Abstract
The serotonin (5-HT) 2A receptor is the primary molecular target of serotonergic hallucinogens, which trigger large-scale perturbations of the cortex. Our understanding of how 5-HT2A activation may cause the effects of hallucinogens has been hampered by the receptor unselectivity of most of the drugs of this class. Here we used 25CN-NBOH (N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine), a newly developed selective 5-HT2A agonist, and tested it with regard to the head-twitch-response (HTR) model of 5-HT2A activity and effects on locomotion. 25CN-NBOH evoked HTRs with an inverted u-shape-like dose-response curve and highest efficacy at 1.5 mg/kg, i.p. HTR occurrence peaked within 5 min after agonist injection, and exponentially decreased to half-maximal frequency at ~11 min. Thorough habituation to the experimental procedures (including handling, saline injection, and exposure to the observational boxes 1 day before the experiment) facilitated the animals' response to 25CN-NBOH. 25CN-NBOH (1.5 mg/kg, i.p.) induced HTRs were blocked by the 5-HT2A antagonist ketanserin (0.75 mg/kg, 30 min pre), but not by the 5-HT2C antagonist SB-242084 (0.5 mg/kg, i.p., 30 min pre). SB-242084 instead slightly increased the number of HTRs occurring at a 3.0-mg/kg dose of the agonist. Apart from HTR induction, 25CN-NBOH also modestly increased locomotor activity of the mice. Repeated once-per-day injections (1.5 mg/kg, i.p.) led to reduced occurrence of 25CN-NBOH induced HTRs. This intermediate tolerance was augmented when a second (higher) dose of the drug (3.0 mg/kg) was interspersed. Short-interval tolerance (i.e., tachyphylaxis) was observed when the drug was injected twice at intervals of 1.0 and 1.5 h at either dose tested (1.5 mg/kg and 0.75 mg/kg, respectively). Inducing ketanserin-sensitive HTRs, which are dependent on environmental valences and which show signs of tachyphylaxis and tolerance, 25CN-NBOH shares striking features common to serotonergic hallucinogens. Given its distinct in vitro selectivity for 5-HT2A over non5-HT2 receptors and its behavioral dynamics, 25CN-NBOH appears to be a powerful tool for dissection of receptor-specific cortical circuit dynamics, including 5-HT2A related psychoactivity.
Highlights
IntroductionThe serotonin (5-HT) 2A receptor is a member of the 5HT2 seven-transmembrane receptor family and is expressed in various cells and tissues across the mammalian body, with highest expression levels in the brain (see GPCR database; Regard et al, 2008). 5-HT2A receptors are enriched in the cerebral cortex, on the apical dendrites of pyramidal cells in layer V (Weber and Andrade, 2010)
The serotonin (5-HT) 2A receptor is a member of the 5HT2 seven-transmembrane receptor family and is expressed in various cells and tissues across the mammalian body, with highest expression levels in the brain. 5-HT2A receptors are enriched in the cerebral cortex, on the apical dendrites of pyramidal cells in layer V (Weber and Andrade, 2010)
Blockade of 5HT2A receptors has been shown to counteract alterations of consciousness induced by serotonergic hallucinogens such as lysergic acid diethylamide (LSD) (Kraehenmann et al, 2017), and 5-HT2A receptors of layer 5 pyramidal cells are thought to be a key mediator of psychedelic activity (Vollenweider and Kometer, 2010; Muthukumaraswamy et al, 2013; Nichols, 2016)
Summary
The serotonin (5-HT) 2A receptor is a member of the 5HT2 seven-transmembrane receptor family and is expressed in various cells and tissues across the mammalian body, with highest expression levels in the brain (see GPCR database; Regard et al, 2008). 5-HT2A receptors are enriched in the cerebral cortex, on the apical dendrites of pyramidal cells in layer V (Weber and Andrade, 2010). 5-HT2A receptors are enriched in the cerebral cortex, on the apical dendrites of pyramidal cells in layer V (Weber and Andrade, 2010). The 5-HT2A receptor is considered as an important drug target, with potential implications of both agonists and antagonists in the treatment of various psychiatric conditions, including depression and anxiety (Mascher, 1967; Quesseveur et al, 2012; Buchborn et al, 2014; Carhart-Harris et al, 2016; Ross et al, 2016; Carhart-Harris and Goodwin, 2017). The 4-iodo-2,5-dimethoxy-analog of amphetamine DOI, for instance, which often has been the drug of choice in animal studies related to 5-HT2A functions, seems to exhibit confounded affinity for 5-HT2 as well as adrenergic receptors (Ray, 2010).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
