Prenatal cocaine produces deficits in serotonin mediated neuroendocrine responses in adult rat progeny: Evidence for long‐term functional alterations in brain serotonin pathways

Abstract

Cocaine produces biochemical alterations in brain serotonin (5-HT) neurons. Since 5-HT is critical to the development of fetal 5-HT neurons and target tissues, we hypothesized that in utero exposure to cocaine could result in long-term alterations in postnatal 5-HT systems. Pregnant Sprague-Dawley rats were administered either saline or (-)cocaine (15 mg/kg, s.c., b.i.d.) from gestational day 13 to 20. Prenatal cocaine exposure did not alter litter size, gender number, or progeny birth weights. Functional alterations in serotonergic systems were determined in postnatal day (PD) 70 male progeny by measuring changes in 5-HT mediated plasma hormones following a single 8 mg/kg injection of the 5-HT releaser p-chloroamphetamine (PCA). Cocaine exposed male progeny exhibited significant reductions in adrenocorticotropic hormone (ACTH, -43%) and renin (-62%) responses to PCA. However, no alterations were observed in the corticosterone or prolactin response to PCA. In utero exposure to cocaine did not alter basal levels of ACTH, renin, corticosterone, or prolactin. There were no significant differences in the density of either hypothalamic or cortical 5-HT uptake sites. Likewise, there were no significant differences in the densities of any of the 5-HT1 receptor subtypes or in the density of 5-HT2 receptors in cortex. These data, which provide the first demonstration of deficits in 5-HT mediated neuroendocrine function in adult progeny following in utero exposure to cocaine, indicate long-term functional alterations of brain 5-HT systems.

Developmental Effects of Prenatal Cocaine Exposure on 5-HT_1A Receptors in Male and Female Rat Offspring

“…The present findings are consistent with previous reports of functional alterations in 5-HT 1A receptors following prenatal cocaine exposure Cabrera et al, 1993Cabrera et al, , 1994 where differences in male and female offspring were reported with respect to changes in hormone release following agonist stimulation of these receptors. Although those studies suggested that altered 5-HT 1A and 5-HT 2A receptor function following prenatal cocaine exposure was only measurable in relatively mature animals [Battaglia et al, 2000], our previous results [Johns et al, 1998] indicate that consequences of prenatal cocaine exposure are evident at birth, when levels of 5-HT 1A receptors already differ in male and female offspring.…”

Impact of gestational cocaine treatment or prenatal cocaine exposure on early postpartum oxytocin mRNA levels and receptor binding in the rat

“…Since prenatal cocaine exposure alters multiple aspects of serotonin signaling, including receptors, affinity, release, etc. (Akbari et al, 1992;Cabrera et al, 1993;Henderson and McMillen, 1993;Johns et al, 2002;McReynolds and Meyer, 1998;Yan, 2002), it seems likely that the effects of cocaine on oxytocin transcription in the supraoptic nucleus could be related to serotonergic disruptions, since there was no effect of cocaine exposure on oxytocin receptor binding. These results suggest that prenatal cocaine exposure could influence oxytocin signaling during the later postpartum period through its effects on mRNA transcription, and add new and important data to the emerging picture on how cocaine influences oxytocin and perhaps maternal and social behavior through multiple generations.…”

Paroxetine is effective in desensitizing 5-HT1A receptor function in adult offspring exposed prenatally to cocaine

“…Previous studies from our laboratory demonstrated that prenatal exposure to cocaine produces deficits in 5-HT neurons (Cabrera et al 1993;Cabrera-Vera et al 2000) and…”

“…Starting on gestational day 8 (GD 8), and continuing throughout the prenatal treatment, all experimental animals were placed on a nutritionally balanced liquid diet consisting of Vitamin Diet Fortification Mixture (ICN Nutritional Biochemicals, Cleveland, OH), chocolate-flavored Boost (Mead Johnson, Evansville, IN) and water, consistent with our previously published studies (Cabrera et al 1993). The foster dams had ad libitum access to rat chow and water.…”