Influence of 5-HT 1A receptors on central noradrenergic activity: microdialysis studies using (±)-MDL 73005EF and its enantiomers

Abstract

Recent studies indicate that 5-HT 1A 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-HT 1A 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-HT 1A 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-HT 1A 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 μM in perfusion medium) did not increase noradrenaline. Although (±)-MDL 73005EF has moderate affinity for dopamine D 2 binding sites, the dopamine D 2 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 5HT 1A receptors that appear to be located postsynaptically. These data are discussed in relation to the antidepressant/anxiolytic effects of 5-HT 1A agonists.