Neurochemical and behavioral differencet between d-methamphetamine and d-amphetamine in rats

Rationale: Methamphetamine (METH) and amphetamine (AMPH) are both abused psychostimulants. Although METH is generally accepted to be more addictive and potent than its analogue AMPH, there are no known neurobiological differences in action between the two drugs that may account for such differences. Objective: METH and AMPH were compared to determine potential mechanisms for such differences between the two drugs in order to provide new targets for the treatment of METH addiction. Methods: Using in vivo microdialysis on rats, dopamine (DA), DA metabolites, and glutamate (GLU) release in the nucleus accumbens (NAC) and prefrontal cortex (PFC) were measured after administration of 2 mg/kg, IP, of METH or AMPH. Based on the neurochemical differences between METH and AMPH, a locomotor activity study was designed to assess differences in locomotor activation for a range of doses (1-4 mg/kg, IP) of METH and AMPH and after pretreatment with intra-accumbens GLU antagonists. Results: METH and AMPH raised NAC DA levels to a similar degree. In the PFC, both METH and AMPH raised DA levels, but METH was less effective than AMPH. In the NAC, AMPH raised GLU levels but METH did not. In the PFC, METH raised GLU levels but AMPH did not. The locomotor activity dose response curve for METH had a lower peak than that of AMPH. This difference was blocked by pretreatment with either the GLU NMDA antagonist AP5 or the GLU AMPA antagonist DNQX locally in the NAC. Conclusions: This study reveals several previously unknown neurochemical and behavioral differences between METH and AMPH. Based on these results, it is suggested that new pharmacotherapeutic agents that produce augmentations of NAC GLU or PFC DA activity, or perhaps inhibition of PFC GLU activity, may someday be useful for the treatment of METH addiction.