Role of nitrergic system in behavioral and neurotoxic effects of amphetamine analogs

Several amphetamine analogs are potent psychostimulants and major drugs of abuse. In animal models, the psychomotor and reinforcing effects of amphetamine, methamphetamine (METH), 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy), and methylphenidate (MPD; Ritalin) are thought to be dependent on increased extracellular levels of dopamine (DA) in mesocorticolimbic and mesostriatal pathways. However, amphetamine analogs that increase primarily serotonergic transmission, such as p-chloroamphetamine (PCA) and fenfluramine (FEN), have no potential for abuse. High doses of METH, MDMA, PCA, and FEN produce depletions of dopaminergic and serotonergic nerve terminal markers and are considered as potential neurotoxicants. The first part of this review briefly summarizes the behavioral and neurotoxic effects of amphetamines that have a different spectrum of activity on dopaminergic and serotonergic systems. The second part discusses evidence supporting involvement of the nitrergic system in dopamine-mediated effects of amphetamines. The nitrergic system in this context corresponds to nitric oxide (NO) produced from neuronal nitric oxide synthase (nNOS) that has roles in nonsynaptic interneuronal communication and excitotoxic neuronal injury. Increasing evidence now suggests cross talk between dopamine, glutamate, and NO. Results from our laboratory indicate that dopamine-dependent psychomotor, reinforcing, and neurotoxic effects of amphetamines are diminished by pharmacological blockade of nNOS or deletion of the nNOS gene. These findings, and evidence supporting the role of NO in synaptic plasticity and neurotoxic insults, suggest that NO functions as a neuronal messenger and a neurotoxicant subsequent to exposure to amphetamine-like psychostimulants.