Cocaine effects on the developing central nervous system: behavioral, psychopharmacological, and neurochemical studies.
IMPLICATIONS and FUTURE DIRECTIONS. The data we have collected thus far support the following conclusions: 1. Subcutaneous administration of cocaine results in dose-dependent increases in brain and plasma cocaine in both dams and fetuses, and maternal plasma levels in the range of or above those observed in human cocaine users. Fetal levels are lower than those of the dam, suggesting that the placenta may partially restrict cocaine entry into the fetus. Concentrations of the active cocaine metabolite benzoylecgonine, however, are greater in fetal than in maternal brain; this may have important implications for brain development given the calcium-binding properties of this metabolite. 2. Chronic subcutaneous administration of 10, 20 or 40 mg/kg cocaine from E8-E20 does not alter litter size, body weights at birth or weaning, or development of reflexes or physical landmarks in the offspring. 3. Offspring exposed gestationally to cocaine exhibit learning and/or retention deficits in some but not all conditioning situations. 4. Behaviorally and psychopharmacologically, there is evidence for a potential attenuation in DA activity in preweanling pups exposed gestationally to cocaine. There is, however, no sign of any alteration in DA turnover in treated offspring sacrificed at weaning, although preliminary data suggest that DA levels may be increased in exposed pups during the neonatal period. Possible alterations in DA receptor function are currently being assessed. We are still at the initial stages of our work, and the data we have collected thus far have raised as many questions as they have answered. We plan to assess further the cognitive deficits observed in cocaine-exposed offspring. Under what contingencies are these learning and/or retention deficits observed, and are they permanent deficits or does recovery eventually occur? Is there actually an attenuation in DA activity in treated offspring? If so, is this attenuation related to compensations at the presynaptic and/or postsynaptic level, and what is the time course for this effect on the DA system? What are the critical periods for the production of these alterations; is cocaine exposure during the second or third trimester alone sufficient? How do our results compare with those of other laboratories that are using other methods for administering cocaine during gestation? At some point in the future we also hope to examine potential therapeutic approaches to reduce the cognitive deficits observed in exposed offspring.(ABSTRACT TRUNCATED AT 400 WORDS)
Spear
L P
LP
Department of Psychology, State University of New York, Binghamton 13901.
Kirstein
C L
CL
Frambes
N A
NA
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D011919:Rats, Inbred Strains; D012018:Reflex / Q000187:drug effects
C005618:benzoylecgonine; D003042:Cocaine; D004298:Dopamine