To date thousands of infants and children have been exposed to cocaine prenatally through maternal drug abuse. Since the neurobehavioral consequences of this exposure are difficult to study in clinical populations, appropriate animal models are necessary. The proposed studies will examine the subacute effects of cocaine on developing rat brain following an exposure pattern which we have shown produces long-term alterations in behavior and neurochemistry. In addition, since cocaine has complex pharmacologic actions which may operate individually or collectively to produce these long-term alterations, we will examine three pharmacologic actions of cocaine including: the local anesthetic effects, the inhibition of dopamine (DA) reuptake and inhibition of serotonin (5-HT) uptake. Each agent will be compared using neurochemical and neurobehavioral measures in perinatal and adult animals. By identifying the effects of cocaine and each of its pharmacologic properties in developing brain, the early steps in the cascade of events which ultimately produce cocaine's long-term effects can be identified.
AIM 1) The local anesthetic effects of cocaine will be examined by administering either cocaine or lidocaine, a drug with relatively pure local anesthetic actions, during early PoN life in the rat. The neurobehavioral consequences of these exposures will be measured in periweanling and adult animals by examining startle reflex or administering the DA agonists, quinpirole and SKF 38393, and measuring activity.
AIM 2) The DA effects of cocaine will be measured by treating developing animals with either cocaine or the DA reuptake inhibitor, GBR 12909. Brain functional studies will be conducted 30 minutes after the last of 10 injections and in animals withdrawn from the acute effects of the drugs. Follow-up studies will examine behavioral responses to quinpirole and SKF 38393 as well as startle responsivity.
AIM 3) The effects of cocaine as an inhibitor of 5-HT reuptake will be determined in developing brain by comparing cocaine with fluoxetine, a selective 5-HT uptake inhibitor. Brain functional studies will be conducted as initial studies and follow-up studies will examine behavioral responses to 5-HT-specific agonists, 8-OH-DPAT and DOI, in activity and startle paradigms. By identifying the functional responses to cocaine and each pharmacologic agent, we will enhance our understanding not only about cocaine's effects on developing brain, but also about basic developmental processes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA004118-06
Application #
2116986
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1987-09-01
Project End
1995-08-31
Budget Start
1992-09-01
Budget End
1993-08-31
Support Year
6
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Suny Downstate Medical Center
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
068552207
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
Dow-Edwards, Diana (2010) Sex differences in the effects of cocaine abuse across the life span. Physiol Behav 100:208-15
Dow-Edwards, D L; Busidan, Y (2001) Behavioral responses to dopamine agonists in adult rats exposed to cocaine during the preweaning period. Pharmacol Biochem Behav 70:23-30
Dow-Edwards, D L; Freed-Malen, L A; Gerkin, L M (2001) Sexual dimorphism in the brain metabolic response to prenatal cocaine exposure. Brain Res Dev Brain Res 129:73-9
Patel, T G; Laungani, R G; Grose, E A et al. (1999) Cocaine decreases uteroplacental blood flow in the rat. Neurotoxicol Teratol 21:559-65
Busidan, Y; Dow-Edwards, D L (1999) Behavioral sensitization to apomorphine in adult rats exposed to cocaine during the preweaning period: a preliminary study. Pharmacol Biochem Behav 63:417-21
Shi, X; Yin, R; Dow-Edwards, D (1999) Chronic haloperidol alters dopamine receptors: effects of cocaine exposure during the preweaning period. Eur J Pharmacol 370:241-9
Applewhite-Black, L E; Dow-Edwards, D L; Minkoff, H L (1998) Neurobehavioral and pregnancy effects of prenatal zidovudine exposure in Sprague-Dawley rats: preliminary findings. Neurotoxicol Teratol 20:251-8
Dow-Edwards, D L; Hurd, Y L (1998) Perinatal cocaine decreases the expression of prodynorphin mRNA in nucleus accumbens shell in the adult rat. Brain Res Mol Brain Res 62:82-5
Dow-Edwards, D; Busidan, Y (1998) Ontogenic cocaine effects. Evidence for multifactorial mechanisms. Ann N Y Acad Sci 846:382-5
Dow-Edwards, D L (1998) Preweaning cocaine administration alters the adult response to quipazine: comparison with fluoxetine. Neurotoxicol Teratol 20:133-42

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