Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
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Advances in Clinical and Experimental Medicine

2008, vol. 17, nr 6, November-December, p. 607–614

Publication type: original article

Language: English

Impairments of the Central Serotoninergic System in Rats Lesioned With DSP−4 as Neonates

Zaburzenia funkcji ośrodkowego układu noradrenergicznego u szczurów z lezją wywołana DSP−4 stosowanym we wczesnym okresie rozwoju postnatalnego

Marzena Ferdyn−Drosik1,, Katarzyna Jelito1,, Eva Kőrössy1,, Kamila Bojanek1,, Mirella Jaksz1,, Michał Świerszcz1,, Przemysław Nowak1,, Ryszard Brus1,

1 Department of Pharmacology, Medical University of Silesia, Zabrze, Poland

Abstract

Objectives. The aim of the present study was to investigate the effect of neonatal DSP−4 treatment on the central serotoninergic system in adult rats.
Material and Methods. On the first and third days after birth, rats were injected with either DSP−4 (50 mg/kg, s.c.) or 0.9% NaCl (1.0 ml/kg s.c., controls). When the rats attained 10 weeks of age, both the control and DSP−4 groups were divided into two subgroups injected with either saline or the inhibitor of serotonin (5−hydroxytryptamine, 5−HT) synthesis p−chlorophenylalanine (p−CPA). Then the rats were subjected to the Porsolt forced swim test following acute administration of the 5−HT1B ligands (agonist CP 94253, 4.0 mg/kg ip, and/or antagonist SB 216641, 4.0 mg/kg ip). Afterwards the content of monoamines and their metabolites as well as the 5−HT synthesis rate were determined in the striatum.
Results. CP 94253 induced depression−like behavior in the control rats, but not in the DSP−4−treated animals. The 5−HT1B receptor antagonist SB 216641 per se did not influence the examined parameters in either group, but when injected 30 min beforehand, it significantly abolished the CP 94253−induced depression−like behavior in the control rats. Depression−like behavior in p−CPA pretreated control rats was no longer observed. The content of noradrenaline (NA) in the striatum was significantly reduced in the DSP−4−treated rats compared with the controls, but the levels of dopamine (DA), 5−HT, and their metabolites were not affected by DSP−4 treatment. Neither CP 94253 nor SB 216641 altered NA, DA, DOPAC (3,4−dihydroxyphenylalanine), HVA (homovanillic acid), 5−HT, or 5−HIAA (5−hydroxyindoleacetic acid) content in the striatum of either examined group (control and DSP−4). In contrast, the 5−HT synthesis rate was significantly attenuated in the striatum after CP 94253 application and SB 216641 was able to antagonize this effect in the tested brain area of the control rats. Conversely, CP 94253 failed to significantly inhibit the rate of 5−HT synthesis in the DSP−4−treated rats.
Conclusion. These data suggest that presynaptic 5−HT1B autoreceptors underwent desensitization in the DSP−4− treated rats. Consequently, a neonatal chemical lesion of central noradrenergic neurons modifies central serotonergic activity in rats in adulthood.

Streszczenie

Cel pracy. Ocena wpływu lezji układu noradrenergicznego wykonanej u noworodków szczurzych na funkcje ośrodkowego układu serotoninergicznego u dorosłych zwierząt.
Materiał i metody. 1. i 3. dnia życia noworodkom szczurzym podano neurotoksynę DSP−4 (50 mg/kg sc). Zwierzęta z grupy kontrolnej otrzymały 0,9% roztwór NaCl (1,0 ml/kg sc). Po osiągnięciu wieku 10 tygodni zwierzęta z grupy kontrolnej i z lezją podzielono na dwie podgrupy, jedna otrzymała sól fizjologiczną, druga inhibitor syntezy serotoniny (5−hydroksytryptaminy; 5−HT) − p−chlorofenyloalaninę (p−CPA). Następnie po podaniu ligandów receptora 5−HT1B (agonisty; CP 94253 4,0 mg/kg ip i/lub antagonisty; SB 216641 4,0 mg/kg ip), posługując się testem rezygnacji Porsolta, oceniono działanie przeciwdepresyjne. Zbadano również zawartość amin biogennych po podaniu ligandów receptora 5−HT1B, oceniono ponadto szybkość syntezy serotoniny w prążkowiu. Wyniki i wnioski. Wteście rezygnacji Porsolta CP 94253 stosowany u szczurów z grupy kontrolnej działał depresjogennie, a wpływ ten znosiło wcześniejsze SB 216641. Takiego działania nie obserwowano natomiast u zwierząt z lezją układu noradrenergicznego. Po podaniu p−CPA depresjogenny efekt CP 94253 zanikał u szczurów z grupy kontrolnej. Zawartość noradrenaliny w prążkowiu była istotnie mniejsza w grupie DSP−4, zawartość dopaminy, serotoniny i ich metabolitów nie różniła się między badanymi grupami zwierząt. CP 94253 oraz SB 216641 nie wpływały na stężenie amin biogennych i ich metabolitów, CP 94253 natomiast istotnie zmniejszył intensywność syntezy 5−HT w prążkowiu u szczurów z grupy kontrolnej, pozostając bez wpływu na badany parametr u zwierząt z lezją układu noradrenergicznego. Na podstawie przeprowadzonych badań należy stwierdzić, że chemiczna lezja ośrodkowego układu noradrenergicznego wywołana podaniem neurotoksyny DSP−4 szczurzym noworodkom prowadzi do desensytyzacji receptorów 5−HT1B i tym samym modyfikuje ośrodkowe przekaźnictwo serotoninergiczne u dorosłych zwierząt.

Key words

DSP−4, lesion, 5−HT1B receptor, depression−like behavior, rats

Słowa kluczowe

DSP−4, lezja, receptor 5−HT1B, działanie depresjogenne, szczury

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