Studies estimate that millions of Americans use cocaine regularly, and increasing numbers of cocaine abusing mothers are delivering infants repeatedly exposed to cocaine throughout their development. While gross malformations are not observed in these infants and the initial irritability often observed disappears, there may be important underlying neurochemical abnormalities that will lead to later psychiatric and/or neurological disorders. In animals, cocaine and amphetamine are both known to have """"""""sensitizing"""""""" effects on the brain's dopamine pathways that produce increased behavioral and biochemical responses to a given dose of the drug and persist for weeks to several months. This phenomena has a parallel in human amphetamine use where reexposure to a low dose of amphetamine can precipitate a psychotic episode in former amphetamine addicts who have been abstinent for months to years. Such long-lasting hypersensitivity suggests that chronic exposure to cocaine or amphetamine has long-term effects on brain neurochemistry. Furthermore, chronic exposure to amphetamine in rats has been shown to produce toxic degeneration of the dopamine neurons. The possibility of such a toxic effect has not been systematically examined in infants exposed prenatally to chronic cocaine or amphetamine. Both drugs are likely to have much more deleterious effects on the dopamine pathways during development. The goal of the proposed experiments is to evaluate the impact of chronic prenatal exposure to cocaine or amphetamine on the two major dopamine pathways in the brain, the mesolimbic and nigrostriatal systems. In each dopaminergic pathway the long-term effects of these drugs on transmitter release and reuptake will be evaluated under basal and activating conditions using in vivo measurement techniques. Microdialysis will be used to measure basal levels of dopamine and its metabolites, and changes in these parameters in response to tail pinch and amphetamine. Fast-scan, carbon-fiber voltammetry will be used to examine the kinetic parameters of the dopamine release-reuptake process. The neurotoxic actions of the drugs will be examined by postmortem analysis of the catecholamines and their metabolites in the major dopaminergic projection areas of the brain. These studies should provide critical information concerning the effects of prenatal stimulant exposure on the functioning of dopaminergic neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA006199-02
Application #
3212766
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1990-03-01
Project End
1994-02-28
Budget Start
1991-03-01
Budget End
1992-02-29
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Albany Medical College
Department
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