This is a proposal to examine the long-term behavioral consequences of fetal exposure to cocaine. Four interrelated subprojects are proposed in Aims l to 4. Projects l and 2 found structural abnormalities in the cingulate cortex of adult rabbits that had been exposed prenatally to cocaine. Associative learning, reaction to noxious stimuli and attentional processes depend on the normal functioning of the cingulate cortex and all three of these functions were impaired in adult cocaine progeny.
Aim l will now determine whether the cognitive deficits in cocaine progeny are due to abnormal training-dependent alterations in the neural activity of the cingulate cortex and related structures. Dopamine (DA) D1 receptor-mediated signal transduction is impaired in anterior cingulate and in striatum (Project 5). The D1 receptor has been implicated in attentional processes. Thus, Aim 2 (in conjunction with Aim 4) will determine whether these cognitive deficits are related to differences between cocaine progeny and controls in the training-induced release of DA within cingulate cortex and whether DA agonists might ameliorate the cognitive deficits.
Aim 3 demonstrated that the deficits in D1 coupling (Project 5) are associated with deficits in d- amphetamine-induced motor responses that rely upon D1-signalling in the striatum. Proposed studies (Aim 3) will: use DA agonists and antagonists to define precisely the impairments in motor function produced by prenatal cocaine exposure, assess the vulnerability of cocaine progeny to behavioral sensitization by chronic cocaine, and test drug therapies to repair D1/G protein coupling or by-pass the deficit in signal transduction in order to normalize motor function.
Aim 4 will use microdialysis in vivo and ligand binding in vitro to analyze neurochemical mechanisms for the behavioral effects of drugs in Aim 3. These experiments will link behavioral abnormalities in cocaine progeny with abnormal functioning in specific brain regions and may offer therapeutic approaches for restoring brain function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011164-06
Application #
6174891
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Volman, Susan
Project Start
1996-09-30
Project End
2002-07-31
Budget Start
2000-08-05
Budget End
2002-07-31
Support Year
6
Fiscal Year
2000
Total Cost
$421,729
Indirect Cost
Name
Mcp Hahnemann University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19102
Harvey, John A (2004) Cocaine effects on the developing brain: current status. Neurosci Biobehav Rev 27:751-64
Dave, Kuldip D; Harvey, John A; Aloyo, Vincent J (2002) A novel behavioral model that discriminates between 5-HT2A and 5-HT2C receptor activation. Pharmacol Biochem Behav 72:371-8
Smith, David M; Freeman Jr, John H; Nicholson, Daniel et al. (2002) Limbic thalamic lesions, appetitively motivated discrimination learning, and training-induced neuronal activity in rabbits. J Neurosci 22:8212-21
Aloyo, V J; Dave, K D; Rahman, T et al. (2001) Selective and divergent regulation of cortical 5-HT(2A) receptors in rabbit. J Pharmacol Exp Ther 299:1066-72
Smith, D M; Monteverde, J; Schwartz, E et al. (2001) Lesions in the central nucleus of the amygdala: discriminative avoidance learning, discriminative approach learning, and cingulothalamic training-induced neuronal activity. Neurobiol Learn Mem 76:403-25
Zhen, X; Du, W; Romano, A G et al. (2001) The p38 mitogen-activated protein kinase is involved in associative learning in rabbits. J Neurosci 21:5513-9
Romano, A G; Hood, H; Harvey, J A (2000) Dissociable effects of the 5-HT(2) antagonist mianserin on associative learning and performance in the rabbit. Pharmacol Biochem Behav 67:103-10
Aloyo, V J; Harvey, J A (2000) Antagonist binding at 5-HT(2A) and 5-HT(2C) receptors in the rabbit: high correlation with the profile for the human receptors. Eur J Pharmacol 406:163-9
Taylor, C L; Freeman Jr, J H; Holt, W et al. (1999) Impairment of cingulothalamic learning-related neuronal coding in rabbits exposed to cocaine in utero: general and sex-specific effects. Behav Neurosci 113:62-77
Romano, A G (1999) Variations in CS associability and multiple unit hippocampal activity in the rabbit. Behav Brain Res 103:163-73

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