Influence of 5-HT1A receptors on central noradrenergic activity: microdialysis studies using (+/-)-MDL 73005EF and its enantiomers.
Recent studies indicate that 5-HT1A receptor agonists stimulate noradrenaline release in the brain. Here we investigate the mechanism underlying the increase in extracellular noradrenaline induced by (+/-)-MDL 73005EF, a weak 5-HT1A receptor agonist. Extracellular noradrenaline was measured in the hippocampus of the awake rat using microdialysis. (+/-)-MDL 73005EF (0.1, 1 and 5 mg/kg s.c.) caused a dose-related increase in noradrenaline. The active S(-)- enantiomer of MDL 73005EF (1 mg/kg s.c.) also increased noradrenaline whereas the inactive R(+)- enantiomer (1 mg/kg s.c.) did not. Measurements of extracellular 5-HT in hippocampus of anaesthetised rats confirmed that the 5-HT1A receptor agonist action of (+/-)-MDL 73005EF resides in the S(-)- enantiomer. Thus, S(-)-MDL 73005EF (0.3 and 1 mg/kg s.c.) markedly decreased 5-HT, whereas R(+)-MDL 73005EF (1 mg/kg s.c.) did not. The noradrenaline response to (+/-)-MDL 73005EF (1 mg/kg s.c.) was significantly blocked by the selective 5-T1A receptor antagonist, WAY 100635 (1 but not 0.3 mg/kg s.c). The noradrenaline response to (+/-)-MDL 73005EF (1 mg/kg s.c.) was not modified by pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine. Intra-hippocampal application of (+/-)-MDL 73005EF (10 microM in perfusion medium) did not increase noradrenaline. Although (+/-)-MDL 73005EF has moderate affinity for dopamine D2 binding sites, the dopamine D2 receptor antagonist, remoxipride (1 mg/kg s.c.) did not increase noradrenaline. In conclusion, our data suggest that (+/-)-MDL 73005EF increases noradrenaline release in rat hippocampus through activation of 5HT1A receptors that appear to be located postsynaptically. These data are discussed in relation to the antidepressant/anxiolytic effects of 5-HT1A agonists.
Hajós-Korcsok
E
E
Department of Clinical Pharmacology, University of Oxford, Radcliffe Infirmary, UK.
McQuade
R
R
Sharp
T
T
D000818:Animals; D004147:Dioxins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008297:Male; D017551:Microdialysis; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004147:Dioxins; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D013141:Spiro Compounds; C063249:binospirone mesylate; D012701:Serotonin; D009638:Norepinephrine