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 propose d 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 inva riably produced either lethality or did not produce neurotoxicity in t he striatum of surviving animals. However, 30 mg/kg of 3-NPA administe red along with 2 doses of 3.75 mg/kg AMPH to 47 animals produced stria tal damage in the 31 survivors with 15 of the surviving rats showing m uscle rigidity/catatonia for several days after dosing, along with dec reased food consumption. Thirteen of these 15 rats showed degeneration of axons and cell bodies in the medial caudate-putamen with minimal d amage to the globus pallidus. However, two rats exhibited hindlimb par alysis and signs of axonal and neuronal soma degeneration in the thala mus and cerebellar nuclei as well as striatum. Sixteen of the rats giv en both AMPH and 3-NPA exhibited only torpidity and loss of muscle ton e 1-3 h after dosing. Such rats showed no signs of neuronal cell degen eration in the striatum, but did show significant dopamine depletions (60% of control) and reductions in tyrosine hydroxylase immunoreactivi ty at 14 days postexposure. The mitochondrial dysfunction produced by 3-NPA combined with activation of neuronal pathways by AMPH may have p redisposed terminals, axons and cell bodies in striatum to degeneratio n.