No abstract

In summary, we have shown that MA is toxic to both 5-HT and DA cells and we have proposed a mechanism that would account for this response, namely, the conversion of the transmitters to neurotoxins. In addition, brain depletions of DA seem regionally specific with larger depletions occurring in some areas than in others. The depletions, however, do not seem to depend entirely on the nuclei of origin, that is, substantia nigra versus VTA. 5-HT was depleted by different amounts in the various regions examined and the 5-HT depletions, although proportional to the DA depletions, were consistently greater. The reasons for this differential sensitivity of the 5-HT and DA systems to the toxic effect of MA is speculative, but may be related to the differential formation of toxins due to the differing availability of oxygen and superoxides at serotonergic and dopaminergic synapses.

Central serotonin (5-HT) axons were visualized by immunocytochemistry to assess both acute and long-lasting changes in innervation density following methamphetamine administration to rats. Two morphologically distinct subtypes of 5-HT axons (fine and beaded) were differentially affected by d-methamphetamine (d-MA); the density of fine serotonergic axons was selectively decreased both 4 hours and 2 weeks after administration of d-MA. Acute depletion of 5-HT from fine axons, but not from beaded axons, was observed in the brains of all rats treated 4 hours previously with either a 100 mg/kg or 15 mg/kg dose of d-MA. Persistent loss of 5-HT axons was observed in 30% of rats treated 1 or 2 weeks previously with doses of d-MA which produce long-term deficits in biochemical markers for 5-HT. In the fraction of animals that exhibited denervation, fine serotonergic fibers were selectively ablated by d-MA, but beaded serotonergic fibers were spared. Thus, d-MA is similar to other amphetamine derivatives (e.g., p-chloroamphetamine, 3,4-methylenedioxyamphetamine) in that it acts selectively upon a morphologically distinct class of 5-HT axons but differs in that it produces long-lasting axon loss in only a fraction of animals. These data provide morphologic evidence of 5-HT axon loss following methamphetamine administration and further confirm the differential vulnerability of a particular morphological subtype of serotonergic axons to the neurotoxic effects of substituted amphetamines.