title: Parvalbumin neuron circuits and microglia in three dopamine-poor cortical regions remain sensitive to amphetamine exposure in the absence of hyperthermia, seizure and stroke.
abstract: The dopamine-releasing and depleting substance amphetamine (AMPH) can make cortical neurons susceptible to damage, and the prevention of hyperthermia, seizures and stroke is thought to block these effects. Here we report a 2-day AMPH treatment paradigm which affected only interneurons in three cortical regions with average or below-average dopamine input. AMPH (six escalating doses/day ranging from 5 to 30 mg/kg for 2 days) was given at 17-18 degrees C ambient temperature (T) to adult male rats. During the 2-day AMPH treatment, peak body T stayed below 38.9 degrees C in 40% of the AMPH treated rats. In 60% of the rats, deliberate cooling suppressed (<39.5 degrees C) or minimized (<40.0 degrees C) hyperthermia. Escalation of stereotypes to seizure-like behaviors was rare and post-mortem morphological signs of stroke were absent. Neurons labeled with the anionic, neurodegeneration-marker dye Fluoro-Jade (F-J) were seen 1 day after dosing, peaked 3 days later, but were barely detectable 14 days after dosing. Only nonpyramidal neurons in layer IV of the somatosensory barrel cortex and in layer II of the piriform cortex and posterolateral cortical amygdaloid nucleus were labeled with Fluoro-Jade. Isolectin B-labeled activated microglia were only detected in their neighborhood. F-J labeled neurons were extremely rare in cortical regions rich in dopamine (e.g. cingulate cortex), and were absent in cortical regions with no dopamine (e.g. visual cortex). Parvalbumin was seen in some Fluoro-Jade-labeled neurons and parvalbumin immunostaining in local axon plexuses intensified. This AMPH paradigm affected fewer cortical regions, and caused smaller reduction in striatal tyrosine hydroxylase (TH) immunoreactivity than previous 1-day AMPH regimens generating seizures or severe (above 40 degrees C) hyperthermia. Correlation between peak or mean body T and the extent of neurodegeneration or microgliosis was below statistical significance. Astrogliosis (elevated levels of the astroglia-marker, glial fibrillary acidic protein (GFAP)) was detected in many brain regions. In the striatum and midbrain, F-J labeled neurons and activated microglia were absent, but astrogliosis, decreased TH immunolabel, and swollen TH fibers were detected. In sum, after this AMPH treatment, cortical pyramidal neurons were spared, but astrogliosis was brain-wide and some interneurons and microglia in three cortical regions with average or below-average dopamine input remained sensitive to AMPH exposure.
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research/FDA, HFT-132, 3900 NCTR Road, Jefferson, AR 72079-9502, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Jakab
authors.forename: John F
authors.initials: JF
authors.lastname: Bowyer
mesh_terms: D000661:Amphetamine / Q000633:toxicity*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D004350:Drug Residues / Q000378:metabolism*; D005334:Fever / Q000139:chemically induced / Q000150:complications; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D007395:Interneurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D010320:Parvalbumins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000150:complications; D020521:Stroke / Q000139:chemically induced / Q000150:complications; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D010320:Parvalbumins; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine