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Psychopharmacology (2010) 212:1323 DOI 10.1007/s00213-009-1694-1
ORIGINAL INVESTIGATION
The serotonin 5-HT2A receptor agonist TCB-2: a behavioral and neurophysiological analysis
Meredith A. Fox & Helen T. French & Justin L. LaPorte &
Adele R. Blackler & Dennis L. Murphy
Received: 12 May 2009 /Accepted: 10 September 2009 /Published online: 13 October 2009 # US Government 2009
AbstractRationale There are few reports on the high-affinity 5-HT2A
agonist (4-Bromo-3,6-dimethoxybenzocyclobuten-1-yl) methylamine hydrobromide (TCB-2).
Objectives Here we provide the first behavioral and neuro-physiological profile of TCB-2 in C57BL/6J mice, with direct comparisons to the 5-HT2A/2C agonist (T)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), in addition to determinations of 5-HT2A mediation via pretreatment with the selective 5-HT2A 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-HT2A
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-HT2A 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 neurophysio-logical effects of this conformationally restricted phenethylamine analog compound, which has 65-fold greater effects on signaling via the phosphoinositide versus arachidonic acid pathways.
Keywords TCB-2 . DOI . MDL 11,939 . 5-HT2A receptors . Serotonin transporter knockout mice . Head twitch response .
Feeding . Hypothermia . Corticosterone . Anxiety
Introduction
Serotonin 5-HT2A receptors are involved in the hallucinogenic effects of serotonergic drugs including lysergic acid diethylamide (LSD), and are also a target for neuroleptics used in the treatment of schizophrenia. Typically, the phenethylamine (T)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI) is used to assess 5-HT2A receptor function, although this compound...