Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication-naïve and medication-free schizophrenic patients.

The association between the pro-inflammatory state of schizophrenia and increased tryptophan degradation into kynurenine has been reported. However, the relationship between metabolites from subdivisions of the kynurenine pathway, kynurenic acid and 3-hydroxykynurenine, remains unknown. The present study tested the relationship between these kynurenine metabolites in the plasma of medication-naïve (n=35) or medication-free (n=18) patients with schizophrenia at admission and following 6-week antipsychotic treatment compared to healthy controls (n=48). The plasma concentrations of kynurenic acid (nmol/l) were lower (difference=-8.44 (-13.22 to -3.65); p=0.001) and of 3-hydroxykynurenine (nmol/l) were higher (difference=11.24 (8.11-14.37); p<0.001) in the patients compared with the healthy controls. The kynurenic acid/kynurenine (difference=-2.75 (-5.115 to -0.336); p=0.026) and kynurenic acid/3-hydroxykynurenine (difference=-1.08 (-1.431 to -0.729); p<0.001) ratios were also lower in the patients. After the 6-week treatment, the patients' plasma kynurenic acid levels (difference=3.85 (-0.23 to 7.94); p=0.064) showed a trend towards an increase, whereas plasma 3-hydroxykynurenine levels (difference=22.41 (19.76-25.07); p<0.001) decreased. As a consequence, the kynurenic acid/3-hydroxykynurenine ratio (difference=-4.41 (-5.51 to -3.3); p<0.001) increased. Higher initial plasma kynurenic acid levels on admission or increased kynurenic acid/kynurenine ratio after treatment were associated with reduction of clinical symptoms scores upon discharge although higher kynurenic acid/kynurenine on admission may induce higher positive symptoms score. In contrast, higher 3-hydroxykynurenine is associated with lower positive symptoms score. These results indicate that there is an imbalance in the kynurenine pathway in schizophrenia. The 6-week antipsychotic treatment may partially reverse the imbalance in kynurenine metabolism and that in turn induces clinical response.

The new '5-HT' hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression.

This paper reviews the body of evidence that not only tryptophan and consequent 5-HT depletion, but also induction of indoleamine 2,3-dioxygenase (IDO) and the detrimental effects of tryptophan catabolites (TRYCATs) play a role in the pathophysiology of depression. IDO is induced by interferon (IFN)γ, interleukin-6 and tumor necrosis factor-α, lipopolysaccharides and oxidative stress, factors that play a role in the pathophysiology of depression. TRYCATs, like kynurenine and quinolinic acid, are depressogenic and anxiogenic; activate oxidative pathways; cause mitochondrial dysfunctions; and have neuroexcitatory and neurotoxic effects that may lead to neurodegeneration. The TRYCAT pathway is also activated following induction of tryptophan 2,3-dioxygenase (TDO) by glucocorticoids, which are elevated in depression. There is evidence that activation of IDO reduces plasma tryptophan and increases TRYCAT synthesis in depressive states and that TDO activation may play a role as well. The development of depressive symptoms during IFNα-based immunotherapy is strongly associated with IDO activation, increased production of detrimental TRYCATs and lowered levels of tryptophan. Women show greater IDO activation and TRYCAT production following immune challenge than men. In the early puerperium, IDO activation and TRYCAT production are associated with the development of affective symptoms. Clinical depression is accompanied by lowered levels of neuroprotective TRYCATs or increased levels or neurotoxic TRYCATs, and lowered plasma tryptophan, which is associated with indices of immune activation and glucocorticoid hypersecretion. Lowered tryptophan and increased TRYCATs induce T cell unresponsiveness and therefore may exert a negative feedback on the primary inflammatory response in depression. It is concluded that activation of the TRYCAT pathway by IDO and TDO may be associated with the development of depressive symptoms through tryptophan depletion and the detrimental effects of TRYCATs. Therefore, the TRYCAT pathway should be a new drug target in depression. Direct inhibitors of IDO are less likely to be useful drugs than agents, such as kynurenine hydroxylase inhibitors; drugs which block the primary immune response; compounds that increase the protective effects of kynurenic acid; and specific antioxidants that target IDO activation, the immune and oxidative pathways, and 5-HT as well.

Imbalance between pro- and anti-inflammatory cytokines, and between Th1 and Th2 cytokines in depressed patients: the effect of electroacupuncture or fluoxetine treatment.

BACKGROUND: An increase in inflammatory response and an imbalance between T-helper (Th) 1 and 2 functions have been implicated in major depression. The aims of the present study were to 1) study the relationship between pro- and anti-inflammatory cytokines and between Th1 and Th2 produced cytokines in depressed patients and 2) evaluate and compare the effect of treatments with electroacupuncture (EA) and fluoxetine on these cytokines. METHODS: 95 outpatients with major depressive disorder were treated for 6 weeks with EA, fluoxetine or placebo. Hamilton Depression Rating Scale (HDRS) and Clinical Global Impression (CGI) were used to assess severity and therapeutic effects. 30 volunteers served as controls. Serum cytokine concentrations were measured by ELISA. RESULTS: Increased proinflammatory cytokine interleukin (IL)-1beta and decreased anti-inflammatory cytokine IL-10 were found in the depressed patients. By contract, Th1 produced proinflammatory cytokines, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were decreased, and Th2 produced cytokine IL-4 was significantly increased in depressed patients. The ratio of IFN/IL-4 was also increased. Both acupuncture and fluoxetine treatments, but not the placebo, reduced IL-1beta concentrations in responders. However, only acupuncture attenuated TNF-alpha concentration and INF-gamma/IL-4 ratio towards the control level. DISCUSSION: These results suggest that an imbalance between the pro- and anti-inflammatory cytokines (IL-1 and IL-10), and between Th1 and Th2 cytokines (INF-gamma or TNF-alpha and IL-4) occurred in untreated depressed patients. Both EA and fluoxetine had an anti-inflammatory effect by reducing IL-1beta. EA treatment also restored the balance between Th1 and Th2 systems by increasing TNF-alpha and decreasing IL-4.

LDR brachytherapy: can low dose rate hypersensitivity from the "inverse" dose rate effect cause excessive cell killing to peripherial connective tissues and organs?

Examined here are the possible effects of the "inverse" dose rate effect (IDRE) on low dose rate (LDR) brachytherapy. The hyper-radiosensitivity and induced radioresistance (HRS/IRR) effect benefits cell killing in radiotherapy, and IDRE and HRS/IRR seem to be generated from the same radioprotective mechanisms. We have computed the IDRE excess cell killing experienced in LDR brachytherapy using permanent seed implants. We conclude, firstly, that IDRE is a dose rate-dependent manifestation of HRS/IRR. Secondly, the presence of HRS/IRR or IDRE in a cell species or tissue must be determined by direct dose-response measurements. Thirdly, a reasonable estimate is that 50-80% of human adjoining connective and organ tissues experience IDRE from permanent implanted LDR brachytherapy. If IDRE occurs for tissues at point A for cervical cancer, the excess cell killing will be about a factor of 3.5-4.0 if the initial dose rate is 50-70 cGy h(-1). It is greater for adjacent tissues at lower dose rates and higher for lower initial dose rates at point A. Finally, higher post-treatment complications are observed in LDR brachytherapy, often for unknown reasons. Some of these are probably a result of IDRE excess cell killing. Measurements of IDRE need be performed for connective and adjacent organ tissues, i.e. bladder, rectum, urinary tract and small bowels. The measured dose rate-dependent dose responses should extended to <10 cGy h(-1) and involve multiple patients to detect patient variability. Results may suggest a preference for high dose rate brachytherapy or LDR brachytherapy without permanent retention of the implant seeds (hence the dose rates in peripheral tissues and organs remain above IDRE thresholds).

Current antidepressant drugs

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Role of paroxetine in interferon-alpha-induced immune and behavioural changes in male Wistar rats.

Treatment with pro-inflammatory cytokine, IFNalpha was documented to result in neuropsychiatric complications including depression and treatment with antidepressant, paroxetine could improve the depressive symptoms. Therefore, the effects of IFNalpha on behaviour and cytokine changes in the whole blood culture and in the prefrontal cortex, hypothalamus and hippocampus areas of the brain in wistar rats were investigated with emphasis on the role of paroxetine in the prevention of depressive behaviour induced by pro-inflammatory cytokines. The group of rats treated with IFNalpha (s.c. 50,000 IU/kg for 3 days/week for 5 weeks) was compared with three other groups; 1) saline control group (s.c. normal saline 0.2 ml/kg/day for 7 weeks), 2) paroxetine control group (paroxetine suspension orally 10 mg/kg/day for 7 weeks) and 3) group treated with paroxetine for 2 weeks followed by IFNalpha for 5 weeks. In open filed, the IFNalpha treated rats showed anxiety behaviour compared to the rats from the other groups. There was no significant difference in home cage emergence test, Morris water maze and object recognition test. There is no significant difference in plasma corticosterone between groups. The pro-inflammatory cytokines (TNFalpha, IL1beta and IFNgamma), were significantly higher whereas the anti-inflammatory cytokine, IL10 was lower in the stimulated whole blood culture of IFNalpha treated rats. In the brain, both pro-inflammatory cytokine IL1beta and anti-inflammatory cytokine IL10 were higher in hypothalamus of the IFNalpha treated rats; by contrast the concentration of IL10 was lowest in hippocampus region of this group compared to the other groups. The paroxetine pretreated rats did not show these cytokine changes following IFNalpha treatment. Thus it appears that paroxetine pretreatment prevents the pro-inflammatory changes in blood and brain following IFNalpha treatment in turn prevents the anxiety behaviour.

Inflammation and depression: is there a causal connection with dementia?

Epidemiological studies show that there is a correlation between chronic depression and the likelihood of dementia in later life. There is evidence that inflammatory changes in the brain are pathological features of both depression and dementia. This suggests that an increase in inflammation-induced apoptosis, together with a reduction in the synthesis of neurotrophic factors caused by a rise in brain glucocorticoids, may play a role in the pathology of these disorders. A reduction in the neuroprotective components of the kynurenine pathway, such as kynurenic acid, and an increase in the neurodegenerative components, 3- hydroxykynurenine and quinolinic acid, contribute to the pathological changes. Such changes are postulated to cause neuronal damage and thereby predispose chronically depressed patients to dementia.

The comparison of changes in behavior, neurochemistry, endocrine, and immune functions after different routes, doses and durations of administrations of IL-1beta in rats.

BACKGROUND: Increased interleukin-1beta (IL-1) in the brain and periphery has been associated with neurodegenerative and psychiatric disorders. However, results from different IL-1 sources, administrating routes, doses and treatment duration were inconsistent and confused. The neuroendocrine-immune mechanism by which IL-1-induced behavioral changes occur is still unclear. METHODS: In the present study, the acute and sub-chronic effects of rat recombinant IL-1, following either intraperitoneal (ip) or intracerebroventricular (icv) injection, were studied on the behavior, corticosterone secretion, peripheral inflammatory responses and brain monoamines. RESULTS: In the open field apparatus, IL-1 (ip) increased locomotor activity but decreased the activity following icv administration. IL-1 had a greater anxiogenic effect in the elevated plus maze after icv than after ip administration. In the Morris water maze spatial memory was only impaired following sub-chronic and icv administration. Both acute and sub-chronic IL-1 increased the serum corticosterone concentration and decreased the release of the anti-inflammatory cytokine IL-10 from whole blood cultures. However, centrally administered IL-1 increased, while peripherally administered decreased, the release of PGE2 from blood cultures. After sub-chronic administration, the noradrenaline concentration was decreased in several limbic regions, while the turnovers of serotonin and dopamine were increased. DISCUSSION: These results suggest that 1) IL-1 effects depended on the dose, route and duration of administration, and 2) IL-1 enhances the responsiveness of rats to stressful environmental stimuli. In addition, the sub-chronic administration of IL-1 induces behavioral, neurotransmitter, hormonal and immune changes that may be causally implicated in the mechanism of some of psychiatric disorders such as depression.

Ketter's hypothesis of the mood effects of antiepileptic drugs coupled to the mechanism of action of topiramate and levetiracetam.

Mood-modulating profiles of antiepileptic drugs (AEDs) have been classified by Ketter, Post, and Theodore [Neurology 1999; 53 (5, Suppl. 2) S53-76] into two classes: the first class is assumed to have deactivating effects related to GABA potentiation, and the second class is assumed to have activating effects that are associated with glutamate attenuation. We tested this hypothesis by reviewing the multiple mechanisms of action of topiramate (TPM) and levetiracetam (LEV) together with clinical behavioral side effects of patients who had been treated with TPM and LEV in a tertiary referral center for epilepsy. We found LEV to manifest activating and deactivating side effects equally and TPM to act as a deactivating AED, with tiredness/sleepiness side effects being predominant. TPM, in comparison to LEV, was found to be associated with a high incidence of side effects. Testing the hypothesis of Ketter et al. (1999) the deactivating effects of TPM may be coupled to a predominance of potentiation of GABA, but the oversimplified basis of the model needs to be acknowledged.

The HPA and immune axes in stress: the involvement of the serotonergic system.

The impact of acute and chronic stress on the hypothalamic-pituitary-adrenal (HPA) axis is reviewed and evidence presented that corticotrophin releasing factor (CRF) is the stress neurotransmitter which plays an important role in the activation of the central sympathetic and serotonergic systems. The activity of CRF is expressed through specific receptors (CRF 1 and 2) that are antagonistic in their actions and widely distributed in the limbic regions of the brain, as well as in the hypothalamus, and on immune cells. The mechanism whereby chronic stress, via the CRF induced activation of the dorsal raphe nucleus, can induce a change in the serotonergic system, involves an increase in the 5HT2A and a decrease in the 5HT1A receptor mediated function. Such changes contribute to the onset of anxiety and depression. In addition, the hypersecretion of glucocorticoids that is associated with chronic stress and depression desensitises the central glucocorticoid receptors to the negative feedback inhibition of the HPA axis. This indirectly results in the further activation of the HPA axis. The rise in pro-inflammatory cytokines that usually accompanies the chronic stress response results in a further stimulation of the HPA axis thereby adding to the stress response. While CRF would appear to play a pivotal role, evidence is provided that simultaneous changes in the serotonergic and noradrenergic systems, combined with the activation of peripheral and central macrophages that increase the pro-inflammatory cytokine concentrations in the brain and blood, also play a critical role in predisposing to anxiety and depression. Neurodegenerative changes in the brain that frequently occur in the elderly patient with major depression, could result from the activation of indoleaminedioxygenase (IDO), a widely distributed enzyme that converts tryptophan via the kynenine pathway to for the neurotoxic end product quinolinic acid.

Sigma receptors and sigma ligands: background to a pharmacological enigma.

Although it is now well established that the sigma receptors are distinct from neurotransmitter, neuropeptide and steroid receptors, their precise physiological role, and possible involvement in the pathology of neurological and psychiatric disorders, remains an enigma. The purpose of this short review is to provide a basis upon which to explain the pharmacological properties of such a diverse group of drugs as the antidepressants, antipsychotics and neuroprotective agents. However, a greater understanding of the importance of the sigma receptors will depend on the development of more potent and selective sigma agonists and antagonists if the therapeutic potential of the sigma receptors is to be fully realised.

Ethyl-eicosapentaenoic acid ingestion prevents corticosterone-mediated memory impairment induced by central administration of interleukin-1beta in rats.

Central or peripheral administration of the proinflammatory cytokine interleukin (IL)-1beta can impair performance on spatial memory tasks and also elevate circulating concentration of corticosterone. The present experiment provides independent confirmation that intracerebroventricular administration of 10 ng IL-1beta in the rat can have a selective effect on the retrieval of trial unique information about the location of food on an eight-arm radial maze. The probable involvement of corticosterone in IL-1beta-induced memory impairment was indicated by elevated corticosterone levels after IL-1beta administration. Further evidence comes from the blockade of the associated impairment in working memory by coadministration of the glucocorticoid receptor antagonist RU486. Ingestion of diet containing omega-3 fatty acid eicosapentaenoic acid (EPA) is known to antagonize the synthesis of prostaglandin (PG) E2 from aracadonic acid, and the present study confirmed that ethyl EPA (1%) reduced IL-1beta-elevated concentrations of PGE2 and corticosterone. Furthermore, rats given the ethyl-EPA diet for 8 weeks were unaffected by the disruptive effects of IL-1beta on working memory. IL-1beta-induced suppression of mitogen-stimulated release of the anti-inflammatory cytokine IL-10 was also blocked by treatment with ethyl-EPA. Collectively, these data demonstrate that IL-1beta can impair memory function by elevating the concentration of corticosterone and that prior consumption of 1% ethyl-EPA can block both the neuroendocrine and cognitive effects of IL-1beta. These findings in turn may indicate beneficial effects of ethyl-EPA in the treatment of cognitive and affective disorders in which inflammation and stress play a critical role.

Effects of acute and chronic administration of selective monoamine re-uptake inhibitors in the rat forced swim test.

The rat forced swim test (FST) is a model that is used extensively as a screening test for antidepressant activity. It has previously been reported that thorough analysis of behaviour in this model reveals two distinct types of active response - climbing and swimming - and that these are separately evoked by re-uptake inhibitors selective for noradrenaline (NA) and serotonin (5-HT), respectively. In the present study, utilising re-uptake inhibitors selective for NA, talsupram, and 5-HT, 5-chloro-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)- phthalan (Lu 10-134-C), we examined if this scoring technique could detect the antidepressant potential of a selective serotonin re-uptake inhibitor (SSRI), and whether re-uptake inhibitors selective for distinct monoamine systems induce exclusive behavioural responses. We also analysed if chronic antidepressant administration for three weeks was more effective than acute treatment. We found Lu 10-134-C (40 mg/kg; PO) to be behaviourally active in this paradigm. Although treatment with talsupram (40 mg/kg; PO) resulted solely in climbing behaviour, Lu 10-134-C induced both climbing and swimming behaviour. However, chronic pre-treatment with either re-uptake inhibitor (20 mg/kg; twice daily; PO) failed to augment the response observed with acute treatment. Similarly, chronic administration of either compound was without effect on the basal, or stress-induced, serum corticosterone concentrations or anterior pituitary (AP) preproopiomelanocorticotropin (POMC) mRNA expression. These results suggest that selective monoamine re-uptake inhibition produces distinct, but not necessarily exclusive, behavioural responses in the forced swim test.

The effect of lofepramine and other related agents on the motility of Tetrahymena pyriformis.

Tricyclic antidepressants (TCAs) were introduced almost 50 years ago. Whilst there is no doubt that TCAs are effective in treating depression, they are also more cardiotoxic when taken in overdose than other antidepressant groups. Lofepramine is a more recently introduced modified TCA, which in animals and man has low toxicity when compared to older TCAs. Paradoxically, lofepramine is extensively metabolised to desipramine, which has considerable toxicity, both experimentally and in overdose. The toxicity of such compounds is attributed, in part, to a membrane stabilising effect (MSA) on cell membranes. This MSA causes gross effects to the cell structure and in turn, normal cell activity. The aim of this study was to compare the MSA of lofepramine with that of desipramine and amitriptyline in order to see if this might help to explain the low toxicity of lofepramine. The local anaesthetic agent lignocaine was also studied for comparison. Each compound was enclosed in a beta-cyclodextrin to increase its solubility in aqueous medium. The extent of MSA was determined as a measure of the effect on the swimming speed of the protozoan Tetrahymena pyriformis using a video image analysis system. The IC50s for the various drugs were then correlated with their respective octanol-water partition coefficient values (Pow). Amitriptyline had an IC50 of 1.26+/-0.29 mM, desipramine 75.99+/-14.40 mM, while lofepramine had an IC50 of 357.40+/-25.00 mM. Lignocaine had an IC50 of 85.73+/-18.30 mM. There was also a significant correlation between the IC50 values and the Pow values.

Stress, norepinephrine and depression.

Stress is an important precipitant factor in depression, and the changes in various body systems that occur in depression are similar to those observed in response to stress. This paper discusses the interactions among the immune, endocrine and norepinephrine systems that are evident in patients with depression, as well as those affected by stress. Many of the stress-induced changes can be reversed by antidepressants, particularly norepinephrine reuptake inhibitors.

Beta-amyloid(1-42)-induced cholinergic lesions in rat nucleus basalis bidirectionally modulate serotonergic innervation of the basal forebrain and cerebral cortex.

Ample experimental evidence suggests that beta-amyloid (A beta), when injected into the rat magnocellular nucleus basalis (MBN), impels excitotoxic injury of cholinergic projection neurons. Whereas learning and memory dysfunction is a hallmark of A beta-induced cholinergic deficits, anxiety, or hypoactivity under novel conditions cannot be attributed to the loss of cholinergic MBN neurons. As mood-related behavioral parameters are primarily influenced by the central serotonergic system, in the present study we investigated whether A beta(1-42) toxicity in the rat MBN leads to an altered serotonergic innervation pattern in the rat basal forebrain and cerebral cortex 7 days postsurgery. A beta infusion into the MBN elicited significant anxiety in the elevated plus maze. A beta toxicity on cholinergic MBN neurons, expressed as the loss of acetylcholinesterase-positive cortical projections, was accompanied by sprouting of serotonergic projection fibers in the MBN. In contrast, the loss of serotonin-positive fiber projections, decreased concentrations of both serotonin and 5-hydroxyindoleacetic acid, and decline of cortical 5-HT(1A) receptor binding sites indicated reduced serotonergic activity in the somatosensory cortex. In conclusion, the A beta-induced primary cholinergic deficit in the MBN and subsequent cortical cholinergic denervation bidirectionally modulate serotonergic parameters in the rat basal forebrain and cerebral cortex. We assume that enhanced serotonin immunoreactivity in the damaged MBN indicates intrinsic processes facilitating neuronal recovery and cellular repair mechanisms, while diminished cortical serotonergic activity correlates with the loss of the subcortical cholinergic input, thereby maintaining the balance of neurotransmitter concentrations in the cerebral cortex.

The immune system, depression and the action of antidepressants.

It is well established that the hypothalamic-pituitary-adrenal axis (HPA) is activated by both external and internal stressors which result in the hypersecretion of adrenal glucocorticoids. In major depression the prolonged elevation of the glucocorticoid concentration leads to a desensitisation of the central glucocorticoid receptors and probably those receptors located on macrophages. These changes may account for the observation that many aspects of cellular immunity are activated in depression (for example, the increased release of pro-inflammatory cytokines from activated macrophages in the periphery and brain, and the increased release of acute phase proteins from the liver) even though other aspects of immunity (for example, natural killer cell activity and T-cell replication) are depressed. It is also known that some of the pro-inflammatory cytokines are potent activators of the HPA axis. Evidence is provided that the consequences of the hypersecretion of glucocorticoids and pro-inflammatory cytokines result in the malfunctioning of noradrenergic and serotonergic neurotransmission in the brain, changes which are reflected in the major symptoms of depression. Support for this view is provided by observations of the effects of some of these cytokines in non-depressed individuals being treated with pro-inflammatory and related cytokines for cancer. This has led to the hypothesis that depression is a form of sickness behaviour which forms the basis of the macrophage theory of depression. The review concludes with a discussion of the role of antidepressants in attenuating the adverse effects of glucocorticoids and pro-inflammatory cytokines on central neurotransmission. Although the precise mechanisms whereby antidepressants these changes is uncertain, there is evidence that they reduce the release of pro-inflammatory cytokines from activated macrophages and thereby facilitate the feedback inhibition of the HPA axis; this results in a reduction in the release of glucocorticoids from the adrenal glands. In addition, many antidepressants have been shown to increase the release of endogenous cytokine antagonists such as interleukin-1 receptor antagonist and interleukin-10. Evidence is also presented to show that different classes of antidepressants act as cyclooxygenase inhibitors which, by lowering the concentration of inflammatory prostaglandins in the brain, reduce the detrimental impact of the inflammatory changes on neurotransmitter function. An advantage of the macrophage hypothesis is that it extends the biogenic amine hypothesis of depression to take account of changes in the endocrine and immune systems which also play a crucial role in the aetiology of depression. In addition, the macrophage hypothesis may broaden the basis of understanding the mechanism of action of antidepressants.

Prior exposure to methylenedioxyamphetamine (MDA) induces serotonergic loss and changes in spontaneous exploratory and amphetamine-induced behaviors in rats.

The substituted amphetamine 3,4 methylenedioxyamphetamine (MDA) is a popular recreational drug of abuse. Administration of MDA to experimental animals has been shown to induce damage to serotonergic axons and nerve terminals. However, there is a lack of information on whether these treatments can produce any long-term changes in behavioural performance particularly under stressful conditions. In the present study, MDA (7.5 mg/kg; i.p.) was administered twice daily to adult male Sprague Dawley rats for four days. Four weeks following the last dose, spontaneous behaviors of these animals were tracked and scored in a novel "open field" environment using an automated video registration and computer interpretation system. Changes in behavior were observed in MDA treated animals including reductions in exploratory oriented behaviors (locomotion and rearing) and increases in grooming behavior when compared to vehicle treated controls. MDA-treated animals also displayed an enhanced locomotor and stereotyped response to d-amphetamine (12 mg/kg; i.p.). Significant reductions in 5-HT concentrations (20-30%) were observed in the frontal cortex, amygdala, striatum, and hypothalamus as a result of MDA treatment. In addition, [3H] paroxetine binding was reduced by (40%) in the cortex of MDA treated rats indicating that the decrease in 5-HT concentrations were accompanied by a reduction in intact presynaptic 5-HT nerve terminals. Changes in behavioural performance in a novel "open field" environment and following d-amphetamine challenge might be considered as a behavioural model of serotonergic deficit induced by MDA. The findings of this study also suggest that MDA use may increase both the abuse potential, and the propensity to develop psychosis as a result of abusing other psychostimulants such as d-amphetamine.