ORAL PRESENTATIONS

EFFECTS OF SOME PSYCHOTROPIC DRUGS ONIMMUNOENDOCRINE PARAMETERS

Agnieszka Basta-Kaim, Marta Kubera, Bogus³awa Budziszewska,Lucylla Jaworska-Feil, Magdalena Tetich, Monika Leœkiewicz,

Barbara Korzeniak, Vladimir Holan�, W³adys³aw Lasoñ

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There is evidence that schizophrenia is associ-ated with various dysfunctions in the immunoendo-crine system. We estimated in vitro the effects ofchlorpromazine, clozapine and sulpiride (i) on theproliferation of mouse lymphocytes stimulated byConA, LPS and PWM, and (ii) on the production ofIL-6 and glucocorticoid-mediated gene transcrip-tion in mouse fibroblast cells stimulated by LPS.The mixed D1/D2 dopaminergic antagonist chlor-promazine (10/ – 10/0 M) inhibited the �H-thymi-dine incorporation into mouse spleen cells stimu-lated by all mitogens. Clozapine (10/ and 10/0 M)decreased the proliferative ability of splenocytesonly after LPS stimulation. On the other hand, se-lective D2 dopaminergic antagonist sulpiride (10/1

to 10/ M) had no inhibitory effect. As estimatedby highly sensitive ELISA method, chlorpromazine

(10/0, 3 × 10/0 and 5 × 10/0 M) significantly de-creased LPS, stimulated production of IL-6. Thetreatment of LMCAT cells with chlorpromazine(3–100 �M) evoked a concentration-dependent in-hibition of the corticosterone-induced gene tran-scription. Also clozapine evoked a significant de-crease in glucocorticoid receptor-mediated genetranscription, but with lower potency. Sulpiride waswithout effect. Chlorpromazine and LPS had syner-gistic inhibitory effect on GR function. This sug-gests that the activation of immune response sensi-tizes the GR receptor to suppressive effects ofchlorpromazine. Our study has demonstrated thatchlorpromazine but not other neuroleptics sup-presses the immunological responsiveness, espe-cially its cell-mediated component and also can acton endocrine parameters.

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EVIDENCE FOR ANTIDEPRESSANT- ANDANXIOLYTIC-LIKE ACTIVITIES OF MELATONIN AND

AGOMELATINE IN ANIMAL MODELS

Ewa Bieñ, Piotr Gruca, Zdzis³aw Galoch, Mariusz Papp

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Chronic administration of melatonin and ago-melatine, a potent agonist of MT�/MT� receptorsand antagonist at the 5-HT�( receptors, evokes a ra-pid and robust antidepressant-like activity in thechronic mild stress (CMS) paradigm, a well vali-dated animal model of depression. The magnitudeand time-course of this effect were comparable tothose observed following similar administration oftraditional antidepressant drugs, imipramine andfluoxetine. Interestingly, melatonin reversed theCMS-induced anhedonia only if administered 2 hbefore the dark phase of the 12-h light/dark cycle(evening administration), while agomelatine wasactive also when administered 2 h after the darkphase of the 12-h light/dark cycle (morning ad-ministration), i.e. when it is devoid of chronobioticactivity. This suggests that the mechanism of action

of agomelatine in the CMS model involves its ac-tivity at both the melatonin and 5-HT�( receptors.This conclusion is further supported by the obser-vation that an acute injection of melatonin antago-nist, S 22153, antagonizes the effect of evening butnot morning administration of agomelatine.

In a second series of experiments, the effects ofmorning and evening administrations of melatoninand agomelatine were studied in three animal modelsof anxiety: the elevated plus-maze and Vogel tests,and the footshock-induced ultrasonic vocalization.The results obtained in these studies indicate that inaddition to the potent antidepressant-like action ob-served in the CMS model, melatonin and agomela-tine may also possess anxiolytic activity, whichmay have beneficial implication for their putativeuse in the therapy of depression in humans.

IMIPRAMINE ADMINISTRATION ENHANCES THE EFFECTSOF NMDA RECEPTOR LIGANDS IN THE RAT FRONTAL

CORTEX IN VITRO

Bartosz Bobula�, Krzysztof Tokarski�, Agnieszka Zahorodna�,Grzegorz Hess���

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It has been demonstrated that excitatory aminoacid transmission may be involved in the neuronalresponse to antidepressant treatment. NMDA re-ceptor antagonists exhibit antidepressant-like ac-tions in animal models, and combined administra-tion of NMDA receptor antagonists and antidepres-sants exerts synergistic effects. Another line ofevidence, obtained using neurochemical, molecular

and behavioral approaches, indicated that chronicadministration of antidepressants affects the NMDAreceptor/channel complex. However, the underlyingmechanisms and functional consequences of theseeffects are still not well understood.

This study assessed the effects of repeated ad-ministration (14 days) of imipramine on the func-tion of NMDA receptors by measuring the fre-

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quency of spontaneous epileptiform discharges,which develop in the rat frontal cortical slices incu-bated in Mg�>-free conditions. Imipramine signifi-cantly enhanced both the excitatory effect of NMDAand the inhibitory effect of the competitive NMDA

receptor antagonist CGP 37849 on the frequency ofdischarges. These results are consistent with thestudies indicating that chronic administration of anti-depressant drugs induces adaptive changes in NMDAreceptor/channel complex in the cerebral cortex.

GROUP I METABOTROPIC GLUTAMATE RECEPTORSCHANGE BEHAVIORAL ACTIVITY OF GABA-B RECEPTOR

Halina Car, Agnieszka Nadlewska, Konstanty Wiœniewski

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Baclofen, a selective GABA-B receptor ago-nist, enhanced locomotor activity, exhibited anxio-genic action and was ineffective in the passiveavoidance tests.

(1S,3R)-ACPD, a nonselective mGluR agonist,did not exhibit any effects in all used behavioraltests, but it reduced baclofen-stimulated motility.Coadministration of baclofen and (1S,3R)-ACPDimproved retrieval of the passive avoidance incomparison with baclofen.

(S)-3,5-DHPG, a selective group I mGluRsagonist, had dose-dependent behavioral effects:used at doses of 0.01 and 1.0 nmol icv it improvedconsolidation and retrieval in passive avoidancesituation, at a dose of 0.1 nmol it impaired retrieval,

and at all used doses it did not change locomotion.(S)-3,5-DHPG changed baclofen activity on anxio-lytic effect, and improved consolidation and retrie-val of passive avoidance.

MCPG, a nonselective antagonist of mGluRs,impaired retrieval. MCPG given with baclofen re-duced motility and impaired consolidation process.

AIDA, a selective antagonist of group I mGluRs,administered alone or with baclofen reduced loco-motor activity, improved consolidation, i.e. changedactivity of the agonist of GABA-B receptor.

In summary, the activation or the blockade ofmGluRs changes the behavioral effects of GABA-Breceptor.

STABLE HIGH AND LOW ETHANOL INTAKE PHENOTYPEIN WHP AND WLP SELECTED LINES OF RATS

Wanda Dyr�, Wojciech Kostowski���

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Among animal models of addiction, geneticallyselected lines of rats with well established pheno-type of high and low preference for alcohol are ofparticular importance. In our laboratory, the alco-

hol-preferring WHP (Warsaw High Preferring) andalcohol-non preferring WLP (Warsaw Low Prefer-ring) lines of rats have been raised (currently F�7���generations) by selective breeding. In order to

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evaluate the level of ethanol preference, the ani-mals were housed individually and during the firstweek, the only source of fluid was 10% ethanol so-lution with food available ad libitum.

Afterwards, during 4 consecutive weeks the ratshad free access to food, water and 10% ethanol so-lution. Rats consuming not less than 5 g/kg/24 h ofabsolute ethanol were considered as ethanol-highpreferring while those consuming less than 2 g/kg/24 h of absolute ethanol were assessed as ethanol--low preferring. The present experiment evaluatedthe effect of two differing ethanol access proce-dures on the magnitude of ethanol intake. In thefirst experiment, rats belonging to WHP and WLP

lines as well as outbred Wistars, had free access tofood, water and 10% ethanol solution during 9 con-secutive weeks. In the second separate experiment,the concentrations of ethanol solution were gradu-ally increased by 1% per week during 9 consecu-tive weeks starting from 2% solution. The resultsshow that WLP rats consumed very low amount ofethanol independently of the access procedureused. The ethanol intake in WLP rats was substan-tially lower not only when compared with WHPrats but also when compared with outbred Wistars.Thus, it appears that high and low ethanol drinkingphenotypes in F�7/�� generation WHP and WLPrats, respectively, are firmly established.

MODULATION OF GLUTAMATE AND ASPARTATE RELEASEIN THE RAT PREFRONTAL CORTEX BY SEROTONIN

RECEPTOR LIGANDS

Anna Dziubina, Krystyna Go³embiowska

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A number of studies have shown serotonin(5-HT) modulatory actions on glutamate (GLU)and aspartate (ASP) release in mammalian centralnervous system. Rat prefrontal cortex (PFCx) re-ceives innervation from serotonergic pathwaysoriginating in the dorsal raphe nucleus, and corticalpyramidal neurons are enriched with several sub-types of 5-HT receptors.

In the present study, we investigated the effectof 5-HT receptor agonists on GLU and ASP releasethe rat PFCx using in vivo microdialysis. The dia-lysate level of GLU and ASP was assayed byprecolumn derivatization with DABS-Cl followedby HPLC with VIS detection (System GOLD,Beckman). Sodium channel activator, veratridine(VER, 500 �M), given locally into PFCx increased

GLU and ASP release up to about 400% of a basallevel. Local perfusion with 5-HT��E�( receptor ago-nist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopro-pane (DOI, 100 �M), and both local (100 �M) andperipheral (0.1 and 1 mg/kg ip) treatment with5-HT�� receptor agonist 8-OH-DPAT did not influ-ence GLU and ASP release. On the other hand,5-HT�2 receptor agonist 1,4-dihydro-3-(1,2,3,6-te-trahydro-4-pyridinyl)-5H-pyrrolo[3,2-b]pyridin-5--one (CP 93129, 50 and 100 �M) decreased VER--evoked amino acid release. This effect was attenu-ated by selective 5-HT�2 receptor antagonist SB216641 (2 mg/kg ip). SB 216641 did not alter dia-lysate GLU and ASP levels. Our findings indicatethat 5-HT may suppress cortical excitatory trans-mission by the activation of 5-HT�2 heteroreceptors.

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INFLUENCE OF NMDA, A POTENT AGONIST OFGLUTAMATE RECEPTOR, ON BEHAVIORAL ACTIVITY OF

RATS WITH EXPERIMENTAL LIVER FAILURE

Ma³gorzata Fedosiewicz-Wasiluk, Zdzis³aw Ho³y, Konstanty Wiœniewski

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The effects of NMDA receptor agonist on thebehavioral activity in rats with experimental liverfailure were investigated in the present study. Theexperiments were performed on adult male Wistarrats. Experimental hepatic failure was induced byintraperitoneal (ip) injection of tioacetamide (TAA,200 mg/kg) for three consecutive days. Rats treatedwith saline (0.9%) served as a control. Stimulationof the NMDA glutamatergic receptor was evokedby ip injection of an agonist, N-methyl-D-aspartateacid (NMDA) at several doses, 30 min before theexperiments. Memory motivated affectively wasevaluated by the passive avoidance responses. More-

over, the speculative influence of the treatment onmotor activity was tested in open field. We ob-served that TAA given alone did not have any sig-nificant influence on motor activity, while NMDAgiven alone increased motor activity of rats in openfield test, but not in rats treaded with TAA. TAAgiven alone, had no influence on a passive avoid-ance latency. The NMDA given alone, and in ratswith experimental liver failure, increased acquisi-tion, consolidation and recall of passive avoidanceresponses. We observed that reactivity of NMDAglutamate receptor in rats with liver failure washigher than in control rats.

EFFECT OF SELECTIVE ADENOSINE A2A RECEPTORANTAGONIST ON L-DOPA BIOTRANSFORMATION IN

THE RAT STRIATUM

Krystyna Go³embiowska, Anna Dziubina

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Motor fluctuations and dyskinesias in Parkin-son’s disease may be due to fluctuations of L-DOPAin the brain. Endogenous dopamine (DA) release isunder autoregulatory control mediated by DA D2autoreceptors. However, this autoregulatory me-chanism is no longer able to modify DA relase de-rived from exogenous L-DOPA. Due to the keyrole played by adenosine A�� receptors in the regu-lation of striatal dopaminergic neurotransmission,drugs acting on these receptors can reduce the ac-tivity of the striatopallidal pathway and modifyL-DOPA-induced DA release from nigrostriatalterminals.

In the present study, we have examined the effectof new selective adenosine A�� receptor antagonist(4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-�]-

[1,3,5]triazin-5-yl-amino]ethyl)phenol) (ZM 241385)on DA release in the rat striatum using in vivo mi-crodialysis. Extracellular level of DA was assayedby HPLC-ED. L-DOPA (2.5 �M) perfused throughmicrodialysis probe for 1 h caused a large increasein DA level in extracellular space. ZM 241385 ap-plied locally into the striatum (50–100 �M) en-hanced DA release in a dose-dependent manner.This effect was not observed when L-DOPA wasperfused at 25 �M. Our findings suggest that adeno-sine A�� receptor antagonist can modulate activityof DA nigrostriatal pathway interacting with ade-nosine A�� receptors expressed in striatopallidalneurons. However, such mechanism does not func-tion in the presence of high concentration of DAprecursor.

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PIRIBEDIL HAS ANTIDEPRESSANT-LIKE ACTIVITY INA CHRONIC MILD STRESS MODEL OF DEPRESSION

Piotr Gruca, El¿bieta Moryl, Mariusz Papp

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The study was designed to determine if chronicadministration of piribedil, an antiparkinsonianagent with dopamine (D�/D�) agonist and adrener-gic (��) antagonist properties, is able to restore adeficit in sucrose consumption caused by thechronic mild stress (CMS) procedure. In the CMSprocedure, the animals are subjected to a variety ofmild stressors for a prolonged period of time, re-sulting in a generalized subsensitivity to rewardingstimuli (anhedonia), which can be measured as de-creased consumption of a palatable 1% sucrose so-lution.

It was found that chronic (5 weeks) administra-tion of piribedil did not change the behavior of con-trol animals and gradually reversed the CMS-in-duced anhedonia. The increases in sucrose drinkingin stressed animals receiving 53, 13 and 3 mg/kg ofpiribedil were statistically significant after 1, 2 or 5

weeks of treatment, respectively. Similar admini-stration of imipramine (10 mg/kg) significantly in-creased sucrose consumption in stressed animalsafter 3 weeks of treatment. The effect of both imi-pramine and piribedil was maintained at similarlevel for at least 1 week after cessation of treatment.

These results demonstrate that piribedil is ableto reverse the stress-induced anhedonia in the CMSmodel, suggesting that, in addition to its known an-tiparkinsonian properties, this drug may also pos-sess antidepressant activity. The magnitude of theeffect of piribedil was comparable to that of imi-pramine. However, the onset of action of piribedil(at 13 and 53 mg/kg) was faster than that of imi-pramine. The synergistic action of piribedil as ��adrenergic antagonist and DA agonist could be re-sponsible for the short delay of action in the CMSmodel.

COMPLEX INTERACTIONS OF ANTIDEPRESSANT DRUGSWITH CYTOCHROME P-450 IN THE RAT LIVER

Anna Haduch, Jacek Wójcikowski, W³adys³awa Daniel

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The influence of antidepressant drugs (imi-pramine and sertraline) on the activity of cyto-chrome P-450 was studied in vitro in the followingmodels: 1) estimation of cytochrome P-450 activityin control liver microsomes in the absence andpresence of antidepressants added in vitro; 2) esti-mation of cytochrome P-450 activity in liver mi-crosomes of rats treated for 1 day with antidepres-sants; 3) estimation of the cytochrome activity inliver microsomes of rats treated chronically withantidepressants.

Cytochrome P-450 activity was assessed by

measuring the rate of testosterone hydroxylation in

the following positions: 2� and 16� (CYP2C11),

2� and 6� (CYP3A1/2), 16� (CYP2B1/2) and 7�

(CYP2A1/2). The amount of the metabolites for-

med in vitro was assayed using the HPLC method.

The hepatic level of cytochrome P-450 proteins

was determined by Western blotting using specific

polyclonal antibodies.Imipramine added to liver microsomes in vitro

distinctly inhibited CYP2A1/2 and CYP2B1/2 but

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it showed only a weak inhibitory effect on the ac-tivity of CYP2C11 and CYP3A1/2. Sertralineturned out to be a strong inhibitor of the four testedisoenzymes. One-day exposure to imipramine de-creased the activity of these isoenzymes, whileone-day exposure to sertraline enhanced the activ-ity of CYP2B1/2. After chronic treatment with imi-pramine, the activity of CYP3A1/2 still remaineddecreased while that of CYP2C11 and CYP2B1/2

was increased. Instead, chronic treatment with ser-traline elevated the activity of all tested iso-enzymes. The obtained results indicate that anti-depressants affect the activity and expression ofcytochrome P-450 isoenzymes involved in the me-tabolism of endogenous substances and drugs.These complex effects depend on the kind of drugand isoenzyme, as well as on the duration of treat-ment.

INFLUENCE OF PRE- END POSTNATAL EXPOSURETO COPPER ON VISUAL EVOKED POTENTIALS (VEP) OF

RATS BEFORE AND AFTER INTRACEREBROVENTRICULARINJECTIONS OF CATECHOLAMINES

Ewa Herba�, Agata R. Plech�, Dorota Pojda-Wilczek�,Katarzyna Makowiecka-Obidziñska�, Stefan M. Pojda�, Ryszard Szkilnik�

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Aim

Copper (Cu) seems to be an essential cofactorfor a variety of proteins in all living organisms.Some diseases, e.g. Wilson’s disease, are due to theCu toxicity in the basal ganglion of the brain. Cuhas the capacity to cause damage due to its abilityto oxidize proteins and lipids and to enhance for-mations of toxic intra- and extracellular free radi-cals. The purpose of this paper was to find out if theCu intoxication modifies the effect of catechola-mines on VEP.

Methods

Wistar albino rats were divided into 3 groups:the dams (CuM) received CuSO at 200 ppm withdrinking water since the time of conception andduring 21 days after delivery, the newborn rats ofboth sexes, prenatally exposed to Cu, and the con-trol group receiving tap water only. VEP were re-corded after the injection of 10 �l of saline, dopa-mine (DA) at 50 and 100 nmols and norepinephrine(NE) at 25 and 50 nmols into the right lateral brainventricle. Amplitudes of N� and P� peaks of VEP

were measured. The Student’s t-test was used forstatistical analysis with statistical significance setat p < 0.05.

Results

The mean values of N� and P� latencies wereshortened in comparison with the control group af-ter both doses of NE. The injection of NE de-creased the amplitude of N� P� by about 5–18% inCuM group, but increased it to 140–160% in off-spring group. The values of N� and P� latencieswere shortened to 92–95% in the rats prenatally ex-posed to Cu, but became longer (112%) in CuMgroup after both doses of DA. The N� P� amplitudedeclined in both examined groups by about 20%after 50 nmols of DA and by about 3–16% after100 nmols of DA. These changes were statisticallysignificant.

Conclusions

Cu diminished the effect of NE and DA onVEP. NE increased the visual transmission in therats prenatally exposed to Cu.

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COGNITIVE EFFECTS OF PROPOFOL AND KETAMINEANESTHESIA IN HUMANS

Piotr Jakubów, Jan J. Braszko

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Cognitive functions following anesthesia gainincreasingly more attention. The aim of this studywas to assess the influence of midazolam, propofol(P) and additional dose of ketamine (K) used in an-esthesia on some aspects of cognitive functioningin humans.

Groups of patients prepared by regional blockRB [0.5% bupivocaine or 1% lidokaine precededby iv (1.5 mg), or po (7.5 mg) dose of midazolam]received in addition P, K, P+K, or no treatment. OnDay 5 before and Day 7 after the surgery, all pa-tients underwent cognitive testing: Mini MentalState Examination, Rey Verbal Learning (RVL),Wechsler Digits Recall (WDR), Beck Depression

Inventory and Hopkins Symptoms Checklist.Twelve drug-free healthy volunteers were evalu-ated with the same battery of tests. Lower scoreswere observed only in the group with RB receivingalso P+K. However, an improvement of perform-ance in RVL and WDR tests was seen in the groupwith RB given small dose of K (p < 0.05).

Conclusions: (i) midazolam used for RB doesnot influence cognitive processes, (ii) K may havesome memory-enhancing effects.

Acknowledgment. This work was supported by MedicalAcademy of Bia³ystok (3 – 66 509).

EFFECT OF SUBSTITUTED BENZAMIDES ON FEEDINGAND HYPOTHALAMIC NEUROPEPTIDE Y-LIKE

IMMUNOREACTIVITY (NPY-LI) IN RATS

Krystyna Kmieciak-Ko³ada, Jaros³aw Paw³owski, Ewa Obuchowicz,Robert Krysiak, Zbigniew S. Herman

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We aimed to evaluate the effects of three substi-tuted benzamides on feeding behavior in rats withfree access to food and with access to food limitedeither to the light or to the dark phase of the diurnalcycle, and to determine whether the hypothalamicneuropeptide Y (NPY) system is involved in theaction of these drugs on feeding. In freely feedingrats, a single dose of eticlopride (ETI 1 mg/kg) orraclopride (RA 1 mg/kg) decreased 24-h food in-take, whereas remoxipride (REM 3 mg/kg) pro-duced no effect. Single doses of ETI and RA butnot of REM decreased hypothalamic NPY-LI im-

munoreactivity. ETI administered for 14 days de-creased both food intake and hypothalamic NPY-LI.When given for 14 days, RA and REM decreasedfood intake in rats with access to food in the dark(19.00–7.00) but not in the light (7.00 and 19.00)phase of the diurnal cycle. Both these compoundsdecreased hypothalamic NPY-LI only in the formergroup of rats. The results suggest that the effects ofsubstituted benzamides on feeding behavior de-pend on the drug and the time of administration,and these effects are related to the altered functionof the hypothalamic NPY system.

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EFFECT OF �-AMINOBUTYRIC ACID AND PHENOBARBITALON KYNURENIC ACID SYNTHESIS IN THE RAT BRAIN

SLICES

Tomasz Kocki, Tomasz Tomczyk, Damian Kuc, Marian Wielosz,Waldemar A. Turski

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Kynurenic acid (KYNA), a substance endoge-nous to the brain, inhibits the activity of all threeionotropic excitatory amino acid receptors. KYNAacts most potently at the glycine site of N-methyl-D-aspartate (NMDA) receptor complex. KYNA issynthesized via the irreversible transamination ofthe tryptophan metabolite L-kynurenine by kynu-renine aminotransferases. KYNA was shown to dis-play potent neuroprotective and anticonvu1siveproperties, and its impaired production was impli-cated in the pathogenesis of epilepsy and neurode-generative disorders.

In the present study, we investigated the influ-ence of inhibitory amino acid, �-aminobutyric acid(GABA), and antiepileptic drug, phenobarbital, onKYNA synthesis in the rat brain cortex. KYNA

was determined by HPLC and detected fluoromet-rically.

GABA at the concentrations of 0.5, 1.0 and 3.0mM diminished KYNA synthesis in the brain corti-cal slices to 87% (NS), 73% (p < 0.05) and 60%(p < 0.001) of the control level, respectively. Anti-epileptic drug, phenobarbital, at the concentrationsof 0.5, 1.0 and 3.0 mM enhanced KYNA produc-tion to 117% (NS), 123% (p < 0.01) and 125%(p < 0.01) of the control, respectively.

Our data suggested that GABA and phenobarbi-tal could modulate KYNA production.

Acknowledgment. This study was supported by grantNo. 6 P05A 053 21 from the State Committee for ScientificResearch, Warszawa, Poland.

NEUROPROTECTIVE EFFECT OF MPEP INMETHAMPHETAMINE-INDUCED LESIONS OF

DOPAMINERGIC NEURONS IN RATS

Jolanta Konieczny, Krystyna Go³embiowska�, Stanis³aw Wolfarth,Krystyna Ossowska

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Degeneration of dopaminergic nigrostriatalneurons is a primary cause of Parkinson’s disease(PD). Oxidative stress and excitotoxicity are thoughtto be key mechanisms responsible for degenerationof dopamine (DA) cells. The abundance of mGluRsin the basal ganglia suggests that they may playa role in the modulation of DA function in the

brain. Recent evidence has shown that the activa-tion of group I mGluRs increases the excitabilityand release of glutamate, and antagonists of group ImGluRs seem to be neuroprotective. The aim ofour study was to examine the role of the selectiveantagonist of mGlu5 receptors, MPEP, in the meth-amphetamine (MTH)-induced neurotoxicity in rats.

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MTH (5 × 10 mg/kg sc) decreased tissue content ofstriatal DA and its metabolites DOPAC and HVA inrats. MPEP (5 × 5 mg/kg ip) given jointly withMTH reversed effect of that neurotoxin on the levelof DA and its metabolites. To investigate the influ-ence of the blockade of mGlu5 receptor subtypewith MPEP on spontaneous and stimulated DA re-lease in the rat striatum, we used in vivo micro-dialysis method. MPEP given ip (5 mg/kg) dimi-nished basal extracellular DA level in the striatum,as well as DA release stimulated either by MTH

(10 mg/kg sc) or veratridine (100 �M). Moreover, ittransiently dimished the MTH-induced hyperther-mia and reduced the body temperature per se. Theresults obtained in our study demonstrate that theblockade of mGluR5 by MPEP may protect dopa-minergic neurons against the MTH-induced toxic-ity. A reduction of the MTH-induced DA efflux inthe striatum due to the blockade of mGluR5, aswell as a decrease in hyperthermia may contributeto neuroprotection afforded by this compound.

NEGATIVE IMMUNOREGULATORY EFFECTS OFFLUOXETINE PARTIALLY DEPENDS ON THE cAMP –

PROTEIN KINASE A PATHWAY

Marta Kubera, Gunter Kenis�, Agnieszka Basta-Kaim,Bogus³awa Budziszewska, Lucylla Jaworska-Feil, Monika Leœkiewicz,Magdalena Tetich, Barbara Korzeniak, M. Maes�, W³adys³aw Lasoñ

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Antidepressants, including selective serotoninreuptake inhibitors (SSRI), such as fluoxetine, havenegative immunoregulatory effects. They suppressthe interferon-� (IFN-�)/interleukin-10 (IL-10) pro-duction ratio. Since some antidepressants stimulatecAMP synthesis, the aim of our study was to exam-ine whether the negative immunoregulatory effectsof fluoxetine may be blocked by antagonists of thecAMP-dependent PKA pathway, i.e. SQ 22536, anadenylate cyclase inhibitor, and Rp-Br-cAMPs, aPKA antagonist. To this end, the diluted wholeblood of 17 normal volunteers was incubated withfluoxetine (10/6 and 10/0 M) with or without SQ22536 (10/6 and 10/ M) and Rp-Br-cAMPs (10/6

and 10/ M), and we determined the levels of

IFN-�, IL-10 and tumor necrosis factor-� (TNF-�)using ELISA method. Fluoxetine (10/6 and 10/0 M)significantly reduced the production of IFN-� andTNF-� and significantly decreased the IFN-�/IL-10production ratio. SQ 22536 and Rp-Br-cAMPswere unable to block the suppressant effects offluoxetine on the IFN-�/IL-10 ratio. Rp-Br-cAMPs(at 10/ M, but not at 10/6 M) blocked thefluoxetine-induced suppression of TNF-� produc-tion. It is concluded that the suppressant effect offluoxetine on the IFN-�/IL-10 production ratio doesnot depend on cAMP-PKA mechanism. On theother hand, the cAMP-PKA pathway may be animportant molecular basis for fluoxetine-inducedsuppression of TNF-� production.

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EFFECT OF NAFADOTRIDE, THE NEW DOPAMINE D3

ANTAGONIST, ON DOPAMINE (DA)AND 5-HYDROXYTRYPTAMINE (5-HT) TURNOVER

IN THE BRAIN OF RATS: COMPARISON WITHHALOPERIDOL AND CLOZAPINE

£ukasz Labus, Przemys³aw Nowak, Aleksandra Bortel, Grzegorz Kuballa,Ryszard Brus

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Central dopamine D� receptor cloned by Soko-loff et al. [4] became a target for novel antipsy-chotic drug which might be free of extrapyramidaleffect. Dopamine D� receptor in rat brain is pre-dominantly localized in limbic regions such as theolfactory tubercles, nucleus accumbens, islands ofCalleja and cerebellum. It seems to be mostly pre-synaptic, controlling activity of dopaminergic neu-rons and theirs transmission, and can be target forneuroleptics of novel generation. Recently, antago-nists relatively selective for the dopamine D� re-ceptor have been developed, and among them nafa-dotride (N-[(n-butyl-2-pyrrolidinyl)methyl]-1-me-thoxy-4-cyano-naphthalene-2-carboxamide), whichis characterized by a 10–20 times higher affinity forthe dopamine D� receptor than for the dopamine D�receptor [3]. Nafadotride easily crosses the blood-brain barrier and is selective for dopamine D� re-ceptor at the doses below 1.0 mg/kg [2, 3]. The bio-logical and pharmacological properties of nafado-tride are intensively studied.

Therefore, in this study, we examined the effectof nafadotride injected intraperitoneally (ip) to ratsat 0.025 mg/kg for 14 days on DA and 5-HT turn-over in the striatum and hippocampus of the brain.Thirty minutes after the last of multiple nafadotridedoses, hydroxybenzylhydrazine (NSD-1015), an in-hibitor of aromatic amino acid, was injected at 100mg/kg ip, 30 min later the rats were scarified, andthe level of L-dihydroxyphenylalanine (L-DOPA)and 5-hydroxytryptophan (5-HTP) was estimatedin the striatum and hippocampus by HPLC/EDtechnique. The results of DA and 5-HT turnoverwere presented in nmol/g of wet tissue/1 h [1]. Theeffect of nafadotride on DA and 5-HT turnover wascompared to that produced by multiple injections

of haloperidol (a dopamine D� receptor antagonist,0.05 mg/kg ip) and clozapine (a dopamine D re-ceptor antagonist, 5.0 and 0.5 mg/kg ip). Controlrats were injected saline at 2.0 ml/kg ip.

We showed that haloperidol injected for 14days increased striatal DA turnover only. No exam-ined substance applied for 14 days influenced 5-HTturnover in the striatum. In the hippocampus, nafa-dotride only decreased the DA turnover. All exam-ined substances did not influence 5-HT turnover inthe hippocampus.

Acknowledgment. This study was supported by thegrant No. NN-4-003/02 from Medical University of Silesia.Authors wish to thank to Dr. Pierre Sokoloff of INSERMfor the generous donation of nafadotride.

REFERENCES

1. Carlson A., Davison J.N., Kehr W., Lindquist M.,Atack C.V.: Simultaneous measurement of tyrosineand tryptophan-hydroxylase activity in brain in vivo,using an inhibitor of the aromatic amino acid decar-boxylase. Naunyn-Schmied. Arch. Pharmacol., 1972,275, 153–168.

2. Sautel F., Griffon N., Sokoloff P., Schwartz J.C., Lau-nay C., Simon P., Costentin J., Schoenfelder A., Gar-rido F., Mann A.: Nafadotride, a potent preferentialdopamine D

�receptor antagonist, activates locomo-

tion in rodents. J. Pharmacol. Exp. Ther., 1995, 275,1239–1246.

3. Sigala S., Missale C., Spano P.F.: Opposite effect ofdopamine D

�and D

�receptor on learning and memory

in the rat. Eur. J. Pharmacol., 1997, 336, 107–112.

4. Sokoloff P., Giros Br., Martres M.P., Bouthenet M.L.,Schwartz J.C.: Molecular cloning and characterizationof a novel dopamine receptor (D

�) as a target for neu-

roleptics. Nature, 1990, 347, 146–151.

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EFFECT OF DESIPRAMINE ON THE TRANSCRIPTIONALACTIVITY OF DOPAMINE D2 RECEPTOR GENE PROMOTER

IN THE NB41A3 CELLS IN VITRO

Beata Legutko, Joanna Siwanowicz, Marta Dziedzicka-Wasylewska

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Antidepressant drugs (ADs) have traditionallybeen assumed to exert their clinical effects throughan interaction with noradrenergic or serotonergicsystems. On the other hand, however, after repeatedadministration, ADs have been also found to affectbrain dopaminergic system, especially by up-regu-lating postsynaptic dopamine D� and D� receptors,and by down-regulating the sensitivity of presynap-tic D� receptors. Since it is still not clear whetherADs exert their effect via stabilization of the intra-cellular mRNA coding for dopamine D� receptors,or at the level of transcription, we designed experi-ments in order to investigate the effects of ADs onthe transcriptional activity of the dopamine D� re-ceptor gene promoter. As an antidepressant drugwe chose desipramine (DMI) which is selectivenoradrenaline reuptake inhibitor, widely used in the

clinic. Experiments were carried out using murineneuroblasoma cell line, NB41A3, which expressesendogenous dopamine D� receptors, and was addi-tionally transfected transiently with the vector withinserted D� receptor gene promoter sequence cou-pled to luciferase (LUC) as a reporter gene. Thepromoter region of the D� receptor gene containsmost of the known regulatory elements of D� re-ceptor transcription, including RARE, Sp1 andAP2 sites.

The obtained results indicate that while retinoicacids (RA, all-trans and 9-cis, 10/6 M), well-knownactivators of dopamine D� receptor gene transcrip-tion, increased the transcriptional activity of thestudied promoter by ca. 80%, DMI dose-depen-dently (1–75 �M) decreased it. The significance ofthese results will be discussed.

1,2,3,4-TETRAHYDROISOQUINOLINE (TIQ) PROTECTSDOPAMINERGIC NEURONS AGAINST THE ROTENONE-INDUCED

LOSS OF DOPAMINE IN THE RAT STRIATUM

El¿bieta Lorenc-Koci, Krystyna Go³embiowska�, Ma³gorzata Zapa³a,Jadwiga Wardas

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Parkinson’s disease (PD) is a progressive neu-rodegenerative disorder with still unknown etiolo-gy. Recently, attention has been focused on thelipophilic pesticide rotenone, which acts as a factorcausing PD. Rotenone is a specific inhibitor of mi-tochondrial complex I which causes destruction ofnigrostriatal dopamine (DA) neurons in rats. Ourrecent study showed that TIQ, an endogenous sub-stance suspected of producing parkinsonism in hu-

mans, elevated GSH level both in the striatum andsubstantia nigra (SN), and lowered the level of re-active oxygen species in the SN.

The aim of our study was to examine the influ-ence of chronic TIQ administration on levels of DAand its metabolites in rotenone-lesioned rats. Rote-none was given at a dose of 2 �g/5 �l unilaterallyinto the left medial forebrain bundle (MFB). TIQwas administered at a dose of 50 mg/kg ip 4 h be-

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fore and once a day for 21 days after rotenone ad-ministration. Control rats received an appropriatevolume of the vehicle. All the rats were killed bydecapitation 4 h after the last injections. DA and itsmetabolites in the striatum were assayed by HPLCwith electrochemical detection. Rotenone causeda dramatic decrease in the level of DA and its me-

tabolites in the lesioned striatum compared to thenon-lesioned side and sham-operated rats. ChronicTIQ administration partially prevented the loss ofDA and its metabolites in rotenone-lesioned rats.Our results suggest for the first time that TIQ pos-sesses neuroprotective properties.

OPPOSITE EFFECTS EVOKED BY ALLOPREGNANOLONEAND MIDAZOLAM ON PICROTOXIN-INDUCED CHANGES

IN DOPAMINE AND SEROTONIN METABOLISM

Piotr Maciejak�, Pawe³ Krz¹œcik�, Agnieszka I. Cz³onkowska�, JanuszSzyndler�, Andrzej Bidziñski�, Marek Siemi¹tkowski�, Jerzy Walkowiak�,

Ma³gorzata Lehner�, Wojciech Kostowski���, Adam P³aŸnik���

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The effects of allopregnanolone and midazo-lam, given intracerebroventricularly, on the behav-ioral and biochemical effects of picrotoxin were ex-amined in a model of neurotoxin-induced seizuresin mice. After acute injections, midazolam (ED07 =39.8 nmol) and allopregnanolone (ED07 = 11.0nmol) produced similar and dose-dependent pro-tection against picrotoxin-induced seizures. Picro-toxin given intraperitoneally at the ED@7 dose sig-nificantly decreased the concentration of serotonin(5HT), dopamine (DA), homovanillic acid (HVA)and 3,4-dihydroxyindoleacetic acid (DOPAC) inthe mouse striatum and frontal cortex, immediately

prior to the onset of seizures. A single injection ofallopregnanolone, most potently of all treatments,antagonized the biochemical effects of picrotoxin,and it abolished the effects of the neurotoxin onDA, HVA and 5-HT concentrationin the mousestriatum and frontal cortex. These results providea direct argument for an involvement of central do-paminergic and serotonergic systems in seizure de-velopment. The present data add also to the accu-mulating evidence suggesting a favorable pharma-cological profile of some neurosteroids, currentlyconsidered to have a future role in the managementof epilepsy.

ANXIOLYTIC EFFECT OF TRAMADOL (TRAM) ANDGABAPENTIN (GBP) SIMULTANEOUSLY INJECTED TO RATS

Ma³gorzata Nawrocka, Izabella Panocka, Marek Kowalczyk

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Chronic pain states are frequently accompaniedby anxiety, so successful therapy may require a

combined treatment with analgesics and anxioly-tics. Our previous study revealed that GBP, a new

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antiepileptic drug effective in neuropathic pain,given concomitantly with TRAM, weak opioid an-algesic, significantly increased its antinociceptiveeffect in rats. Recent studies have shown that GBPpossesses also anxiolytic properties.

The aim of our investigations was to study theanxiolytic activity of TRAM (20 mg/kg) and GBP(25, 50, 100 mg/kg) injected alone or concomi-tantly in elevated plus maze (EPM) test in rats. Theside effect such as muscle relaxation was investi-gated in rota-rod test.

In EPM test, TRAM or GBP�0 given alone wasineffective. GBP07� �77 alone and GBP�0� 07� �77 giventogether with TRAM exerted significant anxiolyticeffect. In rota-rod test, only GBP at the doses of 25

and 50 mg/kg alone and GBP�0 + TRAM did notinfluence rat’s motor coordination. GBP07 bothalone and together with TRAM only slightly im-paired motor coordination in rota-rod test.

Our study showed that at analgesic doses ofGBP + TRAM suppressed anxiety. Taking into ac-count that both these drugs have favorable side ef-fects profile, such analgesic and anxiolytic effectoffers a possibility of developing a single drug thatmay suppress acute and chronic pain states as wellas concomitant anxiety.

Acknowledgment. This study was supported by grantNo. 148103/C-TOO/96 from the State Committee for Sci-entific Research, Warszawa, Poland.

ENHANCEMENT OF D3 RECEPTOR-MEDIATED YAWNINGBEHAVIOR IN AMPHETAMINE-PRIMED RATS

Przemys³aw Nowak

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Repeated exposure to amphetamine (AMPH)results in sensitization to its behavioral stimulantproperties and enhancement of AMPH-induced do-pamine (DA) release in the rat forebrain. On theother hand, the finding that the stereotyped behav-ioral response to apomorphine, a directly acting do-paminergic agonist, is not altered after chronictreatment with AMPH, suggests that postsynapticDA receptors, are not modified in AMPH-sensi-tized rats. Both classes of DA receptors are actuallyheterogeneous families of receptors (i.e. D�, D�,and D belong to D2 class; D� and D0 to D1 class).The aim of the study was to examine behavioral ef-fects of D� receptor stimulation in AMPH-sen-sitized rats. Two direct DA D� receptor agonistswere used: quinpirole (mixed D�/D� agonist) and7-OH-DPAT (specific D� agonist). AMPH-sensi-tization was developed by D-AMPH administration(1.0 mg/kg/day) to rats, starting from 22 day afterbirth and continued for 10 consecutive days. Eightweeks after priming procedure, the rats were usedfor further study. The first part of experiment was

conducted to confirm development of sensitization(acquisition). As expected, acute challenge of thoseanimals with D-AMPH induced more pronouncedlocomotor activity and stereotyped behavior inAMPH-primed rats vs. control, as well as increasedDA content in the neostriatal microdialysate invivo. The second part of the study has focused onthe D� DA receptor reactivity in AMPH-primedanimals. We have found increased D� receptor--mediated yawning behavior in sensitized rats vs.control for all tested doses of 7-OH-DPAT and thelowest used dose of quinpirole. Therefore, it can beconcluded that long-term sensitization of DA neu-rotransmitter system, produced by repeated AMPHtreatments at early stages of ontogeny, is associatedwith enhanced behavioral and neurochemicalAMPH-induced changes, accompanied by evidentalteration in D� receptor functioning, measured bybehavioral methods.

Acknowledgment. This work was supported by thegrant No. NN-4-002/02 from the Medical University ofSilesia, Poland.

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DETERMINATION OF HYDROXYL RADICAL FROM IN VIVOMICRODIALYSATES OF THE RAT NEOSTRIATUM:

METHODOLOGICAL ASPECTS AND PRELIMINARY FINDINGS

Przemys³aw Nowak�, Ryszard Brus�, Richard M. Kostrzewa�

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In rats in which dopamine (DA) innervation toneostriatum was largely destroyed (> 98%) bytreatment of rats with the neurotoxin 6-hydroxy-dopamine (6-OHDA), 67 �g into each lateral ven-tricle; at 3 days after birth, the elevated levels ofhydroxyl radical (HO�) were found in this brain re-gion in adulthood [1]. In the present study we usedan identical salicylate-trap method as the indirectmeasure of hydroxyl radical. Accordingly, the HO�--salicylate byproducts 2,3-dihydroxybenzoic acid(2,3-DHBA) and 2,5-DHBA were analyzed in theeffluent of the in vivo microdialysate (artificialcerebrospinal fluid with 5 mM salicylate) from in-tact and largely DA-denervated neostriatum of rats.We found that the basal level of DA in the micro-dialysate from intact and DA-denervated neostria-tum was virtually identical, as was the level of2,3-DHBA and 2,5-DHBA. Both ketamine (5 mg/kgip) and D-amphetamine (1 mg/kg ip) had no nota-ble effect on these parameters. The apparent dis-crepancy between this latest finding and the pre-viously reported elevation in 2,3-DHBA and2,5-DHBA levels appears to be related to a metho-dological difference. In the prior study, salicylatewould have gained entry to nervous tissue of

neostriatum following icv administration, so HO�

formed in nerves would have interacted with sali-cylate to yield DHBA products. In the currentstudy, salicylate in the microdialysis fluid wouldhave been largely restricted to a small distance re-flecting its diffusion, and DHBA products wouldlikely reflect HO� formation in extraneuronalspaces. Additional studies will explore this hypo-thesis. The emphasis of this report is on methodo-logical details that have a major bearing on the de-termination of reactive oxygen species such as HO�

and on the reasonable interpretation of findings. Itthus is possible to assess HO� and like-species indifferent biological compartments and, thereby, de-rive a more complete assessment of autooxidativeand protective mechanisms in brain tissue.

Acknowledgment. This study was supported by thegrant No. NN-5-001/02 from the Medical University ofSilesia and the grant No. NS 39272 from NIH.

REFERENCE

1. Kostrzewa R.M., Kostrzewa J.P., Brus R.: Dopaminer-gic denervation enhances susceptibility to hydroxylradicals in rat neostriatum. Amino Acids, 2000, 19,183–199.

CGS 21680, A SELECTIVE ADENOSINE A2A RECEPTORAGONIST, COUNTERACTS THE PHENCYCLIDINE-INDUCED

SENSORIMOTOR GATING DEFICIT IN RATS

Ma³gorzata Pietraszek, Ma³gorzata Zapa³a, Jolanta Konieczny, Jadwiga Wardas

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Recently, it has been proposed that adenosine isinvolved in pathophysiology of schizophrenia, and

that adenosine A�� receptor agonists may be poten-tial antipsychotic drugs as they display behavioral

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effects similar to those produced by neuroleptics.Deficit of prepulse inhibition (PPI) induced by do-paminomimetics and uncompetitive NMDA recep-tor antagonists has been proposed as an animalmodel of the sensorimotor gating deficits in schizo-phrenia. Thus, the aim of the present study was tofind out whether CGS 21680, a selective adenosineA�� receptor agonist, influences the phencyclidine--induced PPI deficit. Additionally, the ataxic/seda-tive effects of CGS 21680 were examined in rats bythe use of rota-rod and catalepsy tests. Systemic ad-ministration of phencyclidine (PCP, 5 mg/kg sc)

produced a profound reduction in PPI. CGS 21680(0.1 and 1 mg/kg ip) dose-dependently inhibitedthe disruptive effect of PCP on PPI. Moreover,CGS 21680 (0.1 and 1 mg/kg) was without effecton the motor behavior of rats as measured using the9-cm cork and rota-rod tests. Only after the highestdose used (5 mg), some rats showed signs of dis-turbed balance and loss of the hind limb control.The present results support the view that adenosineA�� receptor agonists may be potentially useful an-tipsychotic agents with low incidence for extrapy-ramidal side effects.

ROLE OF DOPAMINERGIC RECEPTORS OF THE LATERAL GENICULATENUCLEUS IN THE VISUAL TRANSMISSION (VEP) IN RATS

Agata R. Plech�, Ewa Herba�, Dorota Pojda-Wilczek�,Katarzyna Makowiecka-Obidziñska�, Stefan M. Pojda�, Andrzej Plech�

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Purpose

It has been found in our previous study that thestimulation of �-adrenergic receptors in the lateralgeniculate nucleus (LGN) intensifies visual responsein the rat brain. Dopamine (DA) given into cerebrallateral ventricle has similar effect. The aim of thepresent study was to establish the influence of DAand some specific agonists of DA receptors injectedinto LGN on Visual Evoked Potential (VEP).

Method

The experiments were performed on adult fe-male Wistar rats. Under chloral hydrate anesthesia,the rats were stereotaxically implanted with elec-trodes: active under the skull on dura mater in oc-cipital region of the brain and reference one on theskull in the interorbital space. Moreover, the guidecannula was implanted 2 mm above the plannedsite of injection into LGN. After next 5–7 days, theVEP was recorded by the 1000 LKC (USA) elec-trophysiological system, with standard stimulationof both mydriatic eyes (with 1% tropicamid and 1%atropine), under the same anesthesia. Then, we have

recorded VEP curve every 5-min before and afterinjection (in whole volume of 1 �l) into LGN:0.9% NaCl, DA and DA agonists: SKF 38393 (D�)and quinpirole (D�) at doses of 1 and 5 nmols. Wehave analyzed amplitudes and latencies of negativepeak N� and positive P� following it.

Results

After DA treatment, amplitudes of N� increasedto 120–130% and amplitudes of N�P� increased to115%. The latencies of N� and P� were delayed byabout 4%. The effect was not dose-dependent. Pa-rameters of VEP curve have not change after quin-pirole injections. SKF 38393 injections increasedthe visual response by shortening latencies of N�,P� and increasing amplitudes by about 50% (N�);40% (N�P�). The effect was dose-dependent.

Conclusion

The results of this study show that DA injectedinto the LGN intensifies visual transmission in therat brain. We suppose that this effect was mediatedby D� receptor stimulation.

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ROLE OF GABA IN THE LATERAL GENICULATE NUCLEUSIN THE VISUAL TRANSMISSION IN RATS

Dorota Pojda-Wilczek, Agata R. Plech, Ewa Herba,Katarzyna Makowiecka-Obidziñska, Stefan M. Pojda

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Purpose

In our previous study, we found that GABA in-jected into the lateral brain ventricle of rats, intensi-fied the visual transmission. The aim of this paperwas to determine the influence of GABA given intothe lateral geniculate nucleus (LGN) on VisualEvoked Potential (VEP) in rats.

Methods

The experiments were performed on femaleadult Wistar rats with body mass between 240–320g. Under chloral hydrate anesthesia (0.03 g/100 gip), the rats were stereotoxically implanted withelectrodes: active under the skull on dura mater inoccipital region of the brain and reference one onthe skull in the interorbital region. Moreover, guidecannula was implanted 2 mm above the plannedsite of injection into LGN. After next 7 days, theVEP was recorded by the 1000 LKC electrophysio-logically interfaced personal computer system(USA), with standard stimulation of both mydriaticeyes (1% tropicamidum and 1% atropine) under thesame anesthesia. Then, we have recorded VEPevery 5 min, over 1 h before and after injection (in

whole volume of 1 �l) 0.9% NaCl and next GABAat doses of 1 and 5 nmol. We analyzed amplitudesand latencies of negative peak N� and followingpositive P�.

Results

GABA did not change the amplitudes of N�.The amplitudes of P� after 1 nmol of GABA de-creased till 60% and after 5 nmol decreased to 80%of basal volume. Twenty minutes after each injec-tion of GABA the amplitudes of P� stabilized, re-spectively to the doses, at 70% and 80–90% of ini-tial position. This effect lasted till the end of the ex-periment. The amplitudes of delta N�P� decreasedto 80% and remained at this level for a long time.The latencies of N� after GABA treatment were notchanged, and the latencies of P� were delayedabout 2% and 5%, respectively to the doses.

Conclusion

The results of this study show that GABA in-jected into LGN caused long-term decrease in vis-ual transmission in rats.

SOME BEHAVIORAL EFFECTS OF ANTIDEPRESSANTDRUGS ARE TIME-DEPENDENT

Zofia Rogó¿, Maciej Kuœmider, Joanna Solich,Marta Dziedzicka-Wasylewska

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Successful therapy with antidepressant drugs(ADs) requires repeated treatment. Therefore, ani-mal studies designed to define the changes which

might be important for the mechanism of action ofADs entail drug administration for at least twoweeks. However, our recent studies indicate that at

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least some of the so called adaptive changes ob-served in behavioral as well as biochemical ap-proaches are induced also by acute treatment withADs, on the condition, however, that the measure-ments are performed two weeks after acute admini-stration of ADs.

In the present studies, we treated rats with twoADs (10 mg/kg po), imipramine (IMI) or citalo-pram (CIT) repeatedly (twice daily for 14 days).This treatment resulted in the attenuation of salbu-tamol (10 mg/kg)- or clonidine (0.2 mg/kg)-evokedhypoactivity (indicating down-regulation of �- and��-adrenergic receptors, respectively), reversal ofhypoactivity induced by low doses of apomorphine(0.05 mg/kg) as well as of 7-OH-DPAT (0.05mg/kg; indicating subsensitivity of presynaptic do-pamine D� and D� receptors, respectively), enhan-

cement of hyperactivity induced by D-amphet-amine (0.5 mg/kg) and higher dose of 7-OH-DPAT(3 mg/kg; interpreted as supersensitivity of post-synaptic dopamine D�/D� receptors) and reversal ofhead twitches induced by (±)DOI (2.5 mg/kg, indi-cating the decreased sensitivity of 5-HT�� receptors).

Some of these behavioral effects (especially atthe level of ��-adrenergic and presynaptic D� andD� receptors) were also observed in experimentalanimals 14 days (but not 2 or 72 h) after the acutetreatment with IMI or CIT.

In the light of these results, it is tempting tospeculate that there may be no need for repeateddaily dosing schedules of ADs, but instead compa-rable effects might be achieved if the drugs aregiven at weekly or biweekly interval, however, thissuggestion needs to be further investigated.

POLYMORPHISMS IN THE SEROTONIN TRANSPORTERGENE AND THE MAOA GENE AND THEIR RELATIONSHIPTO DIMENSIONS OF TEMPERAMENT MEASURED BY TCI,

NEO-FFI, AND EPQ-R IN HEALTHY VOLUNTEERS

Jerzy Samochowiec, Aneta Ry¿ewska., Szymon Syrek, Micha³ Parus,Genowefa Stêpieñ, Jan Horodnicki

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Several reports suggest that polymorphisms inmonoamine system genes show an association withpersonality dimension. We studied an associationbetween temperamental personality dimensionsand polymorphism of serotonin transporter (SCL6A4), and MAO�. The personality traits weremeasured by the Temperament and Character In-ventory (TCI), NEO Five Factor Inventory (NEO –FFI) and Eysenck Personality Questionnaire-Revi-sed (EPQ-R). The group of 100 healthy volunteerswas identical to Szczecin population in sex, ageand education. There were 53 females and 47 ma-les, whose mean age was 41.46 ± 17.26 years.

Results

The post hoc exploration with Tuckey test indi-cated that women with low activity allele (3 repeats

209 bp.) showed higher score in NS 4 (disorderli-

ness) dimension, than women carrying the high ac-

tivity allele (4 repeats, 239 bp., p = 0.020). Also the

difference remains significant for the male group,

where the high activity MAO� allele was associ-

ated with lower score in RD 3 (attachment) TCI

subscale, than in the group of men carrying the low

activity allele (3 repeats, 209 bp., p = 0.018).The study of male group revealed that those

carrying high activity MAO� allele showed higher

scores in HA2 (fear of uncertainty) TCI subscale

(p = 0.012). The post hoc exploration of association

between NEO FFI dimensions and MAO� pro-

moter region polymorphism indicated that men of

low activity allele showed higher score in neuroti-

cism (p = 0.024), as well as in EPQR test (p =

0.042).

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After comparison of subdimensions, the posthoc evaluation of the whole group indicated thatprobants of high activity allele (L/L 528 bp.) showedhigher score in Reward Dependence 4 (RD4) (de-pendence) dimension, than probants carrying thehigh activity allele (s/s 484 bp., p = 0.035).

Conclusion

Males with higher scores on neuroticism scalein EPQ-R and NEO – FFI have MAO� with loweractivity as well as those possessing high scores onRD3 – TCI subscale – attachment, who prefer inti-macy over privacy. Females bearing the sameMAO� alleles show higher scores on disorderliness

subscale (RD3) and they tend to be quick temperand disorderly.

In contrast, males with higher activity of MAO�prove to show more fear of uncertainty (HA2), i.e.they cannot tolerate uncertainty, unfamiliar circum-stances that are potentially dangerous.

Both genders possessing normal genotype ofserotonin transporter seem to be depended on emo-tional support and approval from others. Due to oursmall sample those findings should be regarded aspreliminary.

Acknowledgment. This study was supported by thegrant No. BMBF 01/063, POL and the grant No. 3 PO 5D146 22 from the State Committee for Scientific Research,Warszawa, Poland.

BEHAVIORAL AND BIOCHEMICAL EFFECTS OF NICOTINEIN RATS

Halina Sienkiewicz-Jarosz�, Pawe³ Krz¹œcik�, Piotr Maciejak�,Aleksandra Wis³owska�, Ma³gorzata Zienowicz�, Paulina Rok�,

Janusz Szyndler�, Agnieszka Cz³onkowska�, Adam P³aŸnik���

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The aim of the present study was to analyze theinfluence of nicotine on rat behavior in the openfield test. Moreover, the effects of behaviorally ef-fective dose of the drug (0.6 mg/kg sc) on the con-centration of dopamine (DA), and its metabolites inthe striatum was also examined. To clarify the be-havioral and biochemical changes after nicotine, invivo microdialysis was conducted in freely movingrats, to measure stratial DA metabolites after acuteand chronic nicotine treatment.

Nicotine at 0.6 mg/kg elevated both locomotoractivity and exploratory parameters (entries to thecentral sector of the open field, time spent in thecentral sector and anti-thigmotactic effect). In in vi-tro study, nicotine (0.6 mg/kg) was found to de-crease DA metabolite, 3-MT (3-methoxytyramine)and DA turnover (3-MT/DA). The drug adminis-

tered acutely at the behaviorally active dose (0.6mg/kg) did not alter dihydroxyindoleacetic acid(DOPAC) and homovanillic acid (HVA) levels inthe striatum of freely moving rats (microdialysis).However, repeated injections of nicotine produceda significant increase in HVA concentration, incomparison to the control and the group acutelytreated with nicotine.

These results indicate that nicotine exerts an ex-citatory effect on rat exploratory activity in theopen field. The in vivo biochemical results showthat nicotine administration causes different effectson DA metabolism after acute and repeated treat-ment. The most interesting finding is an enhance-ment of HVA outflow after repeated nicotine injec-tions indicating disinhibition of DA neuron acti-vity.

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CORRELATION OF EXPLORATORY ACTIVITY ANDCONDITIONED FEAR RESPONSE WITH CORTICAL ANDSUBCORTICAL BINDING OF THE NICOTINIC RECEPTOR

AGONIST [3H]-EPIBATIDINE

Halina Sienkiewicz-Jarosz�, Piotr Maciejak�, Andrzej Bidziñski�,Ma³gorzata Lehner�, Janusz Szyndler�, Marek Siemi¹tkowski�,Agnieszka Cz³onkowska�, Aleksandra Wis³owska�, Ma³gorzata

Zienowicz�, Adam P³aŸnik���

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The aim of the present study was to correlate ratexploratory behavior in the open field and condi-tioned fear response test with specific binding ofthe nicotinic receptor agonist [�H]-epibatidine as-sayed in different brain structures by autoradiogra-phy. A significant positive correlation was foundbetween the ligand binding in the frontal cortex(r = 0.529, p < 0.011), the entorhinal cortex (r =0.603, p < 0.003), and CA1 layer of the hippocam-pus (r = 0.465, p< 0.029), and conditioned freezingreaction in the contextual fear conditioning test. Inthe frontal cortex, there was also a significant posi-

tive correlation between [�H]-epibatidine bindingand baseline, preconditioning freezing reaction (r =0.469, p < 0.028), and a negative correlation withrat motility (r = –0.452, p < 0.035). Rat motor ac-tivity correlated in a negative way with baselinefreezing reaction (r = –0.436, p < 0.043), andin a positive way with the number of entries intothe central sector of the open field (r = 0.690, p <0.001). The present data indicate a significant,structure-dependent correlation between rat condi-tioned emotional reaction and the nicotinic receptorligand binding in the cortical forebrain structures.

EFFECTS OF 5-HT1A AND/OR 5-HT1B ANTAGONISTS GIVENIN COMBINATION WITH PAROXETINE OR FLUOXETINE IN

THE FORCED SWIMMING TEST IN RATS

Ewa Tatarczyñska, Aleksandra K³odziñska, Ewa Chojnacka-Wójcik

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Clinical data suggest that coadministration of

pindolol, a 5-HT��/5-HT�2/�-adrenoceptor antago-

nist, and selective serotonin reuptake inhibitors

(SSRIs) may shorten the time of onset of a clinical

action and may increase beneficial effects of the

therapy of resistant depression. Effects of com-

bined administration of SSRIs and 5-HT receptor

ligands are currently evaluated in animal models

detecting an antidepressant-like activity; however,the obtained results turned out to be inconsistent.

Objective

The aim of the present study was to investigatethe effects of 5-HT�� antagonist (WAY 100635),5-HT�2 antagonists (SB 216641 and GR 127935)or pindolol, given in combination with paroxetine

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or fluoxetine (SSRIs), in a forced swimming test inrats (Porsolt’s test).

Results

When given alone, paroxetine (10 and 20 mg/kg),fluoxetine (10 and 20 mg/kg), WAY 100635 (0.1and 1 mg/kg), SB 216641 (2 mg/kg), GR 127935(10 and 20 mg/kg) and pindolol (4 and 8 mg/kg)did not shorten the immobility time of rats in thattest. Interestingly, SB 216641 administered alone ata dose of 4 mg/kg produced a significant reductionof the immobility time in that test. A combinationof paroxetine (20 mg/kg) and WAY 100635 or pin-dolol failed to reveal a significant interaction. On

the other hand, when paroxetine was given jointlywith SB 216641 (2 mg/kg) or GR 127935 (10 and20 mg/kg), that combination showed a significantantiimmobility action in the forced swimming testin rats. Coadministration of fluoxetine with all an-tagonists used did not affect behavior of rats in thistest.

Conclusion

The obtained results seem to indicate thatblockade of 5-HT�2 receptors, but not 5-HT��ones, is able to facilitate the antidepressant-like ef-fect of paroxetine in the forced swimming test inrats. An interaction was observed between fluoxet-ine and 5-HT��/5-HT�2 receptor antagonists.

EFFECTS OF SOME NEUROSTEROIDS ON EXCITATORYAMINO ACID- AND HYDROGEN PEROXIDE-INDUCED

TOXICITY IN HUMAN NEUROBLASTOMA CELLS

Magdalena Tetich, Monika Leœkiewicz, Bogus³awa Budziszewska,Andrzej Kutner�, W³adys³aw Lasoñ

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Steroids representing various pharmacologicalgroups are known to prevent cell damage in in vivoand in vitro animal models of neurotoxicity. In or-der to find out whether these compounds were alsoactive in a cell line of human origin, we examinedthe effects of dehydroepiandrosterone sulfate(DHEAS), allopregnanolone and two secosteroidson toxic insults in the SH-SY5Y neuroblastomacell line. Twenty four-hour incubation of SH-SY5Ywith 5mM NMDA or 0.2 mM kainate enhanced thedehydrogenase lactate release by ca. 70%. Allo-pregnanolone (3 and 30 �M) and both secosteroids(5–500 nM) completely abolished the toxic effectsof NMDA and partly attenuated the kainate-indu-ced toxicity. DHEAS (1 and 10 �M) reduced boththe NMDA- and the kainate-induced cellular damage

in a concentration-dependent manner. Further studyrevealed high susceptibility of SH-SY5Y cells tothe damaging effect of hydrogene peroxide (0.1–1mM). DHEAS, calcitriol and its low-calcemic ana-log, PRI-2191, but not allopregnanolone, decreasedthe hydrogen peroxide-evoked LDH release.

These data indicate that DHEAS prevents boththe oxidative and the excitatory amino acid-indu-ced cell damage, whereas allopregnanolone is ac-tive in the latter case only. Moreover, secosteroidsused at nanomolar concentrations have protectiveeffects comparable to those of DHEAS in the hy-drogen peroxide test. These observations supportthe hypothesis about potential usefulness of neuro-active steroids in the therapy of neurodegenerativedisorders in humans.

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BOVINE WHEY CONCENTRATE ADMINISTRATIONIMPROVES MEMORY IN RATS

Ewa Widy-Tyszkiewicz, Agnieszka Piechal, Ilona Joniec,Kamilla Blecharz-Klin, Alicja Zobel�

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The tripeptide, cellular antioxidant glutathione(GSH) plays an important role in protecting cellsagainst the toxic effects of free radicals. Depletionof GSH in the brain may also be decreased with ageand may result in free radical-induced neuronaldamage. The effect of supplementation with a whey--based cysteine donor (HMS90) was analyzed inthis study on Morris water task performance in rats.Five months old Wistar rats received orally HMS90at doses of 150 and 300 mg/kg from day 1 to day21 of the experiment. Water maze paradigm wascarried out for 4 days by training rats using fourtraining trials per day. In addition to acquisition la-tency, memory was assessed by a probe trial given24 h after the last training trial. ANOVA for re-

peated measurements did not show any significantdifferences in acquisition in water maze betweenthe groups. However, in the probe trial on day 5,the HMS90 (150 mg/kg)-treated group showed im-proved memory of the position of the platform,compared to the control and HMS90 (300 mg/kg)--treated groups (FH���6I = 3.72, p < 0.05). Follow-updata on brain content of monoamines and metabo-lites in the prefrontal cortex, hippocampus andstriatum revealed significant differences betweenthe groups.

These findings suggest that improvement ofcognitive performance is associated with glu-tathione regulation and may be related to increasedcapacity to respond to oxidative stress.

INFLUENCE OF NMDA RECEPTOR AGONIST AND ANTAGONIST ONISOLATED HEART AND AORTA FROM DIABETIC RATS

Ró¿a J. Wiœniewska, Agnieszka Malinowska, Konstanty Wiœniewski

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In the previous experiments, we indicated thatNMDA receptor agonist and antagonist had cardio-vascular action. Dysfunction of blood vessels andheart in DM may be due to the alterations of the re-activity of blood vessels and heart to neurotrans-mitters.

The aim of this work was to compare the actionof NMDA or its antagonist, DL-AP7 (DL-2-amino--7-phosphonoheptanoic acid), on the isolated heartusing modified Langendorff method and on the iso-lated aorta from intact (C-group) and 1-month dia-betic rats (STZ-DM-group). The effects of NMDAor DL-AP7 on the function of isolated heart andcontraction of isolated aorta were studied. STZ-DM

was induced by intravenous injection of a solutioncontaining 65 mg/kg of streptozotocin.

In STZ-DM group, the positive inotropic effectand bradycardia evoked by NMDA (10/6, 2 × 10/6,10/0 M) have been abolished, and the opposite ef-fect on coronary outflow (increase) has been ob-served. In both studied groups, DL-AP7 used at thesame concentration as NMDA decreased the con-traction amplitude of isolated heart and decreasedheart rate. In STZ-DM group, DL-AP7 evokedsimilar as NMDA increase in coronary outflow.NMDA and DL-AP7 used at the concentrations of10/6, 10/0, 10/ M did not change contraction of theisolated aorta in both studied groups.

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INFLUENCE OF CHRONIC TREATMENT WITH VALPROICACID ON THE BODY MASS OF PATIENTS

Marek Zieliñski, Milan Grundman�, Blanka Koristkova�, Krystyna Kmieciak-Ko³ada,Bogus³aw Okopieñ, Anna Zieliñska-Meus, Zbigniew S. Herman

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The use of valproate (VPA) has traditionallybeen held to be associated with a greater incidenceof weight gain than that of other anticonvulsants.The aim of this paper was to estimate the influenceof protracted usage of VPA in mono- and polyther-apy on body mass of the patients, who had serumdrug levels determined at Department of ClinicalPharmacology in Katowice and in Ostrava.

Methods

The patients were selected from databases (pts).They were 18–60 years of age and used VPA in

monotherapy and in combination with carba-mazepine for a period of 3 and 12 months (Tab. 1).Influence of chronic treatment with VPA (2–8years) on body mass index BMI (Tab. 2) was as-sessed. Student’s t-test for paired data was used forstatistical analysis.

Conclusion

Increase in body mass was observed only in thefirst period of VPA monotherapy.

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