Locomotor, discriminative stimulus, and place conditioning effects of MDAI in rodents

Abstract

5,6-Methylenedioxy-2-aminoindane (MDAI) has become a common substitute for (±)-3,4-methylenedioxymethamphetamine (MDMA) in Ecstasy. MDAI is known to produce MDMA-like discriminative stimulus effects, but it is not known whether MDAI has psychostimulant or hallucinogen-like effects. MDAI was tested for locomotor stimulant effects in mice and subsequently for discriminative stimulus effects in rats trained to discriminate cocaine (10 mg/kg, intraperitoneally), methamphetamine (1 mg/kg, intraperitoneally), ±MDMA (1.5 mg/kg, intraperitoneally), or (-)-2,5-dimethoxy-4-methylamphetamine hydrochloride (0.5 mg/kg, intraperitoneally) from saline. The ability of MDAI to produce conditioned place preference was also tested in mice. MDAI (3 to 30 mg/kg) depressed locomotor activity from 10 to 60 min. A rebound stimulant effect was observed at 1 to 3.5 h following 30 mg/kg. Lethality occurred in 8/8 mice following 100 mg/kg MDAI. Similarly, MDMA depressed locomotor activity immediately following the administration of 0.25 mg/kg and stimulant effects were observed 50-70 min following the administration of 0.5 and 1 mg/kg. MDAI fully substituted for the discriminative stimulus effects of MDMA (2.5 mg/kg), (-)-2,5-dimethoxy-4-methylamphetamine hydrochloride (5 mg/kg), and cocaine (7.5 mg/kg), but produced only 73% methamphetamine-appropriate responding at a dose that suppressed responding (7.5 mg/kg). MDAI produced tremors at 10 mg/kg in one methamphetamine-trained rat. MDAI produced conditioned place preference from 0.3 to 10 mg/kg. The effects of MDAI on locomotor activity and drug discrimination were similar to those produced by MDMA, having both psychostimulant-like and hallucinogen-like effects; thus, MDAI may have similar abuse potential as MDMA.

Fig 1

Time course of locomotor activity in mice. Data are represented as mean number of ambulation counts for each 10-minute period over 8 hours for each dose of MDMA (left) and MDAI (right). Data are from independent groups of 8 mice per dose. Vehicle (0.9% saline) data were obtained from one group of mice and displayed in each panel to indicate dose-dependent differences of drug-induced motor activity from vehicle-treated mice. The gray bars show the time ranges of maximal depressant and stimulant effects. * indicates doses significantly different from vehicle for the period of 0–30 minutes after injection, as determined by a two-way analysis of variance (p < 0.05).

Fig. 2

Substitution of MDAI for the discriminative stimulus effects of MDMA, cocaine, methamphetamine, or DOM in rats. The upper panel shows percentage of total responses on the drug-appropriate lever as a function of log dose of MDAI. The lower panel shows rate of responding in responses per second (r/s). Data are from groups of 6 rats. Ctrl indicates average of responding to vehicle (0.9% saline) and drug controls. * indicates response rate different from vehicle control (p < 0.05).

Fig. 3

Time course of the discriminative stimulus effects of MDAI. Percentage of total responses made on the drug-appropriate lever as a function of time (shown in log increments). The dose of MDAI was the dose that produced peak effects in the dose-effect study without suppressing response rate to the point that rats failed to respond (2.5 mg/kg in MDMA-trained rats, and 5 mg/kg in cocaine-, methamphetamine- and DOM-trained rats. The upper panel shows percentage of total responses on the drug-appropriate lever. The lower panel shows rate of responding in responses per second (r/s). n=6 except where shown. V indicates vehicle values. * indicates rate different (p < 0.05) from vehicle control.

Fig. 4

Conditioned place preference in mice. Preference scores (time spent on drug-paired floor during pre-test subtracted from time spent on drug-paired floor during post-test) as a function of log dose of MDAI. Data are from independent groups of n=16 mice per dose. * indicates doses significantly different from baseline (p < 0.05).