Vasoconstriction, as well as other actions of cocaine in the developing fetus, may be responsible for some of the reported congenital effects in the clinical and animal literature. Ischemia and anoxia have been blamed for minor congenital anomalies, as well as early postnatal neurobehavioral effects reported in the clinical and experimental literature, although the reliability and replicability of some of these reports are being questioned of late. Maybe late prenatal and early postnatal morbidity attributed to cocaine in infants of polydrug abusing pregnant women, or some reports of altered behavior in preweanling or young rats born to dams given cocaine during pregnancy are not evidence of permanent deleterious effects. Nevertheless, the reports of cocaine's developmental effect upon DNA and protein synthesis, upon behavior, or other variables may be secondary to ischemia or other actions which are not mediated by indirect catecholaminergic receptor stimulation of placental, other vascular beds, or in neural tissue. Moreover, the overlapping profile of autonomic activation associated with opiate withdrawal and acute effects of cocaine suggest that drugs which are efficacious against one syndrome may be efficacious against the other. 5-HT/2 receptor antagonists attenuate or block the expression of true and quasi-opiate withdrawal in rats and are used clinically for treatment of hypertension and agitated depression with severe anxiety (also symptoms in opiate withdrawing or high dose cocaine users). 5-HT/2 antagonists have reportedly blocked delayed hippocampal neuronal death after transient ischemia in rodents. They have enhanced poor delayed sample matching in monkeys with hypoxia-induced performance deficits. Ritanserin (RIT) is being tried clinically for treating different drug abusing clients after Janssen Pharmiceutica replicated our findings vis-a-vis its effectiveness against opiate withdrawal and their finding that it suppresses cocaine oral self-administration during use and after withdrawal in rats. Since RIT also blocks the lethal, and herniated umbilicus-inducing effect (abruptus placentae?) of the 5-HT/2 agonist DOI, as well as similar effects of cocaine in chick embryos, it seems reasonable to expect that significant vasoconstrictor and/or other actions of cocaine are mediated via indirect stimulation of this class of 5-HT receptors (5-HT also has trophic properties during development). We propose to study the bases for cocaine's action during development, using chick and rats, and to characterize more fully the late emergence of cognitive dysfunction in aging rats after exposure to cocaine during development. We will determine the utility of a 5-HT/2 antagonist in the treatment of cocaine exposed chick embryos and pregnant rats with the idea that it will attenuate or block one or more of the acutely toxic or long- term congenital actions of cocaine, including aging-related cognitive dysfunction, which seems to emerge prematurely in exposed offspring. We will also study the neurochemical and behavioral effects of cocaine in chick embryos and neonates, so as to determine if cocaine is a more direct behavioral teratogen in the absence of its effects upon the pregnant mother. The contribution of reactive oxygen species, suggesting ischemia/reperfusion injury in cocaine's toxicity will be studied in a separate series of experiments.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37DA004979-04A3
Application #
2117357
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1988-08-01
Project End
2000-06-30
Budget Start
1995-07-01
Budget End
1996-06-30
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Mendoza-Baumgart, Mary Irene; Pravetoni, Marco; Sparber, Sheldon B (2007) Inhibition of nitric oxide synthase enhances cocaine's developmental toxicity: vascular and CNS effects. Neuropsychopharmacology 32:940-5
Schrott, Lisa M; Sparber, Sheldon B (2004) Suppressed fever and hypersensitivity responses in chicks prenatally exposed to opiates. Brain Behav Immun 18:515-25
Mendoza-Baumgart, Mary Irene; Pravetoni, Marco; Sparber, Sheldon B (2004) Vasoconstriction caused by cocaine is enhanced by sodium salicylate: is inducible nitric oxide synthase mRNA related? Neuropsychopharmacology 29:1294-300
Schrott, Lisa M; Baumgart, Mary Irene; Zhang, Xuewei et al. (2002) Prenatal opiate withdrawal activates the chick embryo hypothalamic pituitary-adrenal axis and dilates vitelline blood vessels via serotonin(2) receptors. J Pharmacol Exp Ther 303:257-64
Venturini, L; Sparber, S B (2001) Salicylate and cocaine: interactive toxicity during chicken mid-embryogenesis. Free Radic Biol Med 30:198-207
Larson, E B; Schrott, L M; Bordone, L et al. (2001) Embryonic cocaine exposure and corticosterone: serotonin(2) receptor mediation. Pharmacol Biochem Behav 69:71-5
Schrott, L M; Sparber, S B (2001) Embryonic ""binge"" cocaine exposure alters neural-immune and neural-endocrine interactions in young chickens: involvement of serotonin(2) receptors. Brain Res Dev Brain Res 130:99-107
Castelli, M C; Venturini, L; Sparber, S B (2001) Cocaine and salicylate: documentation of hydroxyl radical formation in hearts and brains of 18-day-old chick embryos and unexpected interactive toxicity. Psychopharmacology (Berl) 156:23-31
Bollweg, G L; Sparber, S B (1999) Voltage associated with spontaneous embryonic motility in the developing chicken: an automated characterization during mid-late embryogenesis. Dev Psychobiol 34:5-19
Schrott, L M; Sweeney, W A; Bodensteiner, K E et al. (1999) Late embryonic ritanserin exposure fails to alter normal responses to immune system stimulation in young chicks. Pharmacol Biochem Behav 64:81-8

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