The influence of aripiprazole and olanzapine on neurotransmitters level in frontal cortex of prenatally stressed rats.

OBJECTIVES: The study aims to verify whether alterations in the level of neurotransmitters have occurred in prenatally stressed rats (animal model of schizophrenia), and whether aripiprazole (ARI) and olanzapine (OLA) modify this level. METHODS: The effects of ARI (1.5mg/kg) and OLA (0.5mg/kg) were studied by means of microdialysis in freely moving rats (observation time 120min). The level of neurotransmitters (DA, 5-HT, NA) and their metabolites (DOPAC, HVA, 5-HIAA) was analyzed by HPLC with coulochemical detection. RESULTS: Obtained results indicate that after a single administration of ARI and OLA in the prenatally stressed rats the increase of DA, DOPAC, and 5-HT was observed. In turn ARI administration increase the level of HVA and 5-HIAA and also decrease the level of NA. After OLA administration the level of NA and HVA increased and no significant change in 5-HIAA was observed. CONCLUSION: Alterations observed as a result of ARI and OLA administration may be pivotal in identifying animal models of mental disorders and in the analysis of neuroleptics effectiveness.

The role of adenosine A1 and A2A receptors in the caffeine effect on MDMA-induced DA and 5-HT release in the mouse striatum.

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") popular as a designer drug is often used with caffeine to gain a stronger stimulant effect. MDMA induces 5-HT and DA release by interaction with monoamine transporters. Co-administration of caffeine and MDMA may aggravate MDMA-induced toxic effects on DA and 5-HT terminals. In the present study, we determined whether caffeine influences DA and 5-HT release induced by MDMA. We also tried to find out if adenosine A1 and A2A receptors play a role in the effect of caffeine by investigating the effect of the selective adenosine A1 and A2A receptor antagonists, DPCPX and KW 6002 on DA and 5-HT release induced by MDMA. Mice were treated with caffeine (10 mg/kg) and MDMA (20 or 40 mg/kg) alone or in combination. DA and 5-HT release in the mouse striatum was measured using in vivo microdialysis. Caffeine exacerbated the effect of MDMA on DA and 5-HT release. DPCPX or KW 6002 co-administered with MDMA had similar influence as caffeine, but KW 6002 was more potent than caffeine or DPCPX. To exclude the contribution of MAO inhibition by caffeine in the caffeine effect on MDMA-induced increase in DA and 5-HT, we also tested the effect of the nonxanthine adenosine receptor antagonist CGS 15943A lacking properties of MAO activity modification. Our findings indicate that adenosine A1 and A2A receptor blockade may account for the caffeine-induced exacerbation of the MDMA effect on DA and 5-HT release and may aggravate MDMA toxicity.

Prenatal lipopolysaccharide treatment enhances MK-801-induced psychotomimetic effects in rats.

The aim of this study was to evaluate the effect of prenatal lipopolysaccharide (LPS) treatment, which is an animal developmental model of schizophrenia, on MK-801-induced psychotomimetic behavioral changes and brain aminergic system activity in adult offspring. Repeated LPS (1 mg/kg) injection in rats, that had started from 7th day of pregnancy and was continued every second day till delivery, resulted in a long-lasting disruption of prepulse inhibition (PPI) and elevation of locomotor activity in their offspring. The prenatally LPS-treated rats showed hypersensitivity to MK-801 (0.1 and 0.4 mg/kg) as evidenced by the enhancement of acoustic startle amplitude, reduced PPI, and enhanced locomotor activity. These behavioral changes were accompanied by a decrease in the dopamine and its metabolite, DOPAC concentration in the frontal cortex, enhanced dopaminergic system activity in the striatum and no changes in noradrenaline (NA) level. Furthermore, the significant augmentation of 5-HT and 5-HIAA content in the frontal cortex of females only was detected. No changes in the cortical NA tissue level were found. Summing up, the present study demonstrated that the activation of the immune system in prenatal period led to persistent behavioral hypersensitivity to psychotomimetic action of a non-competitive NMDA receptor antagonist, and attention/information processing deficits. The foregoing data indicate that prenatal administration of LPS model some of the clinical aspects of schizophrenia and these behavioral effects are connected with neurochemical changes.

Effect of venlafaxine and nicotine on the level of neurotransmitters and their metabolites in rat brains.

Nicotine (NIC) and venlafaxine (VEN) have been proved to exert antidepressant activity in both human and animals. The effect of antidepressant doses of NIC and VEN (our previous results) on noradrenergic (NA), dopaminergic (DA), serotoninergic (5-HT) neurotransmitters and their metabolites: DOPAC, HVA and 5-HIAA in rats' hippocampus in freely moving rats were determined by microdialysis technique and HPLC method. Both drugs release 5-HT and NA, but VEN to a greater degree. DA level was affected only by VEN, however NIC extended the response of the DA system on VEN's effect. Combined administration of drugs caused the greatest changes in the 5-HT system. Both drugs contributed to reduction in neurotransmitter biotransformation.

The involvement of NMDA and AMPA receptors in the mechanism of antidepressant-like action of zinc in the forced swim test.

Antidepressant-like activity of zinc in the forced swim test (FST) was demonstrated previously. Enhancement of such activity by joint administration of zinc and antidepressants was also shown. However, mechanisms involved in this activity have not yet been established. The present study examined the involvement of the NMDA and AMPA receptors in zinc activity in the FST in mice and rats. Additionally, the influence of zinc on both glutamate and aspartate release in the rat brain was also determined. Zinc-induced antidepressant-like activity in the FST in both mice and rats was antagonized by N-methyl-D-aspartic acid (NMDA, 75 mg/kg, i.p.) administration. Moreover, low and ineffective doses of NMDA antagonists (CGP 37849, L-701,324, D-cycloserine, and MK-801) administered together with ineffective doses of zinc exhibit a significant reduction of immobility time in the FST. Additionally, we have demonstrated the reduction of immobility time by AMPA receptor potentiator, CX 614. The antidepressant-like activity of both CX 614 and zinc in the FST was abolished by NBQX (an antagonist of AMPA receptor, 10 mg/kg, i.p.), while the combined treatment of sub-effective doses of zinc and CX 614 significantly reduces the immobility time in the FST. The present study also demonstrated that zinc administration potentiated a veratridine-evoked glutamate and aspartate release in the rat's prefrontal cortex and hippocampus. The present study further suggests the antidepressant properties of zinc and indicates the involvement of the NMDA and AMPA glutamatergic receptors in this activity.

Intraperitoneal zinc administration increases extracellular zinc in the rat prefrontal cortex.

Single administration of zinc evokes pharmacological behavioral effects in rodents, while no brain zinc alterations were detected. The aim of the present study was to examine the effect of a single zinc hydroaspartate intraperitoneal (ip) administration on the extracellular (synaptic) zinc concentration in the rat prefrontal cortex. We used anodic stripping voltammetric (ASV) method of zinc determination in microdialysate, which assays the extracellular zinc concentration. We report that acute (65 mg/kg) zinc hydroaspartate administration (ip) increases the extracellular zinc by 48% in the rat prefrontal cortex. These data for the first time demonstrate: 1) utility of ASV zinc detection in brain microdialysates and 2) that single ip zinc administration increases brain (cortical) extracellular zinc pool. The results indicate zinc-induced fast brain penetration and may explain its rapid pharmacological effects.

Anxiolytic-like action of MTEP expressed in the conflict drinking Vogel test in rats is serotonin dependent.

The purpose of the present study was to investigate whether the anxiolytic-like action of a selective and brain penetrable group I metabotropic glutamate (mGlu5) receptor antagonist 3-[(2-methyl-1,3-tiazol-4-yl)ethynyl]-pyridine (MTEP) is dependent upon the serotonergic system. Experiments were performed on male Wistar rats. The Vogel conflict drinking test was used to detect anxiolytic-like activity. MTEP administered intraperitoneally at doses of 1, 3 and 6 mg/kg induced anxiolytic-like effect. The potential anxiolytic effect of MTEP (1 mg/kg) was inhibited by a nonselective 5-HT receptor antagonist metergoline (2 mg/kg i.p.) and 5-HT2A/2C receptor antagonist ritanserin (0.5 mg/kg i.p.), but not by a 5-HT1A receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl)cyclohexane-carboxamide (WAY 100635) (0.1 mg/kg i.p). The anxiolytic effect of MTEP (6 mg/kg) was attenuated by ritanserin (1 mg/kg i.p.). Moreover, MTEP-induced a dose-dependent release of serotonin in the frontal cortex. The obtained results suggest that the potential anxiolytic effect of the mGlu5 receptor antagonist MTEP is due to the increased serotonin release with subsequent activation of 5-HT2A/2C receptors, most probably located postsynaptically, but not by the 5-HT1A receptors.

Glutamate concentration in whole saliva and taste responses to monosodium glutamate in humans.

It is universally accepted that saliva plays an important role in taste sensations. However, interactions between constituents of whole saliva and the five basic taste modalities are still poorly understood. The aim of the present study was to evaluate possible relationship between endogenous glutamate (Glu) levels in whole saliva and taste responses to a prototypic umami substance, monosodium glutamate (MSG; 0.03-10.0%). Rated intensity and pleasantness of MSG taste was studied in healthy volunteers divided into a high glutamate (HG) in saliva (HG; n = 19) and low glutamate in saliva (LG; n = 18) group based on the median split level of salivary Glu. The HG and LG group did not differ in terms of electrogustometric thresholds, rated intensity of the MSG samples and pleasantness of distilled water and the lower MSG concentrations (0.03-1.0%). Perceived intensity of water taste was significantly (P < 0.05) higher in the LG subjects. The LG group rated the higher MSG concentrations (3.0-10.0%) as more unpleasant (P < 0.01). The difference remained significant after controlling for a between-group difference in age. The present results suggest that individual differences in salivary Glu levels may alter hedonic responses to suprathreshold MSG concentrations.

Neuroprotective action of MPEP, a selective mGluR5 antagonist, in methamphetamine-induced dopaminergic neurotoxicity is associated with a decrease in dopamine outflow and inhibition of hyperthermia in rats.

The aim of this study was to examine the role of metabotropic glutamate receptor 5 (mGluR5) in the toxic action of methamphetamine on dopaminergic neurones in rats. Methamphetamine (10 mg/kg sc), administered five times, reduced the levels of dopamine and its metabolites in striatal tissue when measured 72 h after the last injection. A selective antagonist of mGluR5, 2-methyl-6-(phenylethynyl)pyridine (MPEP; 5 mg/kg ip), when administered five times immediately before each methamphetamine injection reversed the above-mentioned methamphetamine effects. A single MPEP (5 mg/kg ip) injection reduced the basal extracellular dopamine level in the striatum, as well as dopamine release stimulated either by methamphetamine (10 mg/kg sc) or by intrastriatally administered veratridine (100 microM). Moreover, it transiently diminished the methamphetamine (10 mg/kg sc)-induced hyperthermia and reduced basal body temperature. MPEP administered into the striatum at high concentrations (500 microM) increased extracellular dopamine levels, while lower concentrations (50-100 microM) were devoid of any effect. The results of this study suggest that the blockade of mGluR5 by MPEP may protect dopaminergic neurones against methamphetamine-induced toxicity. Neuroprotection rendered by MPEP may be associated with the reduction of the methamphetamine-induced dopamine efflux in the striatum due to the blockade of extrastriatal mGluR5, and with a decrease in hyperthermia.

The role of striatal metabotropic glutamate receptors in Parkinson's disease.

The primary cause of Parkinson's disease is a loss of dopamine in the corpus striatum. It has been postulated that this effect leads to disinhibition of the striopallidal pathway and secondarily, to a functional shift towards glutamatergic stimulation. The aim of the present study was to find out whether inhibition of glutamatergic transmission at a level of metabotropic glutamate receptors (mGluRs) in the striatum may alleviate parkinsonian-like symptoms in rats. The non-competitive antagonist of receptor subtype 5 (mGluR5), MPEP (1.0-10 mg/kg ip), or the agonist of group II mGluRs, LY354,740 (5-10 mg/kg ip), reduced haloperidol-induced muscle rigidity and catalepsy. Intrastriatal injections of the mGluR1 antagonist, (RS) AIDA (7.5-15 microg/0.5 microl), but not of the agonist of group II mGluRs, 2R,4R-APDC (7.5-15 microg/0.5 microl), inhibited the muscle rigidity induced by haloperidol. In order to search for an influence of mGluRs on the striopallidal pathway, the effect of MPEP or of the agonist of group II mGluRs, DCG-IV, on the proenkephalin (PENK) mRNA expression in the dorso-lateral striatum was examined by an in situ hybridization. Repeated MPEP (6 x 10 mg/kg ip) administration did not influence PENK expression in naïve rats, but diminished that increased by haloperidol. In contrast, repeated DCG-IV (3 x 1 nmol/4 microl icv) injections enhanced both the control and the haloperidol-increased levels of PENK expression. The obtained results suggest that blockade of group I mGluRs, or stimulation of group II mGluRs may be important to ameliorate parkinsonian symptoms. Striatal mGluRs may contribute to at least some of these effects.

The role of striatal metabotropic glutamate receptors in degeneration of dopamine neurons: review article.

Degeneration of dopaminergic nigrostriatal neurons is a primary cause of Parkinson's disease. Oxidative stress, excitotoxicity and mitochondrial failure are thought to be key mechanisms responsible for degeneration of dopaminergic cells. We found that the selective antagonist of the mGluR5 subtype MPEP in a dose of 5 mg/kg diminished basal and veratridine (100 microM)-stimulated dopamine release in rat striatum in an in vivo model of microdialysis. In contrast, MPEP given intrastriatally in a high concentration (500 microM) enhanced the striatal extracellular concentration of dopamine. DCG-IV (100 microM), a non-selective agonist of group II mGluRs, inhibited the veratridine-stimulated striatal dopamine release. In an animal model of neuroxicity in vivo, methamphetamine (5 x 10 mg/kg, injected at 2 h intervals) produced deficits in the striatal content of dopamine and its metabolites DOPAC and HVA 72 h after the treatment. MPEP (5 x 5 mg/kg) given before each methamphetamine injection reversed the decrease in the striatal content of dopamine and diminished the methamphetamine-induced dopamine outflow from nigrostriatal terminals. It is concluded that the MPEP-produced blockade of mGluR5 situated on dopaminergic cells, or the suppression of glutamate release in the subthalamic nucleus or substantia nigra pars reticulata may directly and indirectly cause a decrease in striatal dopamine release. However, inhibitory effect of DCG-IV on dopamine release can be induced by attenuation of excitatory input from corticostriatal terminals by activation of mGluR2/3. Regulation of dopamine carriers by MPEP, an antagonist of group I mGluRs may be responsible for the reversal of toxicity induced by methamphetamine.

Involvement of adenosine in the effect of antidepressants on glutamate and aspartate release in the rat prefrontal cortex.

The effect of local administration of amitriptyline (AMI), desipramine (DMI) and citalopram (CIT) on veratridine-evoked glutamate (Glu) and aspartate (Asp) release in the prefrontal cortex of the conscious rat was examined using in vivo reverse microdialysis. The antidepressants (each at 100 microM) significantly reduced Glu and Asp release. The effect of AMI and CIT was attenuated by i.p. administration of the adenosine A1/A2A receptor antagonist caffeine (10 mg/kg), or by local infusion of the adenosine A1 receptor antagonist 8-cyclopentyltheophylline (CPT, 75 microM). Neither caffeine nor CPT influenced the effect of DMI (100 microM). The inhibitory action of DMI at a lower concentration (50 microM) was diminished significantly by CPT, but not caffeine. Perfusion of 5-hydroxytryptamine (5-HT; 100 microM) and the selective agonist of adenosine A1 receptors N6-cyclopentyladenosine (CPA; 50 and 100 microM) also suppressed Glu and Asp release. It is suggested that the blockade of the cellular uptake of adenosine, or indirect enhancement of its release, and subsequent activation of adenosine A1 receptors may be responsible for the inhibitory effect of antidepressants on Glu and Asp release.

Effect of adenosine kinase, adenosine deaminase and transport inhibitors on striatal dopamine and stereotypy after methamphetamine administration.

The effect of adenosine kinase (AKA), adenosine deaminase (ADA) and transport inhibitors on the release of dopamine (DA) induced by methamphetamine (MTH) in rat striatum was assessed using in vivo microdialysis in freely moving rats. MTH injected in a dose of 3 x 5 mg/kg i.p. at 2-hour intervals produced a massive release of DA. This excessive release of DA was inhibited by the ADA inhibitor 2'-deoxycoformycin (DCF), the AKA inhibitor 5'-iodotubercidin (IOT) and the adenosine uptake inhibitor dilazep (DIL), each of them given locally to the striatum via a microdialysis probe at a concentration of 100 microM. Perfusion with the same concentrations of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and 5'-amino-5'-deoxyadenosine (NH(2)dAD), ADA and AKA inhibitors, respectively, induced a considerably weaker effect on DA release. The non-selective antagonist of adenosine A(1)/A(2A) receptor caffeine (75 microM) significantly prevented the inhibitory effect of DCF, IOT and DIL on the MTH-induced DA release. Intrastriatal administration of DCF, IOT and DIL (5 nmol/microl before each injection of MTH) inhibited the stereotypy induced by MTH. The striatal content of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), decreased by MTH administration and measured 5 days after treatment with the toxin, was reversed by all the inhibitors at the order of potency as follows: IOT>DCF>DIL. Direct agonists of adenosine A(1) and A(1)/A(2A) receptors, N(6)-cyclopentyladenosine (CPA) and 5'-N-ethylcarboxamidoadenosine (NECA), respectively, given intrastriatally (5 nmol/microl) completely abolished the MTH-induced stereotypy and the fall in the striatal content of DA, DOPAC and HVA. The above results show that augmentation of endogenous adenosine in rat striatum by inhibition of its metabolism or uptake-despite the differences in the efficacy of various inhibitors-may provide neuroprotection against a toxic action of MTH.

Effect of acute and chronic administration of 1,2,3,4-tetrahydroisoquinoline on muscle tone, metabolism of dopamine in the striatum and tyrosine hydroxylase immunocytochemistry in the substantia nigra, in rats.

The effects of acute and chronic administration of 1,2,3,4-tetrahydroisoquinoline, an endogenous substance suspected of producing parkinsonism in humans, on the muscle tone and metabolism of dopamine in the striatum, and on the number of tyrosine hydroxylase-immunoreactive cells in the substantia nigra were investigated in rats. Muscle tone was examined using a combined mechanomyographic and electromyographic method which measured simultaneously the muscle resistance of the rat's hind foot to passive extension and flexion in the ankle joint and electromyographic activity of the antagonistic muscles of that joint: gastrocnemius and tibialis anterior. 1,2,3,4-Tetrahydroisoquinoline administered at doses of 50 and 100 mg/kg intraperitoneally for 19 days increased muscle resistance 1 h after the first injection (acute treatment), 1 h after the last injection (chronic treatment) and three days after compound withdrawal. Rigidity observed on the third day of 1,2,3,4-tetrahydroisoquinoline withdrawal was accompanied by an increased tonic (resting) electromyographic activity of the gastrocnemius and tibialis anterior muscles. At the same time, a significant reduction in the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra and a decrease in the dopamine level in the striatum were also found. A declining number of tyrosine hydroxylase-immunoreactive neurons in the whole substantia nigra showed a significant negative correlation with the enhanced muscle resistance, as well as with the tonic electromyographic activity recorded at rest, i.e. before the start of movements, from the gastrocnemius and tibialis anterior muscles. Our results suggest that 1,2,3,4-tetrahydroisoquinoline may be one of the endogenous substances involved in the progress of Parkinson's disease.

Effect of acute and chronic administration of citalopram on glutamate and aspartate release in the rat prefrontal cortex.

The present study was designed to determine whether peripheral administration of the selective serotonin reuptake inhibitor (SSRI) citalopram influenced glutamate and aspartate release in the rat prefrontal cortex using in vivo microdialysis. Citalopram was given acutely at doses of 10 and 20 mg/kg or chronically at a dose of 10 mg/kg daily for two weeks, in both cases by intraperitoneal (ip) route. Citalopram given at a single dose of 20 mg/kg, but not 10 mg/kg, significantly inhibited release of glutamate and aspartate induced by sodium channel activator, veratridine (100 microM). Glutamate and aspartate release was also diminished in animals treated chronically with citalopram. Citalopram did not affect extracellular level of 5-hydroxytryptamine (5-HT) after acute doses, but increased it after chronic administration. On the other hand, single and repeated doses of the drug inhibited veratridine-evoked 5-HT release. Neither single nor chronic treatment with citalopram influenced spontaneous and evoked dopamine (DA) release. The results suggest that in the presence of depolarizing agent, e.g. under conditions resembling a disturbed homeostasis of neuronal network, antidepressant drugs with profile of SSRI may influence excitatory systems in the brain. This effect does not seem to be dependent on the interaction with 5-HT or DA neurotransmission, but rather some inhibitory modulators stimulated in stress situations may contribute to the observed results.

Effect of antidepressant drugs on veratridine-evoked glutamate and aspartate release in rat prefrontal cortex.

In vivo microdialysis in conscious rats was used to evaluate the effect of local application, through a microdialysis probe, of desipramine (DMI), imipramine and citalopram (CIT), on veratridine-evoked glutamate and aspartate release in rat prefrontal cortex (PFCx). All antidepressant drugs (ADs), given at a concentration of 0.1 mM, significantly inhibited glutamate release, while aspartate release was affected only by DMI and CIT. In contrast, local administration of ADs markedly potentiated veratridine-evoked dopamine and noradrenaline release. Perfusion of clonidine, quinpirole and 1-[3-(trifluoro-methyl)phenyl]-piperazine (TFMPP) at 0.1 mM concentration also diminished, evoked release of glutamate and aspartate. The regulation of amino acid release in rat PFCx may be achieved by direct effect of ADs on Na+ channels or indirectly, by involvement of D2/D3, alpha 2 or 5-HT1B heteroceptors activated by the increased level of monoamines in response to the blockade of respective transporters.

Agonists of A1 and A2A adenosine receptors attenuate methamphetamine-induced overflow of dopamine in rat striatum.

The effect of adenosine receptor agonists on the release of striatal dopamine (DA), induced by repeated doses of methamphetamine (MTH), was evaluated. Rats received three injections of MTH (5 mg/kg i.p.) at 2-h intervals. The release of DA in the striatum was measured by a microdialysis in freely moving animals. The agonist of adenosine A1 receptor, N6-cyclopentyladenosine (CPA) and the agonist of adenosine A2A receptor, 2-[p-(carboxy-ethyl)phenylethylamino]-5'-N-ethylcarboxyamidoade nosine (CGS 21680), either of them being infused locally into the striatum at concentrations of 50 and 100 microM, produced decreases in the extracellular DA level during exposure to MTH, and a weaker effect on the levels of DOPAC and HVA. The above effects were reversed by the specific antagonists of adenosine A1 and A2A receptors, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 3, 7-dimethyl-1-propargylxanthine (DMPX), respectively. Our results indicate that both the A1 and A2A adenosine receptors appear to be involved in reducing the excessive release of DA in the striatum; furthermore, they suggest a neuroprotective role of adenosine in MTH neurotoxicity.

Effect of EMD 57445, the selective sigma receptor ligand, on the turnover and release of dopamine.

EMD 57445 (1, 3 and 10 mg/kg, po), a selective sigma receptor ligand without an affinity to dopamine receptors, induced potent, dose-dependent increases in the tissue DOPAC and HVA levels in the rat brain cortex, nucleus accumbens and striatum. The extracellular DOPAC and HVA levels after EMD 57445 and (3 and 10 mg/kg, po) administrations, measured by microdialysis in the rat prefrontal cortex, were also increased, without significant effects on the outflow of dopamine.

N6-2-(4-aminophenyl)ethyladenosine (APNEA), a putative adenosine A3 receptor agonist, enhances methamphetamine-induced dopamine outflow in rat striatum.

In the present study, the effect of adenosine A3 receptor agonist, N6-2-(4-aminophenyl)ethyladenosine (APNEA), on methamphetamine (MTH)-induced dopamine (DA) release in rat striatum was evaluated using microdialysis in freely moving animals. MTH at a dose of 5 mg/kg injected 3-times every two hours produced massive overflow of DA and decline in the level of DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid). APNEA perfused locally to the striatum via microdialysis probe triggered opposite effects, at 75 microM it diminished MTH-induced DA overflow during first 2 h of the experiment (p<0.05), but potently enhanced it at higher 100 microM concentration for entire period of treatment (p<0.001). Concomitant release of glutamate in striatum was slightly decreased by MTH alone, and significantly diminished by coadministration of 100 M APNEA (p<0.001). The data indicate that activation of adenosine A3 receptor exerts rather toxic effect on DA neurons and exacerbates neurotoxicity of MTH. In addition, MTH-induced DA overflow does not seem to result from the increased release of striatal glutamate level.

Adenosine receptors--the role in modulation of dopamine and glutamate release in the rat striatum.

The aim of present study was to assess the role of activation of adenosine A-1 and A-2a receptors in the modulation of dopamine (DA) and glutamate release in the rat striatum by microdialysis in freely moving animals. Adenosine A-1 receptor agonist N6-cyclopentyladenosine (CPA) and A-2a receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680) were administered locally into the striatum through microdialysis probe. CPA (10, 100 and 500 microM) did not affect basal levels of DA or glutamate. In contrast, CGS 21680 at the concentrations of 10, 50 and 100 microM increased in a dose-dependent manner the level of DA and at 100 microM also the level of glutamate. Both agonists at the concentration of 100 microM inhibited KCl-induced (100 mM) DA and glutamate release. The present results suggest, that in physiological conditions only excitatory effects of adenosine may be observed and adenosine A-2a receptors seem to be involved. During depolarization with KCl, adenosine, by inhibiting excessive outflow of neurotransmitters mediated via A-1 and A-2a receptors, manifests its protective role as homeostatic neuromodulator.