Facilitation of 5-HT1A-mediated neurotransmission in dorsal periaqueductal grey matter accounts for the panicolytic-like effect of chronic fluoxetine.
Chronic administration of antidepressants such as fluoxetine and imipramine increases the responsiveness of 5-HT(1A) receptors in dorsal periaqueductal grey matter (DPAG), a midbrain area consistently implicated in the pathogenesis of panic disorder. This effect has been related to the clinically relevant anti-panic action of these drugs. In this study we determined whether long-term administration of fluoxetine also affects 5-HT efflux in DPAG. As a comparison, the effect of chronic treatment with the anxiolytic 5-HT(1A) receptor agonist buspirone on DPAG 5-HT levels was assessed. We also investigated whether the inhibitory effect of chronic fluoxetine on escape behaviour in the rat elevated T-maze, considered as a panicolytic-like effect, is counteracted by intra-DPAG injection of the 5-HT(1A) receptor antagonist WAY 100635. Male Wistar rats were treated (1 or 21 d, i.p.) with fluoxetine, buspirone or vehicle, once daily. After treatment, 5-HT in DPAG was measured by in-vivo microdialysis coupled to HPLC. In another study, rats treated (21 d, i.p.) with either fluoxetine or vehicle also received intra-DPAG injection of WAY 100635 or saline 10 min before being tested in the elevated T-maze. Chronic, but not acute, administration of fluoxetine significantly raised extracellular levels of 5-HT in DPAG. Long-term treatment with buspirone was ineffective. In the elevated T-maze, intra-DPAG injection of WAY 100635 fully blocked the anti-escape effect of chronic administration of fluoxetine. Therefore, chronic fluoxetine facilitates 5-HT(1A)-mediated neurotransmission within DPAG and this effect accounts for the panicolytic-like effect of this antidepressant in the elevated T-maze.
Zanoveli
Janaina M
JM
Institute of Neuroscience and Behavior (INeC), University of São Paulo, Brazil.
Pobbe
Roger L H
RL
de Bortoli
Valquiria C
VC
Carvalho
Milene C
MC
Brandão
Marcus L
ML
Zangrossi
Helio
H
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology* / Q000627:therapeutic use; D005473:Fluoxetine / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D016584:Panic Disorder / Q000188:drug therapy / Q000378:metabolism; D010487:Periaqueductal Gray / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D014151:Anti-Anxiety Agents; D058829:Serotonin 5-HT1 Receptor Antagonists; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A