The role of 5-HT2A, 5-HT 2C and mGlu2 receptors in the behavioral effects of tryptamine hallucinogens N,N-dimethyltryptamine and N,N-diisopropyltryptamine in rats and mice

Abstract

Rationale: Serotonin 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.

Objective: The 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).

Methods: Drug 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.

Results: MDL100907 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.

Conclusions: The 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.

Fig. 1

Effects of the 5-HT_2A receptor inverse agonist, MDL100907, on the discriminative stimulus effects of DMT (left panels) and DiPT (right panels). Points represent the mean and error bars represent the standard error of the mean. Top panel shows drug-appropriate responding of the test compounds. The x-axis represents dose of MDL100907. The y-axis represents percentage of drug-lever appropriate responding. Bottom panel shows rate of responding as responses per second as a function of dose. Open circles- saline control; Open diamond- drug control. N=7. Asterisk indicates points that are different from the drug control.

Fig. 2

Effects of the 5-HT_2C receptor antagonist (SB242084) on the discriminative stimulus effects of DMT (left panels) and DiPT (right panels). Points represent the mean and error bars represent the standard error of the mean. Top panel shows drug-appropriate responding of the test compounds. The x-axis represents dose of SB242084. The y-axis represents percentage of drug-lever appropriate responding. Bottom panel shows rate of responding in responses per second (y-axis) as a function of dose. Open circles- saline control; Open diamond- drug control. N=7, except where shown. Asterisk indicates points that are different from the drug control.

Fig. 3

Effects of the mGlu2/3 receptor agonist (LY379268) on the discriminative stimulus effects of DMT (left panels) and DiPT (right panels). Points represent the mean and error bars represent the standard error of the mean. Top panel shows drug-appropriate responding of the test compounds in DMT/DiPT-trained rats. The x-axis represents dose of LY379268. The y-axis represents percentage of drug-lever appropriate responding. Bottom panel shows rate of responding in responses per second (y-axis) as a function of dose. Open circles- saline control; Open diamond- drug control. N=7, except where shown. Asterisk indicates points that are different from the drug control.

Fig. 4

Effects of the mGlu2/3 receptor antagonist (LY341495) at facilitating the effects of DMT (left panels) and DiPT (right panels). Points represent the mean and error bars represent the standard error of the mean. Top panel shows drug-appropriate responding of the test compounds in DMT/DiPT-trained rats. The x-axis represents dose of DMT/DiPT. The y-axis represents percentage of drug-lever appropriate responding. Bottom panel shows rate of responding in responses per second (y-axis) as a function of dose. Open triangles- Dose-effect curve of DMT and DiPT; Closed triangles- 0.5 mg/kg of LY341495; Closed circles- 2.5 mg/kg LY341495. Open circles- saline control; Open diamond- drug control; open squares- LY341495 alone. N=7, except where shown. Asterisk indicates points that are different from the saline control.

Fig. 5

Effects of the 5-HT_2A receptor inverse agonist, MDL100907 on head twitches induced by hallucinogens in C57Bl/6 mice. The x-axis represents vehicle controls or dose of DOI, DMT, or DiPT alone in combination with MDL100907. The y-axis represents mean head twitches in a 10-minute period. Error bars show the standard error of the mean. MDL indicates MDL100907. Sal indicates saline control. # indicates points different from hallucinogen alone (light gray bars); Asterisk indicates points different from the saline controls (Sal).