Cocaine abuse by pregnant women is a serious problem; estimates of rates of maternal cocaine abuse range from 5-20%. Because of variations in administration and gestational timing, the consequences of prenatal cocaine exposure range from """"""""no effect"""""""" to fetal death and include physical and behavioral alterations. Animal models of prenatal cocaine exposure have reproduced many of the associated symptoms. Several lines of evidence suggest that the brain dopamine (DA) systems, which have been shown to be a primary site of action of cocaine and which develop prenatally, are altered by developmental cocaine exposure. Our research has demonstrated that our paradigm of gestational cocaine exposure in rats leads to initial alterations in brain DA systems of the offspring which tend to normalize as the animal ages. Examination of a number of markers identified no supporting neuroanatomical changes in the brain DA systems; however a serotonin hyperinnervation was observed in the striatum, one of the major DA terminal fields. In rats prenatally exposed to cocaine this enhanced innervation of the striatum by serotonin fibers becomes apparent at about three weeks after birth and persists into adulthood. The alterations in extracellular DA and its metabolites return to normal during the time that the enhanced serotonin ingrowth is occurring. Thus the normalization we observed in DA might have occurred directly in the DA system or there might have been compensations brought about by changes in serotonin and/or other systems. Our operating hypothesis is that prenatal cocaine exposure results in an insult to the brain DA systems, expressed as enhanced basal and stimulated release; and over time compensations occur that return the release/reuptake of DA to normal via changes in the DA system, serotonin system, and/or other systems. This application seeks to investigate questions about whether this serotonin hyperinnervation of the DA terminal fields produces the functional consequence of elevated levels of serotonin in the extracellular fluid and, hence, whether serotonergic controls on the release of DA are altered. In addition, we will determine whether there are residual alterations in more complex dopaminergic behaviors, such as self-administration, and whether serotonin's role in this behavior is altered.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA006199-06
Application #
2377372
Study Section
Special Emphasis Panel (SRCD (12))
Project Start
1990-03-01
Project End
1999-01-31
Budget Start
1997-03-20
Budget End
1998-01-31
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Albany Medical College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12208
Snyder-Keller, A; Sam, C; Keller Jr, R W (2000) Enhanced susceptibility to cocaine- and pentylenetetrazol-induced seizures in prenatally cocaine-treated rats. Neurotoxicol Teratol 22:231-6
Snyder-Keller, A; Keller Jr, R W (1998) Stimulant-mediated c-fos induction in striatum as a function of age, sex, and prenatal cocaine exposure. Brain Res 794:88-95
Snyder-Keller, A; Keller Jr, R W (1998) Prenatal cocaine exposure increases susceptibility to drug-induced seizures. c-fos induction and brain cocaine levels. Ann N Y Acad Sci 846:419-22
Keller Jr, R W; LeFevre, R; Raucci, J et al. (1996) Enhanced cocaine self-administration in adult rats prenatally exposed to cocaine. Neurosci Lett 205:153-6
Keller Jr, R W; Johnson, K S; Snyder-Keller, A M et al. (1996) Effects of prenatal cocaine exposure on the mesocorticolimbic dopamine system: an in vivo microdialysis study in the rat. Brain Res 742:71-9
Snyder-Keller, A M; Keller Jr, R W (1995) Prenatal cocaine alters later sensitivity to cocaine-induced seizures. Neurosci Lett 191:149-52
Keller Jr, R W; Maisonneuve, I M; Nuccio, D M et al. (1994) Effects of prenatal cocaine exposure on the nigrostriatal dopamine system: an in vivo microdialysis study in the rat. Brain Res 634:266-74
Snyder-Keller, A M; Keller Jr, R W (1993) Prenatal cocaine increases striatal serotonin innervation without altering the patch/matrix organization of intrinsic cell types. Brain Res Dev Brain Res 74:261-7
Keller Jr, R W; Maisonneuve, I M; Carlson, J N et al. (1992) Within-subject sensitization of striatal dopamine release after a single injection of cocaine: an in vivo microdialysis study. Synapse 11:28-34