The role of 5-HT2A, 5-HT2C and mGlu2 receptors in the behavioral effects of tryptamine hallucinogens N,N-dimethyltryptamine and N,N-diisopropyltryptamine in rats and mice

The 5-HT2A receptor plays a major role in mediating the effects of the hallucinogens DMT and DiPT. A 5-HT2A receptor inverse agonist fully blocked the discriminative stimulus effects of DMT but only partially blocked those of DiPT. A 5-HT2C receptor antagonist partially attenuated DiPT's effects but minimally affected DMT. An mGluR2/3 agonist produced potent but partial blockade of DMT's effects, while an mGluR2/3 antagonist facilitated the effects of both compounds. Both DMT and DiPT induced head twitches, with DiPT producing more, and these were blocked by a 5-HT2A receptor inverse agonist. DiPT acted as a low-potency full agonist at the 5-HT2C receptor in vitro. The findings suggest that 5-HT2C and mGluR2 receptors modulate the effects of these tryptamine hallucinogens to some degree.

Study at a glance

Abstract

RationaleSerotonin 5-HT2A and 5-HT2C receptors are thought to be the primary pharmacological mechanisms for serotonin-mediated hallucinogenic drugs, but recently there has been interest in metabotropic glutamate (mGluR2) receptors as contributors to the mechanism of hallucinogens.ObjectiveThe present study assesses the role of these 5-HT and glutamate receptors as molecular targets for two tryptamine hallucinogens, N,N-dimethyltryptamine (DMT) and N,N-diisopropyltryptamine (DiPT).MethodsDrug discrimination, head twitch, and radioligand binding assays were used. A 5-HT2AR inverse agonist (MDL100907), 5-HT2CR antagonist (SB242084), and mGluR2/3 agonist (LY379268) were tested for their ability to attenuate the discriminative stimulus effects of DMT and DiPT; an mGluR2/3 antagonist (LY341495) was tested for potentiation. MDL100907 was used to attenuate head twitches induced by DMT and DiPT. Radioligand binding studies and inosital-1-phosphate (IP-1) accumulation were performed at the 5-HT2CR for DiPT.ResultsMDL100907 fully blocked the discriminative stimulus effects of DMT, but only partially blocked DiPT. SB242084 partially attenuated the discriminative stimulus effects of DiPT, but produced minimal attenuation of DMT's effects. LY379268 produced potent, but only partial blockade of the discriminative stimulus effects of DMT. LY341495 facilitated DMT- and DiPT-like effects. Both compounds elicited head twitches (DiPT>DMT) which were blocked by MDL1000907. DiPT was a low-potency full agonist at 5-HT2CR in vitro.ConclusionsThe 5-HT2AR likely plays a major role in mediating the effects of both compounds. 5-HT2C and mGluR2 receptors likely modulate the discriminative stimulus effects of both compounds to some degree.