The serotonin 5-HT(2A) receptor agonist TCB-2: a behavioral and neurophysiological analysis.
BACKGROUND
There are few reports on the high-affinity 5-HT(2A) agonist (4-Bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2).


OBJECTIVE
Here we provide the first behavioral and neurophysiological profile of TCB-2 in C57BL/6J mice, with direct comparisons to the 5-HT(2A/2C) agonist (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), in addition to determinations of 5-HT(2A) mediation via pretreatment with the selective 5-HT(2A) antagonist MDL 11,939.


RESULTS
In a dose-dependent manner, TCB-2 induced head twitches, decreased food consumption in food-deprived mice, induced hypothermia, and increased corticosterone levels, with no effects on locomotor activity or anxiety-like behaviors in the open field. Similar effects were observed in side-by-side dose-response comparisons with DOI; although at the highest dose tested (5.0 mg/kg), TCB-2 induced significantly fewer head twitches, and a significantly enhanced hypothermic response, versus DOI. Pretreatment with MDL 11,939 blocked head twitches and temperature change following TCB-2 and DOI, confirming 5-HT(2A) mediation of these responses. Although MDL 11,939 pretreatment blocked DOI-induced suppression of feeding, MDL 11,939 had no effect on TCB-2-induced suppression of feeding. Previous studies show that 5-HT(2A) function is altered by changes in serotonin transporter (SERT) expression and function. In SERT knockout (-/-) mice, TCB-2-induced head twitches and hypothermia were greatly diminished compared to SERT wild-type (+/+) mice.


CONCLUSIONS
The current studies are important, as they are the first to assess the effects of TCB-2 in mice, and are among the first to report the behavioral and neurophysiological effects of this conformationally restricted phenethylamine analog compound, which has 65-fold greater effects on signaling via the phosphoinositide versus arachidonic acid pathways.
Fox
Meredith A
MA
Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1264, USA. mfox@mail.nih.gov
French
Helen T
HT
LaPorte
Justin L
JL
Blackler
Adele R
AR
Murphy
Dennis L
DL
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019416:Head Movements / Q000187:drug effects; D007035:Hypothermia / Q000139:chemically induced; D008297:Male; D008744:Methylamines / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010716:Phosphatidylinositols / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*
C514172:(4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine; D001643:Bridged Bicyclo Compounds; D008744:Methylamines; D010716:Phosphatidylinositols; D058826:Serotonin 5-HT2 Receptor Agonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D016718:Arachidonic Acid