Immunocytochemical evidence for methamphetamine‐induced serotonergic axon loss in the rat brain

Abstract

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.