In vivo electrophysiological assessment of the putative antidepressant Wf-516 in the rat raphe dorsalis, locus coeruleus and hippocampus.
Wf-516 is a potential novel antidepressant. It has high affinity for serotonin (5-hydroxytryptamine; 5-HT) transporters, 5-HT(1A) and 5-HT(2A) receptors. In the present study, the pharmacologic properties of Wf-516 were thus assessed using in vivo electrophysiology in the rat dorsal raphe nucleus (DRN), locus coeruleus (LC) and hippocampus. Glass microelectrodes were lowered into the DRN, LC or hippocampus, and neurons were recorded and tested using systemic or microiontophoretic injections of drugs. In the DRN, cumulative doses of 0.5 mg/kg of Wf-516 were injected intravenously and total inhibition of 5-HT neurons firing was obtained with 2.8 +/- 0.3 mg/kg. The administration of 1 mg/kg of Wf-516, which by itself did not induce a change in the firing of 5-HT neurons, markedly attenuated the inhibitory effect of the 5-HT(1A) autoreceptor agonist LSD, indicating that Wf-516 is a 5-HT(1A) autoreceptor antagonist. In the LC, 1 mg/kg of Wf-516 dampened the inhibitory effect of the preferential 5-HT(2A) agonist DOI on norepinephrine (NE) neurons, indicating that Wf-516 is also a 5-HT(2A) receptor antagonist. In the hippocampus, cumulative intravenous doses of Wf-516 significantly increased the recovery time of firing activity of CA(3) pyramidal neurons after 5-HT applications, indicating an inhibitory effect on 5-HT reuptake. Unlike the 5-HT(1A) antagonist WAY100635, Wf-516 did not block the inhibitory effect of microiontophoretic application of 5-HT, indicating that this drug is devoid of 5-HT(1A) receptor antagonistic activity in this postsynaptic structure. These properties of WF-516 define the transporter/receptorial profile of an antidepressant with superior effectiveness.
University of Ottawa Institute of Mental Health Research, Room 7407, 1145 Carling Avenue, Ottawa, ON K1Z 7K4, Canada. mostafa.elmansari@rohcg.on.ca
M
M
El Mansari
P
P
Blier
D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007275:Injections, Intravenous; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008839:Microelectrodes; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010069:Oxadiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists
D000928:Antidepressive Agents; D010069:Oxadiazoles; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; C527744:Wf-516; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin