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.
Showing the most recent 10 out of 20 publications
