Studies To Examine Potential Tolerability Differences between the 5-HT2CReceptor Selective Agonists Lorcaserin and CP-809101.
Lorcaserin (LOR) is a selective 5-HT2Creceptor agonist that has been FDA approved as a treatment for obesity. The most frequently reported side-effects of LOR include nausea and headache, which can be dose limiting. We have previously reported that in the rat, while LOR produced unconditioned signs characteristic of nausea/malaise, the highly selective 5-HT2Cagonist CP-809101 (CP) produced fewer equivalent signs. Because this may indicate a subclass of 5-HT2Cagonists having better tolerability, the present studies were designed to further investigate this apparent difference. In a conditioned gaping model, a rodent test of nausea, LOR produced significantly higher gapes compared to CP consistent with it having higher emetogenic properties. Subsequent studies were designed to identify features of each drug that may account for such differences. In rats trained to discriminate CP-809101 from saline, both CP and LOR produced full generalization suggesting a similar interoceptive cue. In vitro tests of functional selectivity designed to examine signaling pathways activated by both drugs in CHO (Chinese hamster ovary) cells expressing h5-HT2Creceptors failed to identify evidence for biased signaling differences between LOR and CP. Thus, both drugs showed similar profiles across PLC, PLA2, and ERK signaling pathways. In studies designed to examine pharmacokinetic differences between LOR and CP, while drug plasma levels correlated with increasing dose, CSF levels did not. CSF levels of LOR increased proportionally with dose; however CSF levels of CP plateaued from 6 to 12 mg/kg. Thus, the apparently improved tolerability of CP likely reflects a limit to CNS levels attained at relatively high doses.
InterVivo Solutions Inc. , 120 Carlton Street, Toronto, Ontario M5A 4K2, Canada.|Department of Pharmacology & Toxicology, University of Toronto , 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Guy A
0000-0002-0187-8697
GA
Higgins
InterVivo Solutions Inc. , 120 Carlton Street, Toronto, Ontario M5A 4K2, Canada.
Leonardo B
LB
Silenieks
InterVivo Solutions Inc. , 120 Carlton Street, Toronto, Ontario M5A 4K2, Canada.
Amy
A
Patrick
InterVivo Solutions Inc. , 120 Carlton Street, Toronto, Ontario M5A 4K2, Canada.
Ines A M
IAM
De Lannoy
Centre for Addiction and Mental Health , 250 College St, Toronto, Ontario M5T 1L8, Canada.|Department of Psychology & Psychiatry, University of Toronto , 100 St. George Street, Toronto, Ontario M5S 3G3, Canada.
Paul J
PJ
Fletcher
Department of Psychology, University of Guelph , 50 Stone Road East, Guelph, Ontario N1G 2W1, Canada.
Linda A
LA
Parker
Ontario Veterinary College, University of Guelph , 50 Stone Road East, Guelph, Ontario N1G 2W1, Canada.
Neil J
NJ
MacLusky
Department of Pharmacology, University of Texas Health Science Center at San Antonio , 7703 Floyd Curl Drive, San Antonio, Texas 78229, United States.
Laura C
LC
Sullivan
Department of Pharmacology, University of Texas Health Science Center at San Antonio , 7703 Floyd Curl Drive, San Antonio, Texas 78229, United States.
Teresa A
TA
Chavera
Department of Pharmacology, University of Texas Health Science Center at San Antonio , 7703 Floyd Curl Drive, San Antonio, Texas 78229, United States.
Kelly A
KA
Berg
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology*; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology*; D013649:Taste / Q000187:drug effects*
D001552:Benzazepines; C518685:CP-809,101; D010879:Piperazines; D011719:Pyrazines; D058826:Serotonin 5-HT2 Receptor Agonists; C506658:lorcaserin
5-HT; CP-809101; CSF compartment; Serotonin; biased signaling; conditioned gaping; drug discrimination; lorcaserin; nausea; pharmacokinetics; plasma compartment; rat