNF gene expression was found after prolonged treatment, in the present study we investigated the influence of repeated treatment (twice daily for 14 days) of the new AD mirtazapine (5 or 10 mg/kg) on BDNF mRNA level (the Northern blot) in rat hippocampus and cerebral cortex. Imipramine was used as a reference compound. The experiment was carried out on male Wistar rats. The tissue for biochemical assays was collected 24 h after the last doses of mirtazapine and imipramine. We also studied the effect of repeated mirtazapine on the action of the 5-HT2A receptor agonist (+/-)DOI in the behavioral test (head twitches induced by (+/-)DOI) in rats. The obtained results showed that, like imipramine (10 mg/kg), mirtazapine (10 mg/kg) increased BDNF gene expression in both the examined brain regions: in the hippocampus by 24.0 and 26.5%, in the cerebral cortex by 29.9 and 41.5%, respectively, compared with the vehicle-treated control. Neither mirtazapine nor imipramine administered repeatedly at a lower dose (5 mg/kg) significantly changed BDNF mRNA levels in the hippocampus and cerebral cortex. Repeated treatment with mirtazapine (10, but not 5 mg/kg) inhibited the behavioral syndrome induced by (+/-)DOI. This study provides first conclusive evidence that repeated mirtazapine administration increases BDNF mRNA levels; moreover, it indicates that the enhancement of BDNF gene expression may be essential for the clinical effect of mirtazapine.     

Chronic treatment with antidepressants prevents the inhibitory effect of small doses of apomorphine on dopamine synthesis and motor activity.

In control rats small doses of apomorphine (25 to 100 μg/kg) decreased motor activity and reduced DOPAC content in the caudate nucleus. A larger dose (500 μg/kg) increased motor activity and elicited stereotypy. Chronic treatment with imipramine, amitryptiline and mianserine (10, 10 and 2.5 mg/kg twice daily for 10 days respectively) counteracted or reversed the effect of small doses of apomorphine on motor activity, left DOPAC content unchanged and potentiated the central stimulant response to the larger dose of apomorphine. Changes in apomorphine responses were observed after ten but not after two days of imipramine treatment and persisted unaltered up to 4 days after imipramine withdrawal. It is suggested that chronic treatment with antidepressants induces persistent subsensitivity in presynaptic dopamine receptors. The relevance of the findings in the therapeutic effect of these drugs is discussed.     

Altered response to GABAergic agents following electro and chemo convulsions in mice.

Effects of GABAergic agents and that of electroconvulsive shock (ECS) treatment were studied on bicuculline and picrotoxin (PTX)-induced convulsions in mice. Neither acute nor chronic ECS had any significant effect on bicuculline-induced convulsions, whereas the latency for PTX-induced convulsions was delayed by both acute and chronic ECS. Baclofen treatment delayed significantly the latency for PTX-induced convulsions in animals which were subjected to both acute and chronic ECS, whereas in bicuculline-induced convulsions, it shortened the latency of convulsions 24 hr after acute ECS. Progabide delayed the bicuculline-induced convulsions except in the case of 24 hr after acute ECS and PTX-induced convulsions except in the case of animals treated chronically with ECS. Fengabine showed no significant effect on bicuculline-induced convulsions. However, on PTX-induced convulsions, the latency was delayed in animals not subjected to ECS and in those subjected to chronic ECS. The possible explanations for the alterations in the effect of GABAergic agents following electro and chemo convulsions are (i) differences in the nature of antagonism by bicuculline and PTX, (ii) alterations in receptor sensitivity or number, and (iii) alterations in the levels of endogenous neurotransmitters, the latter two resulting as a result of acute or chronic ECS.     

Chronic Electroconvulsive Seizures Increase the Expression of Serotonin2 Receptor mRNA in Rat Frontal Cortex

Abstract: The present study examines the influence of electroconvulsive seizure (ECS), as well as antidepressant drugs, on levels of serotonin₂ (5-HT₂) receptor mRNA in rat frontal cortex. Using a sensitive RNase protective assay, preliminary studies demonstrated the predicted regional distribution for the 5-HT₂ receptor mRNA: levels of 5-HT₂ mRNA were highest in frontal cortex (2.58 amol/μg of total RNA), intermediate in neostriatum, thalamus, and midbrain, and lowest in hippocampus, cerebellum, and choroid plexus. Chronic (10 or 14 days), but not acute (1 or 3 days), ECS treatment significantly increased levels of 5-HT₂ receptor mRNA. ECS treatment resulted in a similar time-dependent up-regulation of 5-HT₂ receptor ligand binding; chronic, but not acute, ECS treatment significantly increased levels of [³H]ketanserin ligand binding, confirming previous reports. Northern blot analysis demonstrated that 5-HT₂ receptor mRNA occurs as two bands (～5 and 6 kb in size), both of which were increased by chronic ECS treatment. The influence of antidepressant drug treatments on 5-HT₂ receptor mRNA was also examined. Chronic fluoxetine treatment increased levels of 5-HT₂ receptor mRNA, although levels of [³H]ketanserin ligand binding were not altered. In contrast, chronic administration of imipramine, mianserin, and tranylcypromine, treatments that decreased ligand binding, did not decrease levels of 5-HT₂ receptor mRNA. In fact, mianserin treatment caused a small, but significant, increase in levels of receptor mRNA. The results suggest that ECS up-regulation of 5-HT₂ receptor mRNA could underlie the increased density of 5-HT₂ receptor binding sites in response to this treatment, but that other mechanisms likely operate in the down-regulation of 5-HT₂ receptor ligand binding by antidepressant drug treatments.     

Antidepressants attenuate the dexamethasone-induced decrease in viability and proliferation of human neuroblastoma SH-SY5Y cells: A involvement of extracellular regulated kinase (ERK1/2)

Excessive glucocorticoid levels in depressed patients have been associated with atrophic changes in some brain regions, but only few studies suggest that some antidepressants can interfere with deleterious effect of glucocorticoids on neuronal cells. The aim of the present study was to examine the effect of dexamethasone (DEX), a synthetic glucocorticoid and some antidepressants from different chemical groups (imipramine, desipramine, amitriptyline, citalopram, fluoxetine, reboxetine and tianeptine) on SH-SY5Y cells cultured in the medium containing steroid-free serum. DEX in concentrations from 1 to 100 μM did not change LDH release but exposure to 10 μM and 100 μM DEX for 24, 48 and 72 h caused a significant reduction in cell viability and proliferation as confirmed by MTT reduction and BrdU ELISA assays, respectively. Twenty four-hour incubation of cells with antidepressants (0.05–10 μM) and DEX (10 μM) showed that imipramine, amitriptyline, desipramine, citalopram and fluoxetine at concentrations from 0.1 up to 1 μM, reboxetine (0.1 μM) and tianeptine (0.05 μM) prevented the DEX-induced decreases in cell viability and proliferation rate. The protective effects of antidepressants were ameliorated by inhibitors of MAPK/ERK1/2, but not PI3-K/Akt pathway as shown for imipramine, fluoxetine and reboxetine. Moreover, Western blot analysis showed the decrease in the activated form of ERK1/2 (p-ERK) after DEX treatment and this effect was inhibited by imipramine. Thus, the reduction in SH-SY5Y cell viability caused by DEX appears to be related to its antiproliferative activity and some antidepressant drugs in low concentrations attenuate this effect by mechanism which involves the activation of MAPK/ERK1/2 pathway.     

Assessment of rat brain alpha1-adrenoceptor binding and activation of inositol phospholipid turnover following chronic imipramine treatment

Chronic (21 days) treatment of rats with imipramine (10 mg/kg) did not change the density or affinity of alpha₁-adrenoceptors as measured by the specific binding of [³H]prazosin in rat cortical membranes, but produced the expected significant decrease in the density of beta-adrenoceptors labeled by [¹²⁵I]iodocyanopindolol. The functional status of brain alpha₁-adrenoceptors was also assessed by measuring the noradrenaline (NA)-induced accumulation of [³H]inositol 1-phosphate (IP₁) in brain slices from these animals. No apparent change was observed in the concentration-response relationship between NA and [³H]IP₁ accumulation in rat cerebral cortex after chronic treatment with imipramine. At concentrations higher than 1 M in vitro, imipramine and its metabolite, desipramine, produced a concentration-dependent decrease in the [³H]IP₁ accumulation elicited by NA. This inhibitory effect is likely mediated by direct blockade of alpha₁-adrenoceptors by these drugs. As the endogenous drug concentration would not reach 1 M in our preparation, the lack of changes in alpha₁-adrenoceptor response following chronic imipramine treatment are not likely attributable to residual imipramine or desipramine retained in the tissues. In conclusion, the above findings do not support previous suggestions that brain alpha₁-adrenoceptors are upregulated following chronic imipramine administration.     

Effects of chronic electroconvulsive shock on the expression of beta-adrenergic receptors in rat brain: immunological study

The purpose of the present study is to determine the effect of chronic electroconvulsive shock (ECS) on the expression of beta-adrenergic receptors in rat brain by Western blot using mAb beta CO2, a monoclonal antibody against beta-adrenergic receptors. Rats in ECS treated groups received maximal ECS (70 mA, 0.5 second, 60 Hz) through ear-clip electrodes for 12 consecutive days. The experiment was carried out in 14 discrete regions of brain. Chronic ECS reduced the expression of beta-adrenergic receptors in frontal cortex, temporal cortex, parietooccipital cortex, hippocampus and limbic forebrain, but not in other areas of brain. The regional specificity and the magnitude of the reduction of receptor expression are well correlated with those of the reduction of receptor ligand binding, which was determined using [3H]dihydroalprenolol. To the best of our knowledge, this is the first report to demonstrate that chronic ECS decreases the expression of receptor protein in specific regions of rat brain.     

The prototypic antidepressant drug, imipramine, but not Hypericum perforatum (St. John's Wort), reduces HPA-axis function in the rat.

Dysregulation in corticotropin-releasing hormone (CRH) secretion in the hypothalamus-pituitary-adrenal (HPA) axis may be involved in the etiology of major depressive disorder (MDD). Chronic therapy with standard antidepressant drugs, such as imipramine, can downregulate HPA axis function, indicating that the HPA axis may be an important target for antidepressant action. We tested several doses of a standardized commercial preparation of Hypericum perforatum plant extract (popularly known as St. John's Wort), a medicinal herb used for treating mild depressive symptoms, to determine whether it also modulated HPA axis function. Chronic imipramine treatment (daily injections for 8 weeks) of male Sprague-Dawley rats significantly downregulated circulating plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone compared to animals treated with saline. However, chronic St. John's Wort treatment (daily gavage for 8 weeks) had no effect on plasma ACTH or corticosterone, even at the highest doses tested. Our results confirm previous findings that imipramine may have significant peripheral HPA axis-mediated effects. However, our data does not support any role for H. perforatum in modulation of HPA axis function, suggesting that alternative pathways may be involved in mediating its antidepressant effects.     

Quantitative Autoradiographic Analysis of the Effects of Electroconvulsive Shock on Serotonin-2 Receptors in Male and Female Rats

Chronic electroconvulsive shock (ECS) is known to increase the level of serotonin-2 (S2) receptors in male rat brain. Using quantitative autoradiography, we have studied the distribution pattern of these receptors in female as well as male rats and the effect of repeated ECS on the receptor level in both sexes. We find that although the distribution of S2 receptors is generally similar in males and females, they respond differently to repeated ECS. In males we found the expected increase in S2 binding, which was localized to specific cortical, hippocampal, and septal regions. In females, no increase was found in the cortex or septum and relatively small increases were found in the hippocampus. It appears that the regulation of S2 receptors by ECS is sex-dependent.     

Effects of chronic antidepressant treatment on nigrostriatal and mesolimbic dopamine autoreceptors in the rat

Dopamine autoreceptors were studied by determining the effects of chronic antidepressant treatment on the ability of several doses of apomorphine to decrease 3,4-dihydroxyphenylalanine accumulation (an index of dopamine synthesis in vivo) after saline or γ-hydroxybutyric acid lactone (γ-butyrolactone). 3,4-Dihydroxyphenylalanine accumulation was measured in nigrostriatal [nucleus caudatus putamen] and mesolimbic [nucleus accumbens and tuberculum olfactorium] nerve terminals. Apomorphine decreased 3,4-dihydroxyphenylalanine accumulation in the nucleus caudatus putamen, tuberculum olfactorium and nucleus accumbens in a dose-related manner. Chronic imipramine (10 days) treatment attenuated the low and high dose apomorphine-induced decrease in 3,4-dihydroxyphenylalanine accumulation in the nucleus caudatus putamen to a greater extent than the tuberculum olfactorium or nucleus accumbens. In γ-butyrolactone-treated animals chronic treatment with imipramine, amitriptyline or bupropion (10 days) attenuated the low dose apomorphine effect in the nucleus caudatus putamen, but not the tuberculum olfactorium or nucleus accumbens. Only 2 days of imipramine treatment had no effect on the apomorphine-induced decrease in 3,4-dihydroxyphenylalanine accumulation in the nucleus caudatus putamen with or without γ-butyrolactone treatment. These data suggest that chronic treatment with three antidepressants produces dopamine autoreceptor subsensitivity in nigrostriatal neurons more than mesolimbic neurons and that this effect is not seen with short-term imipramine treatment.     

Inhibition of monoamine oxidase activity by antidepressants and mood stabilizers

OBJECTIVE: Monoamine oxidase (MAO), the enzyme responsible for metabolism of monoamine neurotransmitters, has an important role in the brain development and function, and MAO inhibitors have a range of potential therapeutic uses. We investigated systematically in vitro effects of pharmacologically different antidepressants and mood stabilizers on MAO activity. Methods: Effects of drugs on the activity of MAO were measured in crude mitochondrial fraction isolated from cortex of pig brain, when radiolabeled serotonin (for MAO-A) or phenylethylamine (for MAO-B) was used as substrate. The several antidepressants and mood stabilizers were compared with effects of well known MAO inhibitors such as moclobemide, iproniazid, pargyline, and clorgyline. Results: In general, the effect of tested drugs was found to be inhibitory. The half maximal inhibitory concentration, parameters of enzyme kinetic, and mechanism of inhibition were determined. MAO-A was inhibited by the following drugs: pargyline > clorgyline > iproniazid > fluoxetine > desipramine > amitriptyline > imipramine > citalopram > venlafaxine > reboxetine > olanzapine > mirtazapine > tianeptine > moclobemide, cocaine > lithium, valproate. MAO-B was inhibited by the following drugs: pargyline > clorgyline > iproniazid > fluoxetine > venlafaxine > amitriptyline > olanzapine > citalopram > desipramine > reboxetine > imipramine > tianeptine > mirtazapine, cocaine > moclobemide, lithium, valproate. The mechanism of inhibition of MAOs by several antidepressants was found various. Conclusions: It was concluded that MAO activity is acutely affected by pharmacologically different antidepressants at relatively high drug concentrations; this effect is inhibitory. There are differences both in inhibitory potency and in mechanism of inhibition between both several drugs and the two MAO isoforms. While MAO inhibition is not primary biochemical effect related to their therapeutic action, it can be supposed that decrease of MAO activity may be concerned in some effects of these drugs on serotonergic, noradrenergic, and dopaminergic neurotransmission.     

Inhibition of stress- or anxiogenic-drug-induced increases in dopamine release in the rat prefrontal cortex by long-term treatment with antidepressant drugs

The effects of long-term treatment with imipramine or mirtazapine, two antidepressant drugs with different mechanisms of action, on the response of cortical dopaminergic neurons to foot-shock stress or to the anxiogenic drug FG7142 were evaluated in freely moving rats. As expected, foot shock induced a marked increase (+ 90%) in the extracellular concentration of dopamine in the prefrontal cortex of control rats. Chronic treatment with imipramine or mirtazapine inhibited or prevented, respectively, the effect of foot-shock stress on cortical dopamine output. Whereas acute administration of the anxiogenic drug FG7142 induced a significant increase (+ 60%) in cortical dopamine output in control rats, chronic treatment with imipramine or mirtazapine completely inhibited this effect. In contrast, the administration of a single dose of either antidepressant 40 min before foot shock, had no effect on the response of the cortical dopaminergic innervation to stress. These results show that long-term treatment with imipramine or mirtazapine inhibits the neurochemical changes elicited by stress or an anxiogenic drug with an efficacy similar to that of acute treatment with benzodiazepines. Given that episodes of anxiety or depression are often preceded by stressful events, modulation by antidepressants of the dopaminergic response to stress might be related to the anxiolytic and antidepressant effects of these drugs.     

Rapid Activation of the Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Signaling Pathway by Electroconvulsive Shock in the Rat Prefrontal Cortex Is Not Associated with TrkB Neurotrophin Receptor Activation

1. Emerging evidence indicates that brain-derived neurotrophic factor (BDNF) and its receptor TrkB play important roles in the mechanism of action of electroconvulsive shock (ECS) treatment. ECS produces a significant increase in brain BDNF synthesis together with a variety of neuroplastic changes including neurogenesis and axonal sprouting in the rodent brain, which is believed to be associated to the antidepressant effect of ECS. ERK1/2 (extracellular signal-regulated kinase-1/2) and Akt (protein kinase B), both intracellular signaling molecules being linked to neurotrophin signaling and synthesis, are important pathways triggered by TrkB autophosphorylation. 2. We have previously observed that chemical antidepressants induce a rapid activation of TrkB signaling in the rodent prefrontal cortex (PFC), which is likely a consequence of the stimulatory effect of antidepressants on BDNF synthesis. However, it is not known whether ECS triggers TrkB autophosphorylation and if any ECS-induced effect on TrkB function may be associated with the activation of the ERK1/2 and Akt pathways. 3. The present study assayed the phosphorylation levels of TrkB, ERK1/2, and Akt in the PFC of sham and ECS-treated rats. While the TrkB autophosphorylation (pTrkB) levels were decreased 30 min after both acute and chronic ECS, no change in pTrkB levels were observed at any other time points measured. In contrast, acute but not chronic ECS, transiently induced a very rapid and robust hyperphosphorylation of ERK1/2. Akt phosphorylation levels remained unchanged following acute or chronic ECS. Hence, although ECS effectively stimulates the ERK1/2 pathway in the PFC, this effect does not appear to involve upstream activation of TrkB.