Effect of stress on behaviour in rats

The pattern of activity obtained in rats on a regimen of one hour access to food and water was compared to the activity pattern seen when immobilization stress was added to the same regimen. Food and water were provided at the same time of the day. Immobilization stress decreased the body weight, increased the time taken for grooming, maintaining at the same time the food intake. The water intake also increased significantly but the alcohol intake was variable, 3 of the rats showing an increased intake while the rest showed a decreased intake under this stress regimen. The pattern of activity changed from hyper-activity during food restriction alone to increased activity restricted to the first half of the testing time during added immobilization.     

Study of pharmacological activity of complex magnesium-containing preparation based on mineral bishofit and pyridoxine hydrochloride in a rat model of chronic alcoholic intoxication

Nervous disturbances accompanying alcoholic illness were studied in relation to the depletion of magnesium ion content in the organism. The possibility of correcting the development of psychic (behavioral) pathologies by treatment with a complex magnesium-containing preparation based on mineral bishofit and pyridoxine hydrochloride (below, Mg-containing preparation) was studied in rats upon three-month voluntary alcoholization. A decrease in the locomotor (number of crossed squares) and vertical (number of standings) activity as evaluated in the open-field test and an increase in the immobilization time in the forced swim test showed evidence of depressive state in animals after long-term ethanol administration. After treatment with the Mg-containing preparation (50 mg Mg/kg in 2.5 ml volume, p.o.), the immobilization time of alcohol-preferring rats decreased in comparison to that before treatment and showed no statistically significant differences from the value in the intact control group. A decrease in the immobilization time (the main sign of antidepressant action) allows the Mg-containing preparation to be considered as antidepressant. The level of magnesium in rat blood erythrocytes decreased upon three-month voluntary alcoholization by 40.95 +/- 2.41% relative to control (p < 0.05). After a 5-week treatment with Mg-containing preparation under conditions of free access to alcohol, the content of magnesium in the erythrocytes of alcohol-preferring rats restored on a normal level. Chronic alcoholism reduces the content of microelements and vitamins (in particular, B6), these changes being mutually related.     

Effects of antagonists of 1A and 2A/2C subtypes of serotonin receptors on the depressive behavior and expression of c-Fos protein in hypothalamus of ovariectomized rats

We have studied the influence of a chronic administration of the 5-HT(2A/2C) receptor antagonist ketanserin (0.1 mg/kg, i.p.) and the 5-HT(1A) receptor antagonist NAN-190 (0.1 mg/kg, i.p.) alone or in combinations with 17beta-estradiol (0.5 mg per animal, i.m.) for 14 days on the depressive behavior and expression of c-Fos protein in the paraventricular nucleus of hypothalamus in adult ovariectomized (OVX) female rats. The depression in rats was modeled by the Porsolt test. The c-Fos protein expression in the paraventricular nucleus of hypothalamus was determined using immunohistochemical techniques. In the Porsolt test, 17beta-estradiol in OVX rats reduced the immobilization time to some extent. Ketanserin alone significantly decreased the immobilization time in OVX rats. The chronic administration of ketanserin in combination with 17beta-estradiol in OVX females potentiated the antidepressant effect of ketanserin. At the same time, ketanserin administration led to a significant decrease in the level of c-Fos protein in the hypothalamus in OVX rats as compared to the intact control. These results are indicative of a substantial interaction between the ovarian hormonal system and the serotoninergic brain system involved the mechanisms of depression.     

Stress-induced depression of basal motility: effects of antidepressant drugs

Behavioral and biochemical effects of repeated immobilization stress were determined in male Wistar rats. The influence of acute or repeated administration of antidepressant drugs on these effects of stress were also evaluated. It was found that repeated stress (immobilization 3 h/2 degrees C/4 days or various stressors/8 days) reduced basal locomotor activity of rats and prolonged immobility time in Porsolt's despair test. Antidepressant drugs (desmethylimipramine, imipramine, amitriptyline, clomipramine, mianserine), given acutely, restored basal locomotor activity of stressed rats to control level. Desmethylimipramine, imipramine and amitriptyline reduced immobility time in Porsolt's test similarly in control as in stressed rats. However clomipramine, mianserine and trazodone were effective in this test only in stressed rats. Imipramine given for 4 or 8 days (1 h before the stressor) normalized basal locomotor activity. Repeated (for 8 days) various stressors decelerated utilization of noradrenaline (NA) and dopamine (DA) in the brain. Imipramine given once a day for 8 days (1 h before the stressor) normalized brain utilization of catecholamines (CA). It was proposed that depression of basal motility and reduction of CA utilization in the brain induced by repeated stress may be counter acted by antidepressant drugs.     

L-TRYITOPHAN-INDUCED DEPRESSION OF THE PRESSOR RESPONSE TO CLONIDINE IN ANAESTHETIZED RATS

1. The interaction of the serotonin precursor L-tryptophan with the pressor responses of the anaesthetized rat to the intravenous injection of clonidine, adrenaline and angiotensin has been studied. 2. Pretreatment of rats with L-tryptophan (100 mg/kg) depressed the pressor response to clonidine but had no effect on the responses elicited by adrenaline or angiotensin. 3. The L-tryptophan-induced depression of the clonidine response was prevented by pretreating rats with either Rö 44602, carbidopa, BW 172C58, methys-ergide or by pithing. 4. Intravenous infusions of serotonin depressed the pressor responses to clonidine, adrenaline and angiotensin in both intact anaesthetized and pithed rats. 5. It is concluded that the depressant action of L-tryptophan is dependent on its conversion within the periphery to serotonin. This action is also dependent on or mediated by the sympathetic nervous system.     

The influence of L-tryptophan and monoamine oxidase inhibitors on catecholamine metabolism in rat brain.

1. L-Tryptophan (100 mg/kg) was administered to rats with or without pretreatment with a monoamine oxidase inhibitor and the concentration of 5-hydroxyindoleacetic acid, homovanillic acid, dihydroxyphenylacetic acid, 3-methoxy 4-hydroxyphenyl glycol, normetanephrine, noradrenaline and dopamine measured in whole brain one hour later. 2. L-Tryptophan increased the concentration of 5-hydroxyindoleacetic acid, homovanillic acid, dihydroxyphenylacetic acid, 3-methoxy 4-hydroxyphenyl glycol and normetanephrine. The concentration of noradrenaline did not change whilst that of dopamine increased significantly. 3. In animals pretreated chronically with a monoamine oxidase inhibitor, tryptophan increased the concentration of dihydroxyphenylacetic acid and homovanillic acid compared to monoamine oxidase alone. 4. The results suggest either a release of dopamine and noradrenaline by 5-hydroxytryptamine, with a compensatory increase in their synthesis, or an increase in the firing of dopaminergic and noradrenergic neurones after L-tryptophan.     

Stimulation of prostaglandin biosynthesis by drugs: effects in vitro of some drugs affecting gut function.

1 A single electroconvulsive shock (ECS) of 150 V for 1 s increased the concentration of rat brain 5-hydroxyindoleacetic acid (5-HIAA) but did not alter brain 5-hydroxytryptamine (5-HT) or tryptophan concentrations 3 h later. 2 A single ECS decreased 5-HT synthesis 3 h and 6 h later. Synthesis was back to normal after 24 hours. The ECS-treated rats did not show greater hyperactivity produced by the increased brain 5-HT accumulation following administration of L-tryptophan and tranylcypromine at any time up to 24 h later. This suggests that a single electroshock does not alter 5-HT functional activity. 3 Twenty-four hours after the final ECS of a series of 10 shocks given once daily, the rats were given tranylcypromine and L-tryptophan. They displayed greater hyperactivity than control rats not treated with ECS, suggesting that ECS increases 5-HT functional activity. Brain concentrations of 5-HT, 5-HIAA and tryptophan were then unchanged by ECS. 5-HT synthesis and accumulation of 5-HT following tranylcypromine and L-tryptophan were not altered by ECS. 4 The hyperactivity following administration of the 5-HT agonist 5-methoxy N,N-dimethyltryptamine was enhanced by repeated (10 day) ECS, suggesting altered post-synaptic responses to 5-HT receptor stimulation. 5 Repeated ECS enhanced locomotor activity following tranylcypromine and L-DOPA. It did not alter brain noradrenaline or dopamine concentrations. 6 The latent period before a pentylenetetrazol-induced convulsion was shortened by repeated ECS. 7 Following repeated ECS there appears to be increased neuronal sensitivity to certain stimuli producing centrally mediated behavioural stimulation. This is discussed in relation to the mechanism by which electroconvulsive therapy (ECT) produces its therapeutic effect.     

Selegilin exerts antidepressant-like effects during the forced swim test in adrenocorticotropic hormone-treated rats

In the present study, we investigated the effect of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test after the administration of selegiline, a selective and irreversible monoamine oxidase (MAO)-B inhibitor. Single and repeated administration of selegiline significantly decreased the duration of immobility in normal rats. When selegiline was administered for 15 days, we observed a significant decrease in immobility in rats treated with ACTH for 14 days. The immobility-decreasing effect of selegiline was blocked by nafadotride, a selective dopamine D(3)-receptor antagonist in normal and ACTH-treated rats. Selegiline may be useful in an animal model of depressive conditions resistant to tricyclic antidepressant treatment via the dopamine D(3) receptor.     

Effects of L-tryptophan on the development of tolerance to the antitussive effects of dihydrocodeine.

The effects of L-tryptophan on the development of tolerance to the antitussive effects of dihydrocodeine were examined in rats. Chronic co-administration of L-tryptophan with dihydrocodeine prevented the development of tolerance to the antitussive effects of dihydrocodeine. Furthermore, the antitussive effects of dihydrocodeine in dihydrocodeine-tolerant rats were fully restored by acute co-administration of L-tryptophan, as evidenced by a decrease of about 50% in the ED50 value of dihydrocodeine. Thus, it is concluded that L-tryptophan may antagonized the development of tolerance to the antitussive effects of dihydrocodeine.     

Modulating effects of thyroid state on the induction of biotransformation enzymes by 2,3,7,8-tetrachlorodibenzo-p-dioxin

In this study we investigated to what extent the induction of detoxification enzymes by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is modulated by concomitant TCDD-induced changes in thyroid state. Euthyroid (Eu) male Sprague-Dawley rats, surgically thyroidectomized (Tx) rats and Tx rats receiving substitution doses of 3,3',5-triiodothyronine (Tx+T3) or thyroxine (Tx+T4) by osmotic minipumps were treated with a single ip injection of 10 μg TCDD/kg/bwt or with vehicle (corn oil). Three days after TCDD administration, rats were sacrificed and blood and livers were collected for analysis. Total hepatic cytochrome P450 (CYP) content was increased by ≈50% by TCDD in all groups but was not affected by thyroid state. In Eu rats, TCDD increased CYP1A1/1A2 activity 90-fold, CYP1A1 protein content 52-fold and CYP1A1 mRNA levels ≈5.8-fold. Similar findings were obtained in Tx, Tx+T3 and Tx+T4 rats except that TCDD-induced CYP1A1 activity was significantly decreased in Tx rats. NADPH cytochrome P450 reductase activity was not affected by TCDD but was decreased in Tx rats, which may explain the diminished TCDD-induced CYP1A1 activity in Tx rats. Hepatic p-nitrophenol UDP-glucuronyltransferase (UGT) activity was induced ≈4-fold by TCDD in Eu rats. Similar basal and TCDD-induced activities were observed in Tx+T3 and Tx+T4 rats, but TCDD-induced activities were significantly lower in Tx rats. TCDD did not have a significant effect on overall glutathione-S-transferase (GST) activity or hepatic GST 2-2, 3-3 or 4-4 protein levels but produced a marked increase in GST 1-1 protein levels. Thyroid state did not affect basal or TCDD-induced GST activity or subunit pattern. Iodothyronine sulfotransferase (ST) activity was not affected by TCDD treatment and was slightly but not significantly lower in Tx rats than in Eu, Tx+T3 and Tx+T4 rats. These results suggest that the changes in thyroid hormone levels associated with TCDD treatment have little modulating effects on the induction of hepatic detoxification enzymes in Sprague-Dawley rats exposed to this compound.     

噻芬太尼的主要药效和致依赖性潜力的实验研究

本文研究噻芬太尼的镇痛药效和制动作用,评价其致身体依赖性潜力。小鼠热板法测得噻芬太尼的镇痛作用强度分别为吗啡、芬太尼和埃托啡的3260,22和1.5倍。以瘫痪作为制动指标测得噻芬太尼对大鼠、家兔、狗和猴制动作用强度为埃托啡的2～3倍。小鼠跳跃实验和大鼠饮药液自然戒断实验表明该药具有一定致身体依赖性潜力。大鼠ⅳ快速成瘾实验及长达20周的猴身体依赖性实验则未出现依赖性戒断症状。     

Toxicology and safety study of L-tryptophan and its impurities for use in broiler feed

L-tryptophan has been utilized as a feed additive in animal nutrition to improve growth performance, as well as a dietary supplement to alleviate various emotional symptoms in humans. Despite its benefits, concerns regarding its safety arose following the outbreak of eosinophilia-myalgia syndrome (EMS) among individuals who consumed L-tryptophan. The causative material of EMS was determined to be not L-tryptophan itself, but rather L-tryptophan impurities resulting from a specific manufacturing process. To investigate the effect of L-tryptophan and its impurities on humans who consume meat products derived from animals that were fed L-tryptophan and its impurities, an animal study involving broiler chickens was conducted. The animals in test groups were fed diet containing 0.065%–0.073% of L-tryptophan for 27 days. This study aimed to observe the occurrence of toxicological or EMS-related symptoms and analyze the residues of L-tryptophan impurities in meat products. The results indicated that there was no evidence of adverse effects associated with the test substance in the investigated parameters. Furthermore, most of the consumed EMS-causing L-tryptophan impurities did not remain in the meat of broiler chickens. Thus, this study demonstrated the safety of L-tryptophan and some of its impurities as a feed additive.     

THE EFFECTS OF SEROTONIN PRECURSORS ON THE PRESSOR RESPONSE TO INTRAVENOUS CLONIDINE IN CONSCIOUS RATS

1. The interaction of the biosynthetic precursors of serotonin with the a-adrenoceptor-mediated pressor response to intravenous clonidine was investigated in unanaesthetized rats. 2. Pretreatment with 100 mg/kg of either L-tryptophan or 5-hydroxytryptophan (5-HTP) reduced the magnitude of the pressor response elicited by intravenous clonidine (25 μg/kg) to 15% and 11%, respectively, of that observed in control rats. 3. The depression by L-tryptophan of the clonidine-induced pressor response could be prevented by pretreatment with either the L-aromatic amino acid de-carboxylase inhibitor Rö-4– 4602 or the serotonin antagonist methysergide.     

Elevated Brain 5-Hydroxytryptophol Levels in Experimental Portal-Systemic Encephalopathy

Abstract: Brain tissue levels of the two serotonin metabolites 5-hydroxytryptophol and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured in porta-caval shunted rats, an in vivo model of portal-systemic encephalopathy. An intraperitoneal challenge of L-tryptophan (280 mg/kg body weight) to sham-operated rats was also instituted to increase the brain serotonin metabolism in these rats. The results revealed significant increases in 5-hydroxytryptophol (by 31%) and 5-HIAA (by 87%) brain levels in porta-caval shunted rats as compared to sham-operated controls. The brain 5-hydroxytryptophol-to-5-HIAA ratio was lower in the porta-caval shunted rats. The 5-hydroxytryptophol levels in sham rats after the L-tryptophan challenge were intermediate between the porta-caval shunted and sham rats but not statistically significant for either group. These results suggest that increased brain 5-hydroxytryptophol levels might be associated with the pathogenesis of portal-systemic encephalopathy. Further, the elevated brain 5-hydroxytryptophol levels in experimental portal-systemic encephalopathy are probably a result of the increased brain serotonin metabolism prevailing in this condition rather than changes in the brain redox potential.     

Effects of liver fibrosis on verapamil pharmacokinetics in rats

1. Liver fibrosis is the compensatory state of cirrhosis. In the long asymptomatic period, it is imperative to select a proper dosing regimen for drugs that are applicable to hepatic fibrosis owing to altered pharmacokinetics and bioavailability. The present study was designed to observe the changes in verapamil pharmacokinetics in rats with early liver fibrosis with respect to alterations in cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp). 2. A rat liver fibrosis model was successfully established using several inducers, including a high-fat diet, alcohol and carbon tetrachloride. After rats received a single intravenous or oral dose of verapamil (5 mg/kg), the plasma concentrations of verapamil were determined at scheduled time-points using HPLC. The activity of hepatic and small intestinal microsomal erythromycin N-demethylase (a marker for CYP3A) and the expression of small intestinal cyp3a and multidrug resistance (mdr) mRNA were compared between normal rats and rats with liver fibrosis. 3. The results showed that when verapamil was administered intravenously, the area under the curve (AUC), elimination half-life (T((1/2)(K10))) and mean residence time (MRT) increased significantly, whereas clearance (Cl) decreased, in rats with liver fibrosis compared with normal rats. After oral administration of verapamil, the AUC, (T((1/2)(K10))) and maximum concentration (C(max)) increased, Cl decreased and the absorption half-life (T((1/2)(K01))) and time to peak concentration (T(max)) were unchanged compared with normal rats. The oral bioavailability of verapamil was 32.9% in normal rats and 34.4% in rats with liver fibrosis. Furthermore, decreased CYP3A activity in the liver was accompanied by upregulated cyp3a9/18 and unchanged mdr mRNA in the small intestine compared with normal rats. Expression of cyp3a9/18 and mdr mRNA in the intestine was significantly inhibited by verapamil. 4. The results suggest that the lowered Cl and increased AUC of verapamil after intravenous and oral administration in rats with liver fibrosis were due to downregulation of CYP3A in the liver. The absorption rate of verapamil in rats with liver fibrosis was unchanged because mdr was unchanged and cyp3a was inhibited in the intestine by verapamil itself. There was no notable difference in oral bioavailability between normal rats and rats with liver fibrosis.     

Effect of eleutherococcus on hemostasis in immobilized rats

The influence of a chronic (30 days) administration of an eleutherococcus extract on the haemostatic system state was studied in immobilized rats. A 3-h immobilization of untreated animals is accompanied by hypercoagulation and thrombinemia signs on the background of downregulation of the anticoagulant and fibrinolytic activity, which leads to a risk of thrombosis. Preliminary 30-day course of eleutherococcus uptake prevents the immobilization-induced thrombosis in rats.     

Effect of acute and chronic tri-iodothyronine (T3) administration to rats on central 5-HT and dopamine-mediated behavioural responses and related brain biochemistry

The effects of both acute and chronic T₃ administration (100 μg/kg, s.c.) on behavioural responses in the rat mediated by 5-hydroxytryptamine (5-HT) and dopamine (DA) were examined 24 hr after the last injection of hormone at a time when serum T3 levels had almost returned to control values. Concomitant changes in the biochemistry of the 5-HT and DA systems were also examined.Administration of T₃ produced complex changes in both central DA and 5-HT systems. Both acute and chronic T₃ treatment enhanced the hyperactivity response to tranylcypromine (TCP) plus L-DOPA, with chronic treatment giving a much greater enhancement. Paradoxically, the accumulation of brain DA at 20 and 30 min after L-DOPA in chronically treated rats was less than in the controls. In order to study possible T₃ effects at the DA postsynaptic receptor, behavioural responses to the DA agonist apomorphine were measured. The activity responses were slightly attenuated in chronically treated rats only. Furthermore, the cataleptogenic effect of haloperidol (0.3 mg/kg) was significantly potentiated in chronically T3-treated rats only. Because striatal [³H]-spiroperidol binding was unaltered in chronically treated rats, it is thought that T₃ may produce an altered sensitivity postsynaptic to striatal DA receptors, or a change in activity of a modulatory neuronal system.It was found that 24 hr after either acute or chronic T₃ injection, the hyperactivity response to TCP + L-tryptophan (L-TP) was markedly enhanced [350% (chronic) and 220% (acute) increase above control activity]. A similar result was obtained for the 5-HT agonists (quipazine and 5-MeODMT).There was no change in whole brain 5-HT or TP accumulation measured 75 min following TP injection in the chronically-treated animals. This, together with enhanced 5-HT postsynaptic agonist responses, may be due to primary changes occurring at or beyond DA neurones, which appear to be interposed between 5-HT neurones and the site expressing the behavioural response.     

Luminal melatonin stimulates pancreatic enzyme secretion via activation of serotonin-dependent nerves

BackgroundSerotonin (5-HT) is released from enterochromaffin cells in the gastrointestinal tract. Serotonin, via the activation of 5-HT₂ and 5-HT₃ receptors on vagal fibers, mediates pancreatic secretion through the mechanism independent from cholecystokinin. Melatonin (5-HT derivative) or L-tryptophan (melatonin or 5-HT precursor) given systemically or intraduodenally to the rats stimulate amylase secretion, but the mechanism is not clear. The aims of this study was to investigate the involvement of 5-HT in the pancreatostimulatory effect of melatonin or L-tryptophan, administered intraduodenally.MethodsWistar rats were surgically equipped with silicone catheters; inserted into pancreato-biliary duct and into the duodenum. Melatonin, L-tryptophan or serotonin were given to the rats as a bolus. Combination of 5-HT₂ or 5-HT₃ receptor antagonists: ketanserin (100 μg/kg) and MDL72222 (250 μg/kg) was given intraperitoneally to the animals, 15 min. prior to the administration of the examined substances. The role of the vagal nerve, sensory fibers and CCK in the control of pancreatic exocrine function were determined. Blood samples were taken for the determination of 5-HT.ResultsMelatonin, 5-HT or L-tryptophan increased pancreatic amylase secretion. The stimulatory effect of the above substances was decreased by pretreatment of the rats with ketanserin and MDL72222. Bilateral vagotomy completely abolished the increase of amylase output caused by 5-HT, while capsaicin deactivation of sensory nerves or blockade of CCK₁ receptor only partially reversed the stimulatory effect of 5-HT on the pancreas. Intraduodenal L-tryptophan, but not melatonin, increased plasma 5-HT concentrations in a dose- and time-dependent manner.ConclusionStimulation of pancreatic exocrine function caused by intraluminal administration of melatonin, or L-tryptophan is modified, at least in part, by serotoninergic mechanisms and vagal nerves.     

Behavioral and biochemical effects of L-tryptophan and buspirone in a model of cerebellar atrophy

The Lurcher mutant mouse can be considered an adequate model of autosomal dominant spinocerebellar atrophy because of the severe degeneration of its cerebellar cortex and inferior olive. The purpose of this study was to determine whether the motor coordination deficits of Lurcher mutants could be improved after chronic administration of the serotonin (5-hydroxytryptamine; 5-HT) precursor, L-tryptophan, or of the 5-HT(1A) agonist, buspirone. During these treatments, the mice were submitted to behavioral evaluations using the coat hanger and the rotorod tests, as well as an inclined screen and a vertical grid test. At the end of treatments, 5-HT and 5-hydroxindole-3-acetic acid (5-HIAA) were measured in six brain regions. On the coat hanger test, administration of L-tryptophan accelerated movements along the horizontal bar by 44%, while buspirone increased the time spent on the apparatus by 11%. Neither drug had an effect on climbing ability or on the time spent on a rotating beam. Administration of L-tryptophan increased 5-HIAA levels in frontal cortex, neostriatum, thalamus, brainstem, cerebellum and spinal cord, but elevated 5-HT only in neostriatum, brainstem and cerebellum. In contrast, buspirone led to 5-HT increases in cerebellum and augmented 5-HIAA in the spinal cord. The modest test-specific improvements are consistent with some of the clinical data concerning 5-HT pharmacotherapy in patients suffering from cerebellar atrophy.     

Manipulations of brain 5-HT levels affect gene expression for BDNF in rat brain.

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.