Neonatal DSP-4 treatment impairs 5-HT(1B) receptor reactivity in adult rats. Behavioral and biochemical studies.
To examine the effect of a central noradrenergic lesion on the reactivity of the 5-HT(1B) receptor we compared intact male rats with rats in which noradrenergic nerve terminals were largely destroyed with the neurotoxin DSP-4 (50 mg/kg x 2, on the 1st and 3rd days of postnatal life). When rats attained 10 weeks of age, control and DSP-4 rats were divided into two subgroups receiving either saline or the serotonin (5-HT) synthesis inhibitor (p-chlorophenylalanine; p-CPA; 100 mg/kg). Employing an elevated plus maze test, we demonstrated that CP 94,253 (5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine hydrochloride) (4.0 mg/kg; 5-HT(1B) agonist) induced an anxiogenic-like action in control rats; however, it failed to elicit this effect in the DSP-4 group. Surprisingly, in p-CPA pretreated rats anxiogenic-like activity was observed both in control and DSP-4 treated rats. CP 94,253 significantly attenuated 5-HT synthesis in the medial prefrontal cortex (mPFC) of control rats, and SB 216641 (N-{3-[3-(dimethylamino)ethoxy]-4-methoxyphenyl}-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide hydrochloride) (4.0 mg/kg; 5-HT(1B) antagonist) was able to antagonize this effect. Conversely, CP 94,253 failed to significantly inhibit the 5-HT synthesis rate in DSP-4-treated rats. In the microdialysis study CP 94,253 induced long-lasting attenuation of 5-HT release in the mPFC of control rats but had no effect in DSP-4 rats. These data lead to the proposal that presynaptic 5-HT(1B) autoreceptors underwent desensitization in DSP-4 treated rats.
Ferdyn-Drosik
Marzena
M
Department of Pharmacology, Medical University of Silesia, H. Jordana 38, PL 41-808 Zabrze, Poland.
Nowak
Przemysław
P
Bojanek
Kamila
K
Bałasz
Michał
M
Kasperski
Jacek
J
Skaba
Dariusz
D
Muchacki
Rafał
R
Kostrzewa
Richard M
RM
D000818:Animals; D000831:Animals, Newborn; D001549:Benzamides / Q000494:pharmacology; D001596:Benzylamines / Q000633:toxicity*; D004195:Disease Models, Animal; D010134:Fenclonine / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D017551:Microdialysis; D009498:Neurotoxins / Q000633:toxicity*; D010069:Oxadiazoles / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044302:Receptor, Serotonin, 5-HT1B / Q000187:drug effects* / Q000378:metabolism
D001549:Benzamides; D001596:Benzylamines; C097067:CP 94253; C108531:N-(3-(2-dimethylamino)ethoxy-4-methoxyphenyl)-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide; D009498:Neurotoxins; D010069:Oxadiazoles; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; C012102:DSP 4; D010134:Fenclonine