Parenterally administered 3-nitropropionic acid and amphetamine can combine to produce damage to terminals and cell bodies in the striatum.
The combined effects of amphetamine (AMPH) and 3-nitropropionic acid (3-NPA) were investigated to determine how the energy depletion proposed to be produced by AMPH interacts with an inhibitor of mitochondrial respiration to produce striatal neurotoxicity. Neither two doses (2 h apart) of 3.75 mg/kg AMPH alone nor a single dose of 30 mg/kg 3-NPA i.p. produced neurotoxicity in the striatum or lowered striatal dopamine content in rat. Administration of 40 mg/kg of 3-NPA alone almost invariably produced either lethality or did not produce neurotoxicity in the striatum of surviving animals. However, 30 mg/kg of 3-NPA administered along with 2 doses of 3.75 mg/kg AMPH to 47 animals produced striatal damage in the 31 survivors with 15 of the surviving rats showing muscle rigidity/catatonia for several days after dosing, along with decreased food consumption. Thirteen of these 15 rats showed degeneration of axons and cell bodies in the medial caudate-putamen with minimal damage to the globus pallidus. However, two rats exhibited hindlimb paralysis and signs of axonal and neuronal soma degeneration in the thalamus and cerebellar nuclei as well as striatum. Sixteen of the rats given both AMPH and 3-NPA exhibited only torpidity and loss of muscle tone 1-3 h after dosing. Such rats showed no signs of neuronal cell degeneration in the striatum, but did show significant dopamine depletions (60% of control) and reductions in tyrosine hydroxylase immunoreactivity at 14 days postexposure. The mitochondrial dysfunction produced by 3-NPA combined with activation of neuronal pathways by AMPH may have predisposed terminals, axons and cell bodies in striatum to degeneration.
Bowyer
J F
JF
Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
Clausing
P
P
Schmued
L
L
Davies
D L
DL
Binienda
Z
Z
Newport
G D
GD
Scallet
A C
AC
Slikker
W
W
D000661:Amphetamine / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000633:toxicity*; D004347:Drug Interactions; D007839:Functional Laterality / Q000187:drug effects; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000187:drug effects; D009498:Neurotoxins / Q000008:administration & dosage / Q000633:toxicity*; D009574:Nitro Compounds; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000648:ultrastructure; D011422:Propionates / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016622:Silver Staining
D015306:Biogenic Monoamines; D000697:Central Nervous System Stimulants; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D000661:Amphetamine; C015392:3-nitropropionic acid