[Abstract Title]. - Society for Neuroscience

dopaminergic transmission (Gainetdinov et al, Eur J Pharmacol., 1997), but the nature of this
action (dopamine release vs. dopamine transporter (DAT) inhibition) is not clear. The aim of the
present study was to investigate sydnocarb‟s pharmacological actions on the dopaminergic
system and to characterize its wake-promoting and other behavioral effects in rats and mice. In
rat synaptosomes, sydnocarb (100 κM) did not directly release dopamine. However, it potently
(Ki = 10.4 ± 1 nM) blocked DAT in human recombinant CHO-K1 cells; it also blocked the
norepinephrine transporter at higher concentrations (Ki = 10.2 ± 1.5 µM). Sydnocarb [10 µM]
showed no activity at 64 other targets. In a modified rat Irwin test, sydnocarb was well tolerated
at 30 mg/kg ip in Sprague Dawley (SD) rats, but at 100 mg/kg ip, it produced amphetamine-like
behavioral changes (sniffing, rearing, biting, marked stereotypy, etc.). In the EEG/EMG sleepwake
model (7 am - 7 pm lights on, dosing at 5 h after lights on), sydnocarb (3, 10, and 30 mg/kg
ip) increased wake in SD rats. At 30 mg/kg, sydnocarb enhanced wake for about 7 h and
produced a maximum cumulative wake surplus of ~260 min at 7.5 h post dosing, which declined
to 168 min at 22 h post dosing. In contrast to dextroamphetamine (Lin et al, J Sleep Res., 2000),
there was no evidence of rebound hypersomnolence following enhanced wake activity. Since
sydnocarb is used in the treatment of neuropsychiatric comorbidities, and prepulse inhibition
(PPI) is impaired in schizophrenia and bipolar disorders, sydnocarb (1 - 30 mg/kg ip) was tested
in an animal model of PPI. Sydnocarb (30 mg/kg ip) improved PPI of the startle response in
DBA/2 mice. In summary, sydnocarb acts as a selective DAT inhibitor, is well tolerated up to 30
mg/kg ip, produces robust increases in wake without amphetamine-like rebound
hypersomnolence, and shows efficacy in a mouse model of the sensorimotor gating deficits in
schizophrenia.
Disclosures: J.A. Gruner, Cephalon, Inc., A. Employment (full or part-time); Cephalon, Inc.,
E. Ownership Interest (stock, stock options, patent or other intellectual property); D.G. Flood,
Cephalon, Inc., A. Employment (full or part-time); Cephalon, Inc., E. Ownership Interest (stock,
stock options, patent or other intellectual property); J.R. Mathiasen, Cephalon, Inc., A.
Employment (full or part-time); Cephalon, Inc., E. Ownership Interest (stock, stock options,
patent or other intellectual property); L.D. Aimone, Cephalon, Inc., A. Employment (full or parttime);
Cephalon, Inc., E. Ownership Interest (stock, stock options, patent or other intellectual
property); M.J. Marino, Cephalon, Inc., A. Employment (full or part-time); M. Gasior,
Cephalon, Inc., A. Employment (full or part-time).
Poster
285. Sleep: Molecular, Cellular and Pharmacology I
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 285.12/QQ28
Topic: E.08.c. Sleep: Molecular, cellular, and pharmacology