In adulthood, thyroid hormone regulates beta adrenergic responsiveness. We addressed whether similar processes operate in the developing brain, thus playing a role in neurotransmitter control of target cell differentiation. Rats were made hyperthyroid [triiodothyronine (T3)] or hypothyroid [propylthiouracil (PTU)] during the immediate perinatal period, and the development of beta adrenergic signal transduction was evaluated in three brain regions. PTU treatment resulted in an ubiquitous deficit in the number of beta receptor binding sites. Although beta adrenergic stimulation of adenylate cyclase activity was also obtunded by PTU, the effects were much less prominent and were restricted to one region (forebrain); comparison with basal adenylate cyclase and with total enzymatic activity (forskolin stimulation) indicated that the differences in isoproterenol response were at the level of adenylate cyclase expression, rather than in specific receptor coupling. PTU also reduced responsiveness of ornithine decarboxylase (ODC), a key enzyme that couples receptors to differentiation, again, changes in receptor-mediated responsiveness reflected alterations in total enzyme activity, rather than effects on receptor coupling. In contrast, measurements of c-fos, a protooncogene that couples cyclic AMP to induction of ODC, showed increased responses to beta adrenergic or cyclic AMP stimulation in PTU-treated animals. The effect of PTU on c-fos responsiveness occurred in the absence of alterations in basal c-fos expression, a situation different from that seen with adenylate cyclase or ODC. T3 administration had only small effects on any of these variables. The role of thyroid hormones thus involves targeting of beta receptors and receptor-mediated stimulation of nuclear transcription factors (c-fos), as well as basal expression of transduction components in the signalling cascade (adenylate cyclase, ODC). The effects of PTU, contrasted with the failure of T3 to enhance development of beta receptors or their transduction components, suggest that thyroid hormone is obligatory for normal development of this pathway, but that endogenous hormone levels are already optimally permissive.

Nicotine has been hypothesized to induce neurobehavioral teratology by mimicking prematurely the natural developmental signals ordinarily communicated by the ontogeny of cholinergic synaptic transmission. In the current study, the effects of fetal nicotine exposure (2 mg/kg/day or 6 mg/kg/day) on development of central cholinergic pathways were examined in striatum and hippocampus of animals exposed from gestational days 4 through 20, using maternal infusions with osmotic minipumps. Brain region weights and choline acetyltransferase activity, an enzymatic marker for development of cholinergic nerve terminals, were within normal limits in the nicotine-exposed animals. However, development of [3H]hemicholinium-3 binding which labels the presynaptic high affinity cholinergic transporter, was deficient in both striatum and hippocampus. Abnormalities occurred during two distinct phases; in the early neonatal period, when [3H]hemicholinium-3 binding sites are transiently overexpressed, and during or after the period of rapid synaptogenesis, when binding in controls is rising consequent to the increase in nerve impulse activity. These data thus indicate that fetal nicotine exposure, even at doses that do not cause overt signs of maternal/fetal/neonatal toxicity or growth impairment, influences both specific gene expression of cholinergic nerve terminal markers, as well as indices of neuronal function. Comparison of regional selectivity at the two dose levels indicated greater sensitivity of the striatum, a region with a prenatal peak of neuronal mitosis, as compared to hippocampus, where mitosis peaks postnatally; the regional differences are consistent with vulnerability to nicotine during a critical phase of cell development.

beta-Adrenergic agonists used in therapy of premature labor and asthma cross the placenta and can affect development of the fetal nervous system. In the current study, pregnant rats were given 10 mg/kg of terbutaline on gestational days 17, 18 and 19 and adrenergic receptor binding capabilities examined in brain regions of the offspring. Despite the absence of body or brain growth impairment, selective increases were seen postnatally in cerebellar alpha 1- and alpha 2-receptor subtypes, whereas the same receptor populations were decreased by small amounts in cerebral cortex and midbrain + brainstem. beta-Adrenergic receptors showed little or no change in any region. The regional and subtype selectivity are compatible with primary deficits in the development of noradrenergic projections to the cerebellum identified in previous studies and provide further evidence that therapeutic use of beta-adrenergic agonists may produce neurobehavioral teratology.