Abstract
YM992 [(S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride] is a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) and a potent 5-HT2A antagonist. The aim of the present study was to assess, using in vivo extracellular unitary recordings, the effect of acute and sustained administration of YM992 (40 mg kg−1day−1 s.c., using osmotic minipumps) on the spontaneous firing activity of locus coeruleus (LC) norepinephrine (NE) neurons. Acute intravenous injection of YM992 (4 mg kg−1) significantly decreased NE neuron firing activity by 29% and blocked the inhibitory effect of a subsequent injection of the 5-HT2 agonist DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride]. A 2-day treatment with YM992 decreased the firing rate of NE neurons by 66%, whereas a partial recovery was observed after a 7-day treatment and a complete one after a 21-day treatment. Following the injection of the α2-adrenoceptor antagonist idazoxan (1 mg kg-1 i.v.), NE neuron firing was equalized in controls and 2-day YM992-treated rats. This put into evidence an increased degree of activation of α2-adrenergic autoreceptors in the treated rats. The suppressant effect of the α2-adrenoceptor agonist clonidine was significantly decreased in long-term YM992-treated rats. The recovery of LC firing activity after long-term YM992 administration could thus be explained by a decreased sensitivity of α2-adrenergic autoreceptors. Sustained SSRI administration leads to a gradual reduction of the firing activity of NE neurons during long-term administration, whereas YM992 produced opposite effects. The exact basis for the increased synaptic availability of NE by YM992 remains to be elucidated. This NE activity, resulting from 5-HT reuptake inhibition plus 5-HT2Areceptor antagonism, might confer additional benefits in affective and anxiety disorders.
Footnotes
-
This work was supported in part by a Medical Research Council of Canada doctoral award (MRC-1554 to S.T.S.), a Fonds pour la Formation de Chercheurs et L'Aide à la Recherche-Fonds de la Recherche en Santé du Québec (FRSQ-FCAP-Santé-68803 to S.T.S.), and by salary support from the University of Florida to P.B. and S.T.S. This work was presented in part at the European College of Neuropsychopharmacology, Berlin, September 11, 2000; where it received a poster award.
-
DOI: 10.1124/jpet.102.033282
- Abbreviations:
- NE
- norepinephrine
- 5-HT
- 5-hydroxytryptamine (serotonin)
- LC
- locus coeruleus
- YM992
- (S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride
- SSRI
- selective serotonin reuptake inhibitor
- DOI
- 2,5-dimethoxy-4-iodoamphetamine hydrochloride
- 8-OH-DPAT
- 8-hydroxy-2-dipropylaminotetralin
- MDL 100,907
- R-(±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
- WAY-100,635
- N-[4(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexane carboxamide
- Received January 22, 2002.
- Accepted March 27, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|