Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents

Abstract

There has been increasing use of novel synthetic hallucinogenic compounds, 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25B-NBOMe), 2-(4-chloro-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25C-NBOMe), 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25I-NBOMe), and N,N-diallyl-5-methoxy tryptamine (5-MeO-DALT), which have been associated with severe toxicities. These four compounds were tested for discriminative stimulus effects similar to a prototypical hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) and the entactogen (±)-3,4-methylenedioxymethamphetamine (MDMA). Locomotor activity in mice was tested to obtain dose range and time-course information. 25B-NBOMe, 25C-NBOMe, and 25I-NBOMe decreased locomotor activity. 5-MeO-DALT dose dependently increased locomotor activity, with a peak at 10 mg/kg. A higher dose (25 mg/kg) suppressed activity. 25B-NBOMe fully substituted (≥80%) in both DOM-trained and MDMA-trained rats at 0.5 mg/kg. However, higher doses produced much lower levels of drug-appropriate responding in both DOM-trained and MDMA-trained rats. 25C-NBOMe fully substituted in DOM-trained rats, but produced only 67% drug-appropriate responding in MDMA-trained rats at doses that suppressed responding. 25I-NBOMe produced 74-78% drug-appropriate responding in DOM-trained and MDMA-trained rats at doses that suppressed responding. 5-MeO-DALT fully substituted for DOM, but produced few or no MDMA-like effects. All of the compounds, except 25I-NBOMe, fully substituted for DOM, whereas only 25B-NBOMe fully substituted for MDMA. However, the failure of 25I-NBOMe to fully substitute for either MDMA or DOM was more likely because of its substantial rate-depressant effects than weak discriminative stimulus effects. All of the compounds are likely to attract recreational users for their hallucinogenic properties, but probably of much less interest as substitutes for MDMA. Although no acute adverse effects were observed at the doses tested, the substantial toxicities reported in humans, coupled with the high likelihood for illicit use, suggests that these compounds have the same potential for abuse as other, currently scheduled compounds.

Figure 1. Structures of test compounds

The illustration on at the top left shows the basic structure of the 2C phenethylamines. On At the top right is the structure for the NBOMe compounds tested in this study (25B-NBOMe, 25C-NBOMe, and 25I-NBOMe), which are structurally similar to the 2C phenethylamines, with the addition of the N-benzylmethoxy group. On At the bottom is shown the structure for 5-MeO-DALT.

Figure 2. Time course of locomotor activity

Mean horizontal activity (Ambulation counts± SEM) as a function of time (10-min bins) and dose for each test compound (left to right). Each of the compounds produced time- and dose-dependent decreases in ambulation counts. 5-MeO-DALT also produced increases in ambulation counts at and 10 mg/kg. Data are from independent groups of 8 mice per dose, except 25B-NBOMe with 16 mice per dose. * indicates stimulant or depressant effects (p < 0.05) against vehicle control.

Figure 3. Dose effect of locomotor activity

Average horizontal activity counts/10 min (± SEM) during the 30 min of peak effect as a function of dose for each of the test compounds. All of the compounds decreased ambulation. 5-MeO-DALT showed an inverted U-shaped dose response with the peak stimulant dose producing ambulation counts greater than vehicle control, and the highest dose producing ambulation counts less than vehicle control. n=8 for each dose, except 25B-NBOMe with 16 mice per dose. Veh indicates vehicle control. * indicates (p < 0.05) against vehicle control.

Figure 4. Substitution for the discriminative stimulus effects of DOM

Top Upper panels show percentage of total responses made on the drug-appropriate lever. Bottom Lower panels show rate of responding in responses per second (r/s). n=7 for 5-MeO-DALT; all others n=6 except where shown. Ctrl indicates vehicle and DOM control values. * indicates response rate different from vehicle control (p < 0.05).

Figure 5. Substitution for the discriminative stimulus effects of MDMA

Top Upper panels show percentage of total responses made on the drug-appropriate lever. Bottom Lower panels show rate of responding in responses per second (r/s). n=6 except where shown. Ctrl indicates vehicle and MDMA control values. * indicates response rate different from vehicle control (p < 0.05).