NEUROCHEMICAL AND NEUROBEHAVIORAL EFFECTS OF NEONATAL ADMINISTRATION OF BETA-N-METHYLAMINO-L-ALANINE AND 3,3'-IMINODIPROPIONITRILE

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is characterized by a loss of motor neurons in the spina l cord, brain stem, and cortex The present study examined the neuroche mical and neurobehavioral consequences of the neonatal administration of IDPN and BMAA, two neurotoxins previously considered as experimenta l models of ALS. Sprague-Dawley rat pups (male and female) were inject ed SC with IDPN or BMAA. The following treatment groups (n = 5-14 per group) were studied: IDPN [100 mg/kg on postnatal days (PNDs) 2, 4, an d 6], BMAA-A (500 mg/kg PND 5 only), BMAA-B (500 mg/kg PND 2 and 5), a nd BMAA-C (100 mg/kg PND 2 and 5). Neurobehavioral testing was perform ed and the rats were sacrificed at 101 days of age. Monoamine and amin o acid content was measured by HPLC in brain regions and the spinal co rd. IDPN treatment impaired the righting reflex and decreased forepaw suspension times. BMAA-A and BMAA-B males exhibited an increase in ope n field behavior. The hindlimb splay of BMAA-A females was increased. Other significant behavioral and endocrine effects were also seen with neonatal IDPN or BMAA treatment. IDPN females had increased spinal co rd content of norepinephrine (NE), serotonin, and 5-hydroxyindoleaceti c acid (5-HIAA). IDPN males had no alterations in spinal cord content of NE or Glu, but serotonin and 5-HIAA content were increased. BMAA-A and BMAA-B males also had elevated spinal cord 5-HIAA content whereas females were unaffected. Glu and Asp content in the spinal cord was el evated in the female BMAA-C group. Monoamines were also altered in the cerebellum, mediobasal hypothalamus, and hippocampus by IDPN and BMAA treatment. az-Adrenergic binding sites were increased in the spinal c ord by IDPN and in the cerebellum by BMAA treatment. The results of th is study clearly demonstrated that both IDPN and BMAA given neonatally can produce changes in motor function and spinal cord neurochemistry, although the pattern of the effects is both treatment and sex depende nt. Neonatal exposure to either IDPN or BMAA resulted in permanent cha nges in adult neurochemistry that may be related to reorganizational e ffects induced by toxin-mediated neuroplasticity in developing neurons . (C) 1998 Elsevier Science Inc.