Dissertation Abstract

Neurotensin Gene Expression in a Rat Model of Prenatal Cocaine Exposure

Publication Number:  AAT9932303
Author:  Collins, Lucille Marie
School:  University of Massachusetts Amherst
Date:  1999
Pages:  109
Subject:  Neurology, Molecular Biology, Anatomy and Physiology, Animals, Toxicology

These studies examined the pharmacokinetics of cocaine following its chronic subcutaneous (s.c.) administration to pregnant rats and the effects of this treatment on neurotensin/neuromedin (NT/N) mRNA expression in the brains of their offspring. First, I examined the distribution of cocaine and its metabolites benzoylecgonine (BE) and norcocaine in pregnant rats following twice-daily s.c. injections of 20 mg/kg cocaine from gestational day (GD) 8-GD 21. Following a single injection on GD 21, maternal and fetal trunk blood, fetal brains, and amniotic fluid (AF) were collected at 8 separate time points from 5 min to 12 h. Cocaine peaked in maternal plasma at 1 h and at 2 h in fetal plasma, fetal brain and AF. Peak BE levels were detected at 4 h in maternal plasma, fetal plasma, and fetal brain, and at 8 h in the AF. An additional group of dams given both injections on GD 21 and sacrificed 2 h later showed increased concentrations of BE in both fetal compartments and in the AF. Previously undetectable, norcocaine was now measurable in the AF.

Chronic cocaine administration increases NT/N mRNA in the nucleus accumbens. To further understand the mechanisms involved, I conducted a dose response study evaluating the role of the D3 receptor on the expression of NT/N mRNA in the nucleus accumbens shell using in situ hybridization. Animals were sacrificed 3 h following an acute challenge with either the D3 agonist PD 128904 or the antagonist nafadotride. As neither compound significantly altered NT/N mRNA levels, no further work was performed with these drugs.

To examine the effects of prenatal cocaine exposure on neurotensin expression, adult male offspring from either cocaine (40 mg/kg daily, GD 8-21) or saline-injected dams were treated with a single daily i.p. injection of cocaine or saline for 10 days and sacrificed 1 h after the last injection. This treatment resulted in increased NT/N mRNA in the nucleus accumbens, fundus, striati, and dorsomedial striatum regardless of prenatal treatment, and significantly greater NT/N mRNA expression within the medial preoptic nucleus (MPN) of offspring from pair-fed saline dams. Thus, prenatal cocaine exposure alters the NT/N response in the MPN to postnatal cocaine challenge.


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