Behavioral effects of N-methylamphetamine and N,N-dimethylamphetamine in rats and squirrel monkeys

The N-methylated derivative of N-methamphetamine (MA), N,N-dimethylamphetamine (NNDMA), has recently been synthesized for illicit use. The present study compared the psychomotor stimulant, discriminative stimulus, reinforcing and lethal effects of these analogs in rats and squirrel monkeys. NNDMA was 6 to 12 times less potent than MA in decreasing rates of responding in rats or monkeys under fixed interval or fixed ratio schedules of food presentation. Both MA and NNDMA produced dose-dependent increases in the percentage of cocaine-lever responses in rats trained to discriminate 10 mg/kg of cocaine from saline, with NNDMA 12 times less potent than MA. Response-produced i.v. infusions of MA or NNDMA maintained rates of responding that were higher than those maintained by saline infusions in squirrel monkeys trained to self-administer cocaine; NNDMA was 10 times less potent than MA in producing these reinforcing effects. Both drugs increased fixed interval responding in squirrel monkeys; MA was more efficacious than NNDMA. MA also increased rates of responding in rats during time-out periods in which responses had no scheduled consequences, whereas NNDMA did not. Onset and time course data suggested that conversion of NNDMA to MA was probably not necessary for the behavioral effects of NNDMA. In contrast to the relative potencies in behavioral tests, NNDMA was only 3 times less potent than MA in its lethal effects in rats. However, lethality of both drugs was prevented by haloperidol. In general, MA displayed a wider separation in the doses required to produce behavioral vs. lethal effects than did NNDMA. These data indicate that NNDMA displays most of the characteristics of a psychomotor stimulant and is likely to produce similar subjective effects and abuse in humans, although higher doses may be required. The lower potency, efficacy and neurotoxicity of NNDMA raise the possibility of dissociating the myriad of behavioral and toxic effects of amphetamines and related compounds by structural modification of the amine moiety.