title: Cocaine acutely inhibits DNA synthesis in developing rat brain regions: evidence for direct actions.
abstract: Perinatal exposure to cocaine has been shown to cause morphological and neurobehavioral abnormalities. In the current study, neonatal rats were given an acute injection of cocaine (30 mg/kg s.c.) at 1, 3, 5, 8, 11 or 15 days of age, and [3H]thymidine incorporation into DNA examined over the ensuing 30 min period. Three brain regions were used that differ in their timetables of cell maturation: cerebellum, cerebral cortex and midbrain + brainstem. Cocaine inhibited DNA synthesis in all brain regions, with diminishing impact as the animals matured; by 15 days of age, the effect of cocaine was no longer significant. Inhibition of macromolecule synthesis was selective for DNA, as [3H]leucine incorporation into protein was much less affected by cocaine. Although inhibition of [3H]thymidine incorporation by a single injection of cocaine was short-lived, repeated administration could have cumulative effects: chronic treatment on days 2, 3 and 4 did not desensitize the adverse effect of a subsequent dose administered on day 5. Additionally, with chronic cocaine, the cerebellum displayed a pronounced rebound elevation of DNA synthesis 24 h after the last dose, a characteristic finding in delayed cell maturation. Inhibition of DNA synthesis by cocaine in developing brain was not secondary to ischemia, nor to local anesthesia, as alpha-adrenergic blockade with phenoxybenzamine afforded no protection, and lidocaine could not substitute for cocaine. In contrast, a small amount (15 micrograms) of cocaine injected directly into the central nervous system readily caused inhibition of DNA synthesis; the same dose given systemically had no effect. These data suggest that cocaine damages the developing brain, in part, through direct interference with DNA synthesis.
authors.affiliation: Department of Pharmacology, Duke University Medical Center, Durham, NC 22710.
authors.forename: T
authors.initials: T
authors.lastname: Anderson-Brown
authors.forename: T A
authors.initials: TA
authors.lastname: Slotkin
authors.forename: F J
authors.initials: FJ
authors.lastname: Seidler
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis*; D005260:Female; D007930:Leucine / Q000378:metabolism; D008012:Lidocaine / Q000494:pharmacology; D008729:Methoxamine / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D010643:Phenoxybenzamine / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D013936:Thymidine / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D010643:Phenoxybenzamine; D004247:DNA; D008012:Lidocaine; D007930:Leucine; D008729:Methoxamine; D003042:Cocaine; D013936:Thymidine