TY - JOUR
T1 - F15599, a highly selective post-synaptic 5-HT1A receptor agonist
T2 - In-vivo profile in behavioural models of antidepressant and serotonergic activity
AU - Assié, Marie Bernadette
AU - Bardin, Laurent
AU - Auclair, Agnès L.
AU - Carilla-Durand, Elisabeth
AU - Depoortère, Ronan
AU - Koek, Wouter
AU - Kleven, Mark S.
AU - Colpaert, Francis
AU - Vacher, Bernard
AU - Newman-Tancredi, Adrian
PY - 2010/11
Y1 - 2010/11
N2 - F15599 is a novel agonist with high selectivity and efficacy at serotonin 5-HT1A receptors (5-HT1ARs). In signal transduction, electrophysiological and neurochemical tests, F15599 preferentially activates post-synaptic 5-HT1ARs in rat frontal cortex. Such a profile may translate to an improved profile of therapeutic activity for mood disorders. The in-vivo effects of F15599 were therefore compared with those of a related compound, F13714, in rat models of antidepressant activity and 5-HT 1AR activation: forced swimming test (FST), conditioned stress-induced ultrasonic vocalization, 5-HT syndrome, plasma corticosterone and body temperature. Acute administration of F15599 or F13714 reduced immobility in the FST at low doses; these effects were long lasting and the effects of F15599 were maintained after repeated (5 d, p.o.) administration. Both compounds decreased ultrasonic vocalization duration at low doses. In contrast, higher doses of F15599 were required to induce lower lip retraction, elements of the 5-HT behavioural syndrome, hypothermia and to increase plasma corticosterone levels. Notably, there was a greater separation of ED50 between FST and other effects for F15599 than for F13714. Thus, the in-vivo potency of F15599 in models of antidepressant/anti-stress activity is similar to that of F13714, despite the fact that the latter has an in-vitro potency two orders of magnitude greater. In contrast F15599 has a lower propensity than F13714 to induce other serotonergic signs. The distinctive pharmacological profile of F15599 suggests that preferential targeting of post-synaptic 5-HT1ARs constitutes a promising strategy for improved antidepressant therapy.
AB - F15599 is a novel agonist with high selectivity and efficacy at serotonin 5-HT1A receptors (5-HT1ARs). In signal transduction, electrophysiological and neurochemical tests, F15599 preferentially activates post-synaptic 5-HT1ARs in rat frontal cortex. Such a profile may translate to an improved profile of therapeutic activity for mood disorders. The in-vivo effects of F15599 were therefore compared with those of a related compound, F13714, in rat models of antidepressant activity and 5-HT 1AR activation: forced swimming test (FST), conditioned stress-induced ultrasonic vocalization, 5-HT syndrome, plasma corticosterone and body temperature. Acute administration of F15599 or F13714 reduced immobility in the FST at low doses; these effects were long lasting and the effects of F15599 were maintained after repeated (5 d, p.o.) administration. Both compounds decreased ultrasonic vocalization duration at low doses. In contrast, higher doses of F15599 were required to induce lower lip retraction, elements of the 5-HT behavioural syndrome, hypothermia and to increase plasma corticosterone levels. Notably, there was a greater separation of ED50 between FST and other effects for F15599 than for F13714. Thus, the in-vivo potency of F15599 in models of antidepressant/anti-stress activity is similar to that of F13714, despite the fact that the latter has an in-vitro potency two orders of magnitude greater. In contrast F15599 has a lower propensity than F13714 to induce other serotonergic signs. The distinctive pharmacological profile of F15599 suggests that preferential targeting of post-synaptic 5-HT1ARs constitutes a promising strategy for improved antidepressant therapy.
KW - 5-HT syndrome
KW - Corticosterone
KW - F13714
KW - F15599
KW - forced swimming test
KW - ultrasonic vocalization
UR - http://www.scopus.com/inward/record.url?scp=79952662179&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79952662179&partnerID=8YFLogxK
U2 - 10.1017/S1461145709991222
DO - 10.1017/S1461145709991222
M3 - Article
C2 - 20059805
AN - SCOPUS:79952662179
VL - 13
SP - 1285
EP - 1298
JO - The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)
JF - The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)
SN - 1461-1457
IS - 10
ER -