Differential effects of (R)-, (R, S)- and (S)-8-hydroxy-2-(di-n-propylamino)tetralin on hippocampal serotonin release and induction of hypothermia in awake rats.
The effects of (R)- and (S)-optical isomers of 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and of the racemate (R,S)-8-OH-DPAT on serotonin (5-HT) release in the ventral hippocampus of awake rats and on induction of the whole-body hypothermia were studied. Extracellular 5-HT levels were determined by a newly developed high-sensitive HPLC method based on derivatization with benzylamine and fluorescence detection. The basal levels of 5-HT in 20 min microdialysates from rats perfused with Ringer solution or with Ringer solution containing 1 microM citalopram were 6.3 +/- 1.3 fmol/20 microl and 36.1 +/- 4.2 fmol/20 microl (n=20), respectively. The reduction of hippocampal 5-HT levels induced by subcutaneous (s.c.) administration of (R,S)-8-OH-DPAT (0.3 mg/kg) was significantly attenuated by the presence of 5-HT reuptake inhibitor citalopram in Ringer solution only at its peak value at 40 min (maximal reduction to 60% compared to 46% of control values in Ringer-perfused rats), whereas the overall effects were comparable at both experimental conditions. Injection of (R)-8-OH-DPAT (0.3 mg/kg s.c.) caused further reduction of 5-HT levels, to 49% and 41%, respectively, whereas (S)-8-OH-DPAT (0.3 mg/kg s.c.) caused maximal reduction of 5-HT levels only to 74% of controls in both perfusion groups. Similar pattern and time-courses were observed in rats with hypothermia induced by injection of 8-OH-DPAT enantiomers, where (R,S), (R)-forms were about two-times more potent than the (S)-isomer. It is concluded that the acute systemic dose of (R)-, (S)- and (R,S)-8-OH-DPAT enantiomers exerted enantiomer-specific effects on 5-HT(1A) receptor-mediated function both at the presynaptic and postsynaptic sites as revealed by monitoring hippocampal 5-HT levels and body temperature.
Yoshitake
Takashi
T
Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden.
Kehr
Jan
J
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D015283:Citalopram / Q000494:pharmacology; D004336:Drug Antagonism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007036:Hypothermia, Induced; D007279:Injections, Subcutaneous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013237:Stereoisomerism; D014851:Wakefulness / Q000187:drug effects* / Q000502:physiology
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D015283:Citalopram; D012701:Serotonin; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors