Prenatal cocaine exposure reduces glial cell line-derived neurotrophic factor (GDNF) in the striatum and the carotid body of the rat: implications for DA neurodevelopment

Glial cell line-derived neurotrophic factor (GDNF) is a glycosylated, disul fide-bonded homodimer, and a member of the transforming growth factor-beta superfamily, GDNF has been shown to promote the survival and morphological differentiation of dopamine (DA) neurons and increase their high-affinity d opamine uptake. in order to determine whether the mechanism for our previou sly observed cocaine-induced DA reductions in brain and carotid body were G DNF-mediated, we exposed Sprague-Dawley rat fetuses to cocaine via maternal subcutaneous injections (30 mg/kg b.i.d., E7-E19). Brains and carotid bodi es of fetuses were excised and processed for assessment of GDNF levels usin g an Enzyme-Linked ImmunoadSorbent Assay (ELISA). ANOVA indicated that coca ine reduced carotid body GDNF by 36% (F-(1,F-5) = 28.11, p < 0.05) and stri atal GDNF by 41% (F-(1,F-5) = 41.77, p < 0.01). Although there was no inter action between drug exposure and fetal uterine position, post-hoc pairwise comparisons indicated that reductions in GDNF in the cocaine groups were du e to differences at more distal positions (positions 4-8). The magnitude of the reductions in striatal GDNF (but not carotid body GDNF) in both cocain e-exposed and control fetuses followed a cervical (smallest GDNF reductions ) to ovarian (greatest GDNF reductions) uterine position gradient. This pat tern was similar to that which we observed in prior studies examining DA re ductions in brain following prenatal cocaine exposure. The finding that coc aine reduces GDNF levels in striatum and carotid body support the hypothesi s that cocaine's ability to reduce striatal and carotid body DA may be indi rect through its ability to reduce GDNF. These data along with previous fin dings support the hypothesis that cocaine's effects on DA neurons are at le ast partially due to its indirect effects on trophic activity. The possible mechanisms whereby cocaine affects trophic activity are discussed. (C) 199 9 Elsevier Science B.V. All rights reserved.