The effect of prenatal treatment with MPTP or MPP+ on the development of dopamine-mediated behaviors in rats.
Systemic exposure to the neurotoxin MPTP produces a Parkinsonian syndrome in man and primates, but not in adult rats. However, embryonic rat dopamine neurons in cell cultures are selectively destroyed by MPTP. This study examined whether similar effects on dopamine neurons occur in vivo, by studying dopamine-mediated behaviors in rats prenatally treated with MPTP or its active metabolite MPP+. Pregnant rats were injected daily with MPTP, MPP+, or vehicle from gestational day (E)13 until birth. There were time-dependent increases in spontaneous locomotor and rearing activity. Offspring of both the MPTP and MPP+ groups were hyporesponsive to d-amphetamine (1 mg/kg IP) at postnatal day 21. This hyporesponsiveness persisted at postnatal day 50 in the pups from MPTP-treated mothers. However, the striatal concentration of dopamine and its metabolites DOPAC and HVA were not significantly affected by the prenatal MPTP or MPP+ treatments. Both MPTP and MPP+ groups had significantly increased stereotypic responses to apomorphine (0.2 mg/kg SC) on both postnatal days 21 and 50. These results demonstrated persistent postsynaptic supersensitivity to dopaminergic agonists following prenatal MPTP/MPP+ treatment. That fetal rats develop long-term sequelae after prenatal exposure to MPTP/MPP+ suggests a different sensitivity of the immature rat dopamine neurons than in adult rats. Understanding this difference may provide useful information in the development of animal models of Parkinson's Disease.
Weissman
E M
EM
Department of Psychiatry, University of Cincinnati College of Medicine, OH 45267.
Norman
A B
AB
Calderon
S F
SF
Zubrycki
E M
EM
el-Etri
M M
MM
Shipley
M T
MT
Sanberg
P R
PR
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage*; D015655:1-Methyl-4-phenylpyridinium / Q000008:administration & dosage*; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D005260:Female; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D013239:Stereotyped Behavior / Q000187:drug effects*
D000662:Amphetamines; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D001058:Apomorphine; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine