The incidence of cocaine and methamphetamine (METH) drug abuse among women of child-bearing age has paralleled the increase of abuse in the population as a whole. The consequences of the fetus of maternal cocaine and/or METH abuse have been addressed in only a limited number of studies. Among the behavioral deficits identified in those studies, however, are effects that point to the lower brainstem as a possible site of drug involvement. . Since cells of the raphe nuclei in the medulla oblongata, long defined by their use of serotonin (5-hydroxytryptamine; 5-HT) as a neurotransmitter, play a role in a vast array of physiological behaviors including sleep,, cardiovascular, respiratory, and thermo-regulation, drug-induced effects on 5-HT neurons may help explain some of the behavioral and physiological abnormalities described in humans. Moreover, since long-term cocaine and METH administration profoundly affect serotonin in the adult, it may well affect serotonin in the developing animal as well. However, he pharmacology of this brain region is complicated by the fact that serotonergic cells within the medullary raphe also contain peptide neurotransmitters substance P (SP) and thyrotropin-releasing hormone (TRH). We, therefore, propose to examine the effects of both maternal cocaine and METH administration on the developing raphe nuclei by examining effect on developing tryptophan hydroxylase (TPH) activity, 5-HT levels, and co- localized peptide neuromodulators throughout fetal development and into adulthood. Since access to the developing mammalian CNS is limited, however, we include the investigation of embryonic raphe maintained in organotypic tissue culture where manipulation of the microenvironment is more easily accomplished. Specifically, we will study the development of raphe nuclei grown in the presence or absence of cocaine (or METH) for possible consequences to TPH, 5-HT, SP, and TRH.
