(M.C. Nassogne and P.J. Courtoy, in collaboration with P. Gressens and Ph. Evrard, Hôpital Debré, Paris, France).
Using an in vitro system of mouse embryonic neuronal cell co-cultures,
we have previously reported that the severe cerebral alterations found in
children born to cocaine-addicted models could be due to inappropriate neuronal
apoptosis (Nassogne et al., 1995, PNAS 92:11029-11033: Nassogne et
al., 1997, J. Neurochem. 68:2442-2450; Ref. 19). The relevance of these
observations in an animal model and the safety of methadone substitution
in detoxification programs were assessed in pregnant mice. Methadone (40
mg/kg/day, i.e., 40-fold detoxification dosage) or cocaine (30 mg/kd/day,
as in severe addiction) was injected into mice from day 8 to day 18 of gestation.
Pre- and postnatal brain development was analyzed at the anatomical and
microscopical levels, including by immunostaining of post-mitotic cells,
neurites, and astrocytes. Prenatal mice exposure to cocaine caused neuronal
misaddressing among neocortical layers, abnormal gliogenesis, and defective
neuritic outgrowth and bundling. Methadone produced small-for-date offspring
with normal brain development. In conclusion, supratherapeutic methadone
doses induce intrauterine growth retardation in mice, but spare brain cytoarchitecture.
In contrast, cocaine produces less growth retardation, but severely disturbs
neocortical layering (Ref. 7).