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 spinal cord, brain stem, and cortex. The present study examined the neurochemical and neurobehavioral consequences of the neonatal administration of IDPN and BMAA, two neurotoxins previously considered as experimental models of ALS. Sprague-Dawley rat pups (male and female) were injected 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, and 6], BMAA-A (500 mg/kg PND 5 only), BMAA-B (500 mg/kg PND 2 and 5), and BMAA-C (100 mg/kg PND 2 and 5). Neurobehavioral testing was performed and the rats were sacrificed at 101 days of age. Monoamine and amino acid content was measured by HPLC in brain regions and the spinal cord. IDPN treatment impaired the righting reflex and decreased forepaw suspension times. BMAA-A and BMAA-B males exhibited an increase in open 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 cord content of norepinephrine (NE), serotonin, and 5-hydroxyindoleacetic 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 elevated in the female BMAA-C group. Monoamines were also altered in the cerebellum, mediobasal hypothalamus, and hippocampus by IDPN and BMAA treatment. alpha 2-Adrenergic binding sites were increased in the spinal cord by IDPN and in the cerebellum by BMAA treatment. The results of this 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 dependent. Neonatal exposure to either IDPN or BMAA resulted in permanent changes in adult neurochemistry that may be related to reorganizational effects induced by toxin-mediated neuroplasticity in developing neurons.
Dawson
R
R
Department of Pharmacodynamics, College of Pharmacy, JHMHC, University of Florida, Gainesville 32610, USA. dawson@cop.health.ufl.edu
Marschall
E G
EG
Chan
K C
KC
Millard
W J
WJ
Eppler
B
B
Patterson
T A
TA
D000596:Amino Acids / Q000378:metabolism; D000599:Amino Acids, Diamino / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D000087522:Cyanobacteria Toxins; D005260:Female; D006728:Hormones / Q000378:metabolism; D008297:Male; D009498:Neurotoxins / Q000633:toxicity*; D009570:Nitriles / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism
D000596:Amino Acids; D000599:Amino Acids, Diamino; D000087522:Cyanobacteria Toxins; D006728:Hormones; D009498:Neurotoxins; D009570:Nitriles; C001824:beta-N-methylamino-L-alanine; C008110:3,3'-iminodipropionitrile