Selective analyzers of dopamine D2 receptors modulate serotonin metabolism in the striatum and nucleus accumbens of the rat brain during blockade of dopaminergic impulse flow]

Effects of D2 dopamine receptor selective agonists: quinpirole (0.1, 0.3 and 1 mg/kg, i. p.), pergolide (0.3 mg/kg, i. p.), lisuride (0.1 mg/kg, i. p.) and antagonist raclopride (1.2 mg/kg, i. p.) on the metabolism and synthesis of DA and serotonin in the rat brain striatum and nucleus accumbens after GBL treatment were studied. GBL as well as dopamine D2 receptor selective drugs were shown not only to change neurochemical parameters of dopaminergic brain systems, but also to modulate serotonin metabolism without affecting its biosynthesis.     

In vivo and in vitro synthesis, release, and uptake of [3-H]-dopamine in mouse striatal slices after in vivo exposure to chlordecone

Effects of treatment of mice with chlordecone (25 mg/kg/d) on striatal dopaminergic activities such as synthesis, turnover, uptake, and release were investigated in vivo and in vitro. In mice receiving chlordecone for five days, there were no significant changes in in vivo dopamine (DA) synthesis and turnover in striatum and in vitro [3-H]-dopamine uptake and K+-stimulated [3-H]-dopamine release in striatal slices. In mice receiving chlordecone for eight days, the in vivo synthesis of [3-H]-dopamine from [3-H]-tyrosine in striatum was slightly inhibited and the in vitro [3-H]-dopamine synthesis in striatal slices was significantly decreased. Furthermore, both uptake and K+-stimulated release of [3-H]-dopamine from striatal slices were significantly reduced. The turnover rate of newly synthesized [3-H]-dopamine from [3-H]-tyrosine in striatal slices was unchanged after eight consecutive days of chlordecone administration. These results suggest that chlordecone may cause impairments in pre- and/or postsynaptic membranes of dopaminergic neurons which modulate motor function.     

Concurrent Determination of Brain Dopamine and 5-Hydroxytryptamine Turnovers in Individual Freely Moving Rats Using Repeated Sampling of Cerebrospinal Fluid

5-Hydroxytryptamine (5-HT) turnover and dopamine (DA) turnover values were obtained in individual conscious rats by measuring the rates of accumulation of 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in cisternal CSF samples taken from each rat at 0, 30, and 60 min after probenecid (200 mg/kg i.p.) administration. In a separate experiment, 5-HT and DA turnover values were determined in CSF, striatum, and rest of brain of groups of rats killed 0, 30, or 60 min after probenecid. Whole brain turnover values were calculated from striatal and rest of brain values. Mean turnover values using CSF were comparable with both procedures. DA turnover values were greater when based on total (i.e., free + conjugated) DA metabolites than when based on free metabolites. After partial inhibition of monoamine synthesis with the decarboxylase inhibitor DL-alpha- monofluoromethyl -DOPA ( MFMD , 100 mg/kg p.o.) DA and 5-HT turnover values were comparably reduced in whole brain, rest of brain, and CSF but more markedly reduced in the striatum. Mean DA and 5-HT turnover values obtained using CSF were similar with probenecid doses over the range 150-250 mg/kg i.p. but were variable when repeatedly determined in the same rats after administration of 200 mg/kg probenecid. Results in general show that the CSF procedure may be used to determine concurrently both 5-HT and DA turnover (when estimated from the sum of total but not free metabolites) and that it provides a good index of whole brain turnover of these transmitters in the conscious individual rat.     

An In Vivo Study of Dopamine Release and Metabolism in Rat Brain Regions Using Intracerebral Dialysis

Intracerebral dialysis was used with a specifically designed HPLC with electrochemical detection assay to monitor extracellular levels of endogenous 3,4-dihydroxyphenylethylamine (dopamine, DA) and its major metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in brain regions of the halothane-anesthetized rat. Significant amounts of DA, DOPAC, and HVA were detected in control perfusates collected from striatum and n. accumbens whereas the medial prefrontal cortex showed lower monoamine levels. The ratio of DA in perfusate to DA in whole tissue suggests that in f. cortex, compared to n. accumbens and striatum, there is a greater amount of DA in the extracellular space relative to the intraneuronal DA content. The DOPAC/HVA ratio in control perfusates varied between regions in accordance with whole tissue measurements. This ratio was highest in n. accumbens and lowest in f. cortex. The monoamine oxidase inhibitor pargyline (100 mg/kg i.p.) caused an exponential decline in DOPAC, but not of HVA, in regional perfusates, an effect that was associated with an increase in DA. The data indicated a higher turnover of extracellular DOPAC in n. accumbens than in striatum and the lowest DOPAC turnover in f. cortex. The rate of decline in extracellular DA metabolite levels was slow compared to whole tissue measurements. In the perfusates there was no statistical correlation between basal amounts of DA in the perfusates and DOPAC and HVA levels or DOPAC turnover for any of the areas, indicating that measurement of DA metabolism in the brain under basal conditions does not provide a good index of DA release. In summary, this study shows clear regional differences in basal DA release and metabolite levels, metabolite patterns, and DOPAC turnover rates in rat brain in vivo.     

Halothane attenuated haloperidol and enhanced clozapine-induced dopamine release in the rat striatum

The effect of halothane anesthesia on changes in the extracellular concentrations of dopamine (DA) and its metabolites (3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA)) induced by neuroleptics was studied using in vivo microdialysis techniques. Halothane attenuated haloperidol-induced dopamine release and enhanced clozapine-induced dopamine release in the rat striatum.A microdialysis probe was implanted into the right striatum of male SD rats. Rats were given saline or the same volume of 200 microg kg(-1) haloperidol (D(2) receptor antagonist), 10 mg kg(-1) sulpiride (D(2) and D(3) antagonist), or 10 mg kg(-1) clozapine (D(4) and 5-HT(2) antagonist) intraperitoneally with or without 1-h halothane anesthesia (0.5 or 1.5%). Halothane anesthesia did not change the extracellular concentration of DA, but increased the metabolite concentrations in a dose-dependent manner. The increased DA concentration induced by haloperidol was significantly attenuated by halothane anesthesia, whereas the metabolite concentrations were unaffected. Halothane had no effect on the changes in the concentrations of DA or its metabolites induced by sulpiride. The clozapine-induced increases in DA and its metabolites were enhanced by halothane anesthesia.Our results suggest that halothane anesthesia modifies the DA release modulated by antipsychotic drugs in different ways, depending on the effects of dopaminergic or serotonergic pathways.     

Selective stimulation of serotonin2c receptors blocks the enhancement of striatal and accumbal dopamine release induced by nicotine administration

The effects of acute and repeated nicotine administration on the extracellular levels of dopamine (DA) in the corpus striatum and the nucleus accumbens were studied in conscious, freely moving rats by in vivo microdialysis. Acute intraperitoneal (i.p.) injection of nicotine (1 mg/kg) increased DA outflow both in the corpus striatum and the nucleus accumbens. Repeated daily injection of nicotine (1 mg/kg, i.p.) for 10 consecutive days caused a significant increase in basal DA outflow both in the corpus striatum and the nucleus accumbens. Acute challenge with nicotine (1 mg/kg, i.p.) in animals treated repeatedly with this drug enhanced DA extracellular levels in both brain areas. However, the effect of nicotine was potentiated in the nucleus accumbens, but not in the corpus striatum. To test the hypothesis that stimulation of 5-HT (5-hydroxytryptamine, serotonin)(2C) receptors could affect nicotine-induced DA release, the selective 5-HT(2C) receptor agonist RO 60-0175 was used. Pretreatment with RO 60-0175 (1 and 3 mg/kg, i.p.) dose-dependently prevented the enhancement in DA release elicited by acute nicotine in the corpus striatum, but was devoid of any significant effect in the nucleus accumbens. RO 60-0175 (1 and 3 mg/kg, i.p.) dose-dependently reduced the stimulatory effect on striatal and accumbal DA release induced by an acute challenge with nicotine (1 mg/kg, i.p.) in rats treated repeatedly with this alkaloid. However, only the effect of 3 mg/kg RO 60-0175 reached statistical significance. The inhibitory effect of RO 60-0175 on DA release induced by nicotine in the corpus striatum and the nucleus accumbens was completely prevented by SB 242084 (0.5 mg/kg, i.p.) and SB 243213 (0.5 mg/kg, i.p.), two selective antagonists of 5-HT(2C) receptors. It is concluded that selective activation of 5-HT(2C) receptors can block the stimulatory action of nicotine on central DA function, an effect that might be relevant for the reported antiaddictive properties of RO 60-0175.     

Amperozide, a Novel Antipsychotic Drug, Inhibits the Ability of d-Amphetamine to Increase Dopamine Release In Vivo in Rat Striatum and Nucleus Accumbens

The in vivo effects of amperozide, a novel atypical antipsychotic drug, on the release of dopamine (DA) and the output of its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), were investigated in the striatum and the nucleus accumbens of awake, freely moving rats using microdialysis. Amperozide (2-10 mg/kg, s.c.) significantly increased extracellular levels of DA in both the striatum and nucleus accumbens in a dose-dependent manner. It had a similar but lesser effect on extracellular DOPAC levels in both regions. d-Amphetamine (2 mg/kg, s.c.) alone produced a very large (43-fold) increase in DA release, together with a 70% decrease in DOPAC levels in both the striatum and the nucleus accumbens. Amperozide (1-5 mg/kg, s.c.) 30 min before d-amphetamine (2 mg/kg) dose-dependently attenuated d-amphetamine-induced DA release but had no effect on the d-amphetamine-induced decrease in extracellular DOPAC levels in both regions. The effect of amperozide on d-amphetamine-induced DA release in the nucleus accumbens may explain the inhibitory effect of amperozide on amphetamine-induced locomotor activity. However, the failure of amperozide to block amphetamine-induced stereotypy, despite marked inhibition of striatal DA release, suggests the need to reexamine the importance of striatal DA for amphetamine-induced stereotypy.     

Central antidopaminergic properties of 2-bromolisuride, an analogue of the ergot dopamine agonist lisuride

2-Bromolisuride (2-Br-LIS), a derivative of the ergot dopamine (DA) agonist lisuride, was investigated in rodents in comparison with the DA antagonist haloperidol with regard to its influence on DA related behaviour, cerebral DA metabolism and prolactin (PRL) secretion. 2-Br-LIS produced catalepsy in mice (ED50 3.3 mg/kg i.p.), antagonized apomorphine-induced stereotypies in mice (ED50 0.4 mg/kg i.p.), antagonized DA agonist-induced stereotypies in rats (0.1-1.56 mg/kg i.p.), inhibited locomotor activity in rats (0.025-6.25 mg/kg i.p.), antagonized the hyperactivity produced by various DA agonists in rats (0.025-6.25 mg/kg i.p.) and inhibited the apomorphine-induced hypothermia in mice (0.05-0.78 mg/kg i.p.). 2-Br-LIS (0.03-10 mg/kg i.p.) stimulated DA biosynthesis and DOPAC formation in the striatum and DA rich limbic system of rats, but had no effect on serotonin turnover. In striatum and limbic forebrain of gamma-butyrolactone-pretreated rats 2-Br-LIS reversed the apomorphine-induced inhibition of DOPA accumulation. 2-Br-LIS (0.03 - 3 mg/kg) enhanced PRL secretion in intact male rats. These findings indicate DA antagonistic properties of 2-Br-LIS presumably due to blockade of central pre- and postsynaptic DA receptors being of approximately the same order of potency as haloperidol. 2-Br-LIS is the first ergot compound with definite antidopaminergic properties suggesting its potential usefulness as a neuroleptic.     

Transmitter-Like Basal and K+-Evoked Release of 3,4-Dihydroxyphenylalanine from the Striatum in Conscious Rats Studied by Microdialysis

Using microdialysis and HPLC, characteristics of the release of endogenous 3,4-dihydroxyphenylalanine (DOPA) from striatum in conscious rats were studied in comparison with those of 3,4-dihydroxyphenylethylamine (dopamine; DA). Purified L-aromatic amino acid decarboxylase (AADC) converted a putative peak of DOPA to DA. The retention time of DOPA differed from that of DA and major metabolites of DA and norepinephrine. The DOPA peak of dialysates comigrated with that of authentic DOPA when the pH of the HPLC buffer was modified. The ratio of the basal release of DOPA:DA was 1:2. 3-Hydroxybenzylhydrazine (NSD-1015; 100 mg/kg, i.p.), an AADC inhibitor, markedly increased the basal release of DOPA but produced no effect on DA. The basal release of DOPA was markedly decreased by alpha-methyl-p-tyrosine (200 mg/kg, i.p.), substantially tetrodotoxin (1 microM) sensitive, and Ca2+ (removal plus 12.5 mM Mg2+ addition) dependent. Fifty millimolar K+ released DOPA and this release was also Ca2+ dependent. These characteristics of the basal and evoked release of DOPA were similar to those of DA. The ratio of the evoked release of DOPA:DA was 1:3. These results indicate that DOPA is released under physiological conditions and by K(+)-induced depolarization in a manner similar to that for transmitter DA from striatum in freely moving rats.     

Different effects of typical and atypical neuroleptics on K+-stimulated dopamine release from isolated rat striatum]

Effects of haloperidol (10(-7)-alpha 10(-5) M), trifluoperazine, metoclopramide, tiapride, sulpiride, thioridazine, clozapine remoxipride, raclopride, cis- and trans-isomers of carbidine, SCH 23390 (all at the 10(-6) M) on the K(+)-stimulated (28 mM) dopamine (DA) release from isolated rat striatum were studied. Haloperidol at the concentration of 10(-7) and 10(-6) M failed to affect, while at 10(-5) M the drug decreased the stimulated striatal DA release. Trifluoperazine, metoclopramide and tiapride were shown not to modify this process. Sulpiride, thioridazine, clozapine, remoxipride, raclopride, isomers of carbidine were found to increase significantly the stimulated striatal DA release. SCH 23390 failed to affect K(+)-stimulated release of DA in the striatum and also did not change K(+)-stimulated release enhancement produced by raclopride. It is suggested that the mechanism underlying observed effects of the drugs may contribute to pharmacological profile of atypical neuroleptics.     

Role of Serotonin2A and Serotonin2B/2C Receptor Subtypes in the Control of Accumbal and Striatal Dopamine Release Elicited In Vivo by Dorsal Raphe Nucleus Electrical Stimulation

This study investigates, using in vivo microdialysis, the role of serotonin2A (5-HT2A) and 5-HT(2B/2C) receptors in the effect of dorsal raphe nucleus (DRN) electrical stimulation on dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) extracellular levels monitored in the nucleus accumbens (NAC) and the striatum of halothane-anesthetized rats. Following DRN stimulation (300 microA, 1 ms, 20 Hz, 15 min) DA release was enhanced in the NAC and reduced in the striatum. The 5-HT2A antagonist SR 46349B (0.5 mg/kg) and the mixed 5-HT(2A/2B/2C) antagonist ritanserin (0.63 mg/kg) significantly reduced the effect of DRN stimulation on DA release in the NAC but not in the striatum. DA responses to DRN stimulation were not affected by the 5-HT(2B/2C) antagonist SB 206553 (5 mg/kg) in either region. None of these compounds was able to modify the enhancement of DOPAC and 5-HIAA outflow induced by DRN stimulation in either the NAC or the striatum. Finally, in both brain regions basal DA release was significantly increased only by SB 206553. These results indicate that 5-HT2A but not 5-HT(2B/2C) receptors participate in the facilitatory control exerted by endogenous 5-HT on accumbal DA release. Conversely, 5-HT(2B/2C) receptors tonically inhibit basal DA release in both brain regions.     

Ethanol triggers sphingosine 1-phosphate elevation along with neuroapoptosis in the developing mouse brain

Recent studies suggest that l-3,4 dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), a severe complication of conventional L-DOPA therapy of Parkinson's disease, may be caused by dopamine (DA) release originating in serotonergic neurons. To evaluate the in vivo effect of a 5-HT(1A) agonist [(±)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide, 8-OHDPAT] on the L-DOPA-induced increase in extracellular DA and decrease in [(11) C]raclopride binding in an animal model of advanced Parkinson's disease and LID, we measured extracellular DA in response to L-DOPA or a combination of L-DOPA and the 5-HT(1A) agonist, 8-OHDPAT, with microdialysis, and determined [(11) C]raclopride binding to DA receptors, with micro-positron emission tomography, as the surrogate marker of DA release. Rats with unilateral 6-hydroxydopamine lesions had micro-positron emission tomography scans with [(11) C]raclopride at baseline and after two pharmacological challenges with L-DOPA?+?benserazide with or without 8-OHDPAT co-treatment. Identical challenge regimens were used with the subsequent microdialysis concomitant with ratings of LID severity. The baseline increase of [(11) C]raclopride-binding potential (BP(ND) ) in lesioned striatum was eliminated by the L-DOPA challenge, while the concurrent administration of 8-OHDPAT prevented this L-DOPA-induced displacement of [(11) C]raclopride significantly in lesioned ventral striatum and near significantly in the dorsal striatum. With microdialysis, the L-DOPA challenge raised the extracellular DA in parallel with the emergence of strong LID. Co-treatment with 8-OHDPAT significantly attenuated the release of extracellular DA and LID. The 8-OHDPAT co-treatment reversed the L-DOPA-induced decrease of [(11) C]raclopride binding and increase of extracellular DA and reduced the severity of LID. The reversal of the effect of L-DOPA on [(11) C]raclopride binding, extracellular DA and LID by 5-HT agonist administration is consistent with the notion that part of the DA increase associated with LID originates in serotonergic neurons.     

Effects of Selective Monoamine Oxidase Inhibitors on the In Vivo Release and Metabolism of Dopamine in the Rat Striatum

Brain microdialysis was used to examine the in vivo efflux and metabolism of dopamine (DA) in the rat striatum following monoamine oxidase (MAO) inhibition. Relevant catecholamines and indoleamines were quantified by HPLC coupled with a electrochemical detection system. The MAO-B inhibitor selegiline only affected DA deamination at a dose shown to inhibit partially type A MAO. Alterations in DA and metabolite efflux were not observed when using the MAO-B-selective dose of 1 mg/kg of selegiline. At 10 mg/kg, selegiline reduced the efflux of DA metabolites to approximately 70% of basal values without affecting DA efflux. K(+)- and veratrine-stimulated DA efflux was not affected by selegiline. Experiments using amphetamine and the DA uptake inhibitor nomifensine demonstrated that the effect of selegiline on DA metabolism was unlikely to be mediated either by inhibition of DA uptake or by an indirect effect of its metabolite amphetamine. The possibility that the effect of selegiline is mediated via a nonspecific inhibition of MAO is discussed. In contrast, the MAO-A inhibitor clorgyline inhibited basal DA metabolism and increased basal and depolarisation-induced DA efflux. A 1 mg/kg dose of clorgyline reduced basal DA metabolite efflux (40-60% of control values) without affecting DA efflux. At 10 mg/kg of clorgyline, DA efflux increased to 253 +/- 19% of basal values, whereas efflux of DA metabolites was reduced to between 15 and 26% of control values. The release of DA induced by K+ and veratrine was not affected by 1 mg/kg of clorgyline but was increased by approximately 200% following pretreatment with 10 mg/kg of clorgyline. The nonselective MAO inhibitor pargyline caused similar but more pronounced alterations in these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute effects of the cannabinoid receptor agonist WIN55212-2 on dopamine release in rat: an in vivo electrochemical study

The aim of this study was to investigate the effects of the cannabinoid receptor agonist, WIN55212-2, and the cannabinoid receptor antagonist, SR141716A, on dopamine (DA) release evoked by KC1 (120 mM) microinjected into the striatum. The cannabinoid agonist WIN55212-2 (1 and 5 mg/kg, i.p.) dose-dependently attenuated DA release in the striatum, whereas the cannabinoid receptor antagonist SR141716A (3 mg/kg, i.p.) produced the opposite effect. SR141716A (3 mg/kg, i.p.) blocked the effects on DA release by WIN55212-2 (5 mg/kg, i.p.). Vehicle alone did not change DA release. These results suggest that cannabinoids modulate DA release in the striatum.     

Ketanserin pretreatment attenuates MDMA-induced dopamine release in the striatum as measured by in vivo microdialysis

Systemic administration of the amphetamine analogue, 3,4-methylenedioxymethamphetamine (MDMA) produced a dose-dependent increase in the extracellular concentration of dopamine (DA) in the striatum as measured by in vivo microdialysis in awake, freely-moving rats. The extracellular concentration of the DA metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), was significantly decreased in dialysate samples following the administration of MDMA (10 and 20 mg/kg, i.p.). The serotonin-2 (5-HT2) antagonist ketanserin (3 mg/kg, i.p.) had no effect on the extracellular concentration of DA or DOPAC in the striatum of vehicle- treated rats. The administration of ketanserin (3 mg/kg) 1 hr prior to MDMA (20 mg/kg) significantly attenuated the MDMA- induced increase in the extracellular concentration of DA without affecting the decrease in DOPAC concentrations. These data are suggestive that MDMA administration increases DA release in the striatum of awake, freely-moving rats. In addition, MDMA-induced increase in the extracellular concentration of DA in the striatum is mediated, in part, via 5-HT2 receptor mechanisms.     

Effects of nootropic drugs on brain cholinergic and dopaminergic transmission

High affinity choline uptake (HACU) in the hippocampus and striatal concentration of dopamine (DA) and homovanillic acid (HVA) as measures of the in vivo acetylcholine and DA turnover, respectively, were estimated in male rats, Long-Evans, following 6-day administration of various nootropics in clinically relevant doses: piracetam and its derivatives pramiracetam and oxiracetam (100 mg/kg/day), pyritinol (50 mg/kg/day). Piracetam treatment was without effect on HACU, but induced significant increase of HVA in the striatum leaving striatal DA concentration unchanged. On the contrary, pyritinol, pramiracetam and oxiracetam increased HACU, but did not change striatal DA and HVA levels.     

Dopaminergic Regulation of Septohippocampal Cholinergic Neurons

Abstract: The extent to which acetylcholine (ACh) release in the hippocampus is regulated by dopaminergic mechanisms was assessed using in vivo microdialysis in freely moving rats. Systemic administration of the dopamine (DA) receptor agonist apomorphine (1.0 mg/kg) or the specific D₁ agonist CY 208–243 (1.0 mg/kg) increased microdialysate concentrations of ACh in the hippocampus. The D₂ receptor agonist quinpirole (0.5 mg/kg) produced a small but statistically significant decrease in hippocampal ACh release. d -Amphetamine (2.0 mg/kg) increased ACh release, an effect that was blocked by the D₁ receptor antagonist SCH 23390 (0.3 mg/kg) but not by the D₂ antagonist raclopride (1.0 mg/kg). These findings suggest that endogenous DA stimulates septo-hippocampal cholinergic neurons primarily via actions at D₁ receptors. In addition, these results are similar to previous findings regarding the dopaminergic regulation of cortical ACh release, and suggest that the anatomical continuum formed by basal forebrain cholinergic neurons that project to the cortex and hippocampus acts as a functional unit, at least with respect to its regulation by DA.     

On the relation between haloperidol-induced alterations in DA release and DA metabolism in rat striatum

Haloperidol (1 mg/kg) was administered to rats pretreated with α-methyl-para-tyrosine-methylester. HCl (αMpT) and the levels of dopamine (DA) as well as HVA and DOPAC were measured in the striatum. While the release of DA was stimulated by haloperidol for at least 60 min, HVA and DOPAC levels were markedly increased only at 30 min, but not at 60, 90, or 120 min, after haloperidol administration. In rats not pretreated with αMpT, on the other hand, a strong increase in metabolite levels was observed between 60 and 120 min after haloperidol administration. It is concluded that a direct relation between DA release and metabolite levels does not exist in the present experiments. DA biosynthesis and processes involved with the clearance of metabolites appear to be important factors in the haloperidol-induced increase in metabolite levels. The relative importance of these three processes remains to be clarified.     

Modulation of dopaminergic neurotransmission in rat striatum upon in vitro and in vivo diclofenac treatment

Diclofenac (DCF) is a widely used non-steroidal anti-inflammatory drug, which also act as a mitochondrial toxin. As it is known that selective mitochondrial complex I inhibition combined with mild oxidative stress causes striatal dopaminergic dysfunction, we tested whether DCF also compromise dopaminergic function in the striatum. [3H]Dopamine ([3H]DA) release was measured from rat striatal slices after in vitro (2 h, 10-25 micromol/L) or in vivo (3 mg/kg i.v. for 28 days) DCF treatment. In vitro treatment significantly decreased [3H]DA uptake and dopamine (DA) content of the slices. H2O2 (0.1 mmol/L)-evoked DA release was enhanced. Intracellular reactive oxygen species production was not significantly changed in the presence of DCF. After in vivo DCF treatment no apparent decrease in striatal DA content was observed and the uptake of [3H]DA into slices was increased. The intensity of tyrosine hydroxylase immunoreactivity in the striatum was highly variable, and both decrease and increase were observed in individual rats. The H2O2-evoked [3H]DA release was significantly decreased and the effluent contained a significant amount of [3H]octopamine, [3H]tyramine, and [3H]beta-phenylethylamine. The ATP content and adenylate energy charge were decreased. In conclusion, whereas in vitro DCF pre-treatment resembles the effect of the mitochondrial toxin rotenone, in vivo it rather counteracts than aggravates dopaminergic dysfunction.