Abstract
The present studies characterized the functional profile of N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3-H-benzo[e]indole-3-carboxamide) (S32212), a combined serotonin (5-HT)2C receptor inverse agonist and α2-adrenoceptor antagonist that also possesses 5-HT2A antagonist properties (J Pharmacol Exp Ther 340:750–764, 2012). Upon parenteral and/or oral administration, dose-dependent (0.63–40.0 mg/kg) actions were observed in diverse procedures. Both acute and subchronic administration of S32212 reduced immobility time in a forced-swim test in rats. Acutely, it also suppressed marble burying and aggressive behavior in mice. Long-term administration of S32212 was associated with rapid (1 week) and sustained (5 weeks) normalization of sucrose intake in rats exposed to chronic mild stress and with elevated levels of mRNA encoding brain-derived neurotrophic factor in hippocampus and amygdala (2 weeks). S32212 accelerated the firing rate of adrenergic perikarya in the locus coeruleus and elevated dialysis levels of noradrenaline in the frontal cortex and hippocampus of freely moving rats. S32212 also elevated the frontocortical levels of dopamine and acetylcholine, whereas 5-HT, amino acids, and histamine were unaffected. These neurochemical actions were paralleled by “promnemonic” properties: blockade of scopolamine-induced deficits in radial maze performance and social recognition and reversal of delay-induced impairments in social recognition, social novelty discrimination, and novel object recognition. It also showed anxiolytic actions in a Vogel conflict procedure. Furthermore, in an electroencephalographic study of sleep architecture, S32212 enhanced slow-wave and rapid eye movement sleep, while decreasing waking. Finally, chronic administration of S32212 neither elevated body weight nor perturbed sexual behavior in male rats. In conclusion, S32212 displays a functional profile consistent with improved mood and cognitive performance, together with satisfactory tolerance.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
ABBREVIATIONS:
- S32212
- N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3-H-benzo[e]indole-3-carboxamide)
- 5-HT
- serotonin
- ACh
- acetylcholine
- AR
- adrenoceptor
- BDNF
- brain-derived neurotrophic factor
- CMS
- chronic mild stress
- DA
- dopamine
- DRN
- dorsal raphe nucleus
- EEG
- electroencephalogram
- EMG
- electromyogram
- FCX
- frontal cortex
- LC
- locus coeruleus
- LRR
- loss of righting reflex
- MED
- minimal effective dose
- NA
- noradrenaline
- NOR
- novel object recognition
- REM
- rapid eye movement
- SND
- social novelty discrimination
- SSRI
- selective serotonin reuptake inhibitor
- SWS
- slow-wave sleep
- VTA
- ventral tegmental area
- ANOVA
- analysis of variance
- AP
- anteroposterior
- ML
- mediolateral
- DV
- dorsoventral
- HPLC
- high-performance liquid chromatography
- T1
- first 5-min session
- T2
- second 5-min session
- P1
- first 5-min period
- P2
- second 5-min period
- AUC
- area under the curve
- S18616
- (S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4,2′-(1′,2′,3′,4′-tetrahydronaphthalene)].
- Received September 30, 2011.
- Accepted November 29, 2011.
- Copyright © 2012 by 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.
|