N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) neonatal treatment, feeding behavior and 5-HT1B receptor reactivity in adult rats

• Authors: Marzena Ferdyn-Drosik , Przemysław Nowak , Jacek Kasperski , Rafał Muchacki , Beata Maksym , Michał Bałasz , Magdalena Beśka , Ryszard Brus

Title variants

PL

Wpływ podania N-(-2-chloroethylo)-N-ethylo-2-bromobenzylaminy (DSP-4) u noworodków szczurzych na zachowania związane z przyjmowaniem pokarmów i reaktywność receptora 5-HT1B u dorosłych szczurów

• Languages of publication: EN

Abstracts

EN

BACKGROUND: We investigated the reactivity of 5-HT1B receptor in adult rats administered as neonates with noradrenergic neurotoxin N-(-2-chloroethyl)-N-ethyl-2- bromobenzylamine (DSP-4; 50 mg/kg sc x2, P1 and P3). MATERIAL AND METHODS: At 8-10 weeks (after lesion), control and DSP-4 rats were divided into two subgroups injected either with saline or 5-hydroxytryptamine (serotonin; 5-HT) synthesis inhibitor (p-chlorophenylalanine; p-CPA; 100 mg/kg ip x 2 every 24h). On the following day food intake was examined after 5-HT1B receptor ligands administration; agonist CP 94,253, 4.0 mg/kg ip; and antagonist, SB 216641, 4.0 mg/kg ip respectively. Additionally, the level of monoamines, their metabolites and 5-hydroxytrptophane (5- HTP) as an indicator of 5-HT synthesis rate were analyzed by HPLC/ED methods. RESULTS AND CONCLUSIONS: CP 94,253 in a dose of 4.0 mg/kg ip signifi cantly decreased food intake in control and DSP-4 rats in comparison to respective control (saline). 5-HT1B antagonist (SB 216641) alone did not alter the examined parameter but injected 30 min before CP 94,253 markedly abolished its eff ect in both tested groups. Similar results were obtained in p-CPA pretreated animals. The level of amines and their metabolites was not diff erent between control and DSP-4 treated rats. Administration of p-CPA (2 x 100 mg/kg ip) reduced the concentration of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the hypothalamus of control rats by 94.9 % and 96.7 % respectively. In DSP-4 rats the percentage of 5-HT displacement was 92.5 % (5-HT) and 95.7 % (5-HIAA). As it was presented CP 94,253 and SB 216641 alike, administered in doses of 4.0 mg/kg ip, did not alter biogenic amines and their metabolites content in the hypothalamus of both examined groups (control and DSP-4). There were also no diff erences in the 5-HT synthesis rate in the hypothalamus between control and DSP-4 rats after 5-HT1B receptor ligands injection. We concluded that in contrast to our previous studies, DSP-4 being without eff ect on hypothalamus noradrenalin (NA) level and 5-HT synthesis rate did not also aff ect reactivity of terminal 5-HT1B autoreceptors in this brain area. On the basis of this experiments, it should be noted that in contrast to our previous studies which have shown that the consequence of DSP-4 administration is dramatic reduction in the NA contents in the frontal cortex, hippocampus, striatum, etc., with concomitant desensitization of 5-HT1A and 5-HT1B receptors (evaluated by behavioral and biochemical methods), in this experiment, there were no such eff ects. This proves that the noradrenergic fi bers in the hypothalamus are much more resistant to the neurotoxic action of DSP-4, furthermore, for the development of 5-HT1B receptors desensitization in the specifi c brain structure, decrease in NA contents in this part of the brain is required. In other words, a profound dysfunction of the noradrenergic system expresses as noradrenergic fi ber damage in the striatum, frontal cortex, hippocampus, etc. does not aff ect the status of 5-HT1B receptors in the hypothalamus.

PL

WSTĘP: W niniejszej pracy zbadano reaktywność ośrodkowego receptora serotoninergicznego 5-HT1B u dorosłych szczurów, które w okresie noworodkowym otrzymały neurotoksynę N-(-2-chloroethyl)- N-ethyl-2-bromobenzylamine (DSP-4; 50 mg/kg sc x 2, 1-go i 3-go dnia). MATERIAŁ I METODY: W 8-10-tym tygodniu życia zwierzęta kontrolne i z lezją podzielono na dwie podgrupy, jedna otrzymała sól fi zjologiczną, 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) oceniono ilość spożywanej karmy. Dodatkowo zbadano również zawartość amin biogennych po podaniu ligandów receptora 5-HT1B oraz oceniono szybkość syntezy serotoniny w podwzgórzu. WYNIKI I WNIOSKI: CP 94253 stosowany zarówno u szczurów kontrolnych jak i DSP-4 zmniejszał ilość spożywanej karmy w porównaniu do odpowiednich grup kontrolnych (po podaniu soli fi zjologicznej). Podobne efekty zaobserwowano u zwierząt, które wcześniej otrzymały p-CPA. Nie stwierdzono zmian zawartości amin biogennych po podaniu DSP-4. Również CP 94253 oraz SB 216641 nie wpływały na stężenie amin biogennych i ich metabolitów w badanej strukturze mózgu. Po podaniu p-CPA (2 x 100 mg/kg ip) obserwowano spadek zawartości 5-HT oraz 5-HIAA w podwzgórzu u kontroli odpowiednio o 94.9% i 96.7%, natomiast w grupie DSP-4 o 92.5 % (5-HT) i 95.7 % (5-HIAA). Szybkość syntezy 5-HT nie różniła się pomiędzy kontrolą a grupą DSP-4, również CP 94253 4.0 mg/kg ip i/lub SB 216641 4.0 mg/kg ip pozostawały bez wpływu na badany parametr. Na podstawie przeprowadzonych eksperymentów stwierdzić należy, że w przeciwieństwie do naszych poprzednich badań, w których wykazaliśmy, że konsekwencją podania DSP-4 jest spadek zawartości NA w korze czołowej, hipokampie i prążkowiu, które wywołuje zjawisko desensytyzacji receptorów 5-HT1A i 5-HT1B (oceniane metodami behawioralnymi i biochemicznymi), w niniejszym doświadczeniu nie stwierdzono takich efektów. Powyższe przemawia za tym, iż zakończenia noradrenergiczne w podwzgórzu są znacznie bardziej oporne na neurotoksyczne działanie DSP-4 oraz, że dla rozwoju desensytyzacji receptorów 5-HT1B w określonej strukturze mózgu konieczny jest spadek zawartości NA w tej części mózgu. Innymi słowy głęboka dysfunkcja układu noradrenergicznego pod postacią zniszczenia zakończeń noradrenergicznych w korze czołowej, prążkowiu oraz hipokampie pozostaje bez wpływu na „status” receptorów 5-HT1B w podwzgórzu.

Keywords

EN

5-HT1B receptor; food intake; lesion; lezja; noradrenergic system; przyjmowanie karmy; rats; receptor 5-HT1B; szczury; układ noradrenergiczny

Discipline

• MEDICINE: MEDICINE

• Publisher: Śląski Uniwersytet Medyczny w Katowicach
• Journal: Annales Academiae Medicae Silesiensis
• Year: 2009
• Volume: 63
• Issue: 2
• Pages: 16-23

Contributors

author

Marzena Ferdyn-Drosik

• Department of Pharmacology

author

Przemysław Nowak

• Katedra i Zakład Farmakologii SUM, 41-808 Zabrze, ul. H. Jordana 38, tel./fax [phone]

author

Jacek Kasperski

• Department of Prosthetic Dentistry, Medical University of Silesia, Zabrze, Poland

author

Rafał Muchacki

• Department of Pharmacology

author

Beata Maksym

• Department of Pharmacology

author

Michał Bałasz

• Department of Pharmacology

author

Magdalena Beśka

• Department of Pharmacology

author

Ryszard Brus

• Department of Pharmacology

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• Document Type: article