Prenatal Cocaine Produces Biochemical and Functional Changes in Brain Serotonin Systems in Rat Progeny

Abstract

These studies demonstrate that prenatal cocaine produces differential changes in neuroendocrine responses following challenge with a 5-HT releaser versus a 5-HT1A agonist and suggest differential functional alterations in both pre- and postsynaptic components of 5-HT pathways. The attenuated neuroendocrine responses in adult male progeny following challenge with a 5-HT releaser, in the absence of reductions in 5-HT receptors, provide additional evidence in support of a presynaptic 5-HT deficit in adult male cocaine-exposed progeny. Furthermore, since prenatal cocaine produced a differential profile of alterations in 5-HT-mediated neuroendocrine responses in adult male (i.e., decreases ACTH and renin) versus prepubescent female (i.e., decreases ACTH and corticosterone) progeny following challenge with a 5-HT releaser, these data indicate that the differences could be due to gender and/or postnatal developmental ages. Gender differences in prenatal cocaine effects on postsynaptic receptor function were more clearly shown in study II, which demonstrated that at the same postnatal age, 5-HT1A-mediated neuroendocrine responses were significantly potentiated in male but not female cocaine-exposed progeny. In summary, the data presented in this chapter indicate that the biochemical and functional changes in 5-HT systems observed following prenatal exposure to cocaine are unique with respect to pre- versus postsynaptic alterations, pre- versus postpubescent developmental times, and differences between genders. A number of general conclusions can be drawn from the data presented. The presence of marked neurochemical deficits at both pre- and postpubescent timepoints, in the absence of any visually apparent physical terata, emphasizes the importance of investigating the neurochemical teratogenic potential of cocaine and other psychostimulants. Furthermore, data from these studies demonstrate the importance of investigating male and female progeny separately, as prenatal cocaine exposure may produce gender-specific alterations in some, but not all, aspects of brain neurotransmitter systems. Another important point that can be discerned from the present data is the necessity of subjecting cocaine-treated animals to challenge tests in order to reveal alterations that might not be readily apparent from measuring basal values for specific biochemical or functional parameters (e.g., basal hormone levels). In addition, the differential biochemical and functional changes in 5-HT systems, manifested at pre- versus postpubescent times, suggests that prenatal cocaine may adversely affect the normal maturational changes occurring in 5-HT systems. This may be of consequence in evaluating developmental stages in human offspring exposed to cocaine in utero. Furthermore, the ability of prenatal cocaine to alter 5-HT-mediated ACTH and renin responses in progeny suggest that offspring may exhibit alterations in their response to physiologic stimuli such as stress. Since neuroendocrine challenge tests can be performed in humans, the present data indicate the potential clinical utility of this approach to provide peripheral markers that can be used to identify changes in brain 5-HT pathways in human offspring exposed in utero to cocaine. Prenatal cocaine-induced alterations in brain 5-HT systems may be of significant clinical importance as dysfunction of 5-HT systems has been implicated in various psychiatric disorders including depression, anxiety, aggression, and drug-seeking behavior.