Escalating dose-multiple binge methamphetamine exposure results in degeneration of the neocortex and limbic system in the rat.
Abuse of stimulant drugs such as methamphetamine (METH) and cocaine has been associated with long-lasting persistent behavioral alterations. Although METH-induced changes in the striatal dopaminergic system might play a role in these effects, the potential underlying neuroanatomical substrate for the chronic cognitive dysfunction in METH users is unclear. To investigate the involvement of non-dopaminergic systems in the neurotoxic effects of METH, we treated rats with an escalating dose-multiple binge regimen, which we have suggested may more closely simulate human METH exposure profiles. Combined neuropathological and stereological analyses showed that 30 days after the last binge, there was shrinkage and degeneration in the pyramidal cell layers of the frontal cortex and in the hippocampal CA3 region. Further immunocytochemical analysis showed that METH exposure resulted in loss of calbindin interneurons in the neocortex and selective damage to pyramidal neurons in the CA3 region of the hippocampus and granular cells in the dentate gyrus that was accompanied by microglial activation. Taken together, these studies suggest that selective degeneration of pyramidal neurons and interneurons in the neocortex and limbic system might be involved in the cognitive alterations in METH users.
Kuczenski
Ronald
R
Department of Psychiatry and HIV Neurobehavioral Research Center, University of California, San Diego/La Jolla, CA 92093-0624, USA.
Everall
Ian P
IP
Crews
Leslie
L
Adame
Anthony
A
Grant
Igor
I
Masliah
Eliezer
E
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D064026:Calbindins; D000697:Central Nervous System Stimulants / Q000008:administration & dosage* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005625:Frontal Lobe / Q000187:drug effects / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008032:Limbic System / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage* / Q000494:pharmacology; D019579:Neocortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology*; D009498:Neurotoxins / Q000008:administration & dosage / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013997:Time Factors
D064026:Calbindins; D000697:Central Nervous System Stimulants; D009498:Neurotoxins; D064030:S100 Calcium Binding Protein G; D008694:Methamphetamine