© Neuroscience-Net Volume 1, Article #00009

Received July 6, 1996 Accepted for Publication September 18, 1996 Published October 22, 1996

Recently, abuse of the hallucinogenic drug methamphetamine (MA), known on the street as "crystal", has increased. It has not been conclusively determined whether MA causes depletion or degeneration of serotonin (5-HT), as well as dopamine system, in the brain. This important difference is difficult to resolve since detection markers are subject to 5-HT levels. In this study, using immunocytochemistry with antibodies against the serotonin transporter (5-HTT), we report that MA at doses of 25-50 mg/kg i.p. caused dose dependent damage to 5-HT fibers within hours. An apparent varicosis of 5-HTT immunoreactive (im) fibers is reported for the first time, which has not previously been seen using anti-5-HT antibodies. At 25-50mg/kg, the vesicular cysts enlarged from 2 to as large as 15 µm, and began to perforate when exceeding approximately 7 µm. At 50mg/kg, in addition to the vesicular enlargement, a complete disintegration and disappearance of a small population of 5-HTT-im fibers in the subareas of the cortices occurred. A subpopulation of 5-HTT-im fibers had already been reduced in density within hours after injection. Four days after MA injection, perforated 5-HTT-im fibers became fragmented, which may have led to the degradation of distal 5-HT fibers. The 5-HTT-im fibers were greatly reduced in many regions of the brain, particularly in the frontal and parietal cortices, hippocampus, striatum, and thalamus. In summary, staining with our 5-HTT antibody confirmed that 25-50mg/kg MA causes structural damage and axonal degeneration of 5-HT fibers. In addition, for the first time, we report that depending on the dosage, there are two phases of 5-HT fiber damage caused by MA: (a) acute phase: varicosis, perforation, and disintegration of 5-HTT-im fibers within hours, and (b) chronic phase: fragmentation and appearance of terminal stumps over days. The definition of 5-HT fiber degeneration is discussed. As a result of 5-HT fiber destruction, MA administration would most likely alter the normal 5-HT function in the brain for an extended period of time.