Reduced inhibitory effect of imipramine on radiolabeled serotonin uptake into platelets in geriatric depression.

Tritiated imipramine binding, uptake of radiolabeled serotonin, and inhibition of uptake by imipramine in vitro were studied in platelets obtained from four groups of subjects: (1) normal controls 50 years of age or younger, (2) patients with major depression 50 years of age or younger, (3) normal controls 60 years of age or older, and (4) patients with major depression 60 years of age or older. Depression in both age groups was associated with a substantial decrease in the number of [3H]imipramine binding sites; the elderly depressed patients exhibited a small but significant (p less than 0.05) reduction in platelet [3H]serotonin uptake. However, the inhibition of serotonin uptake into platelets by imipramine was markedly reduced only in the elderly depressed patients. This reduced sensitivity to imipramine may explain the reduced responsiveness of patients with geriatric depression to the therapeutic effects of imipramine and other tricyclic antidepressants.

Trophic control of lung development by sympathetic neurons: effects of neonatal sympathectomy with 6-hydroxydopamine.

The onset of peripheral sympathetic neuronal function is thought to provide trophic regulatory signals for development of adrenergic target tissues. In the current study, we examined the effects on lung development of neonatal sympathectomy with 6-hydroxydopamine. The completeness of the lesion and effectiveness in reducing sympathetic input to the tissue were confirmed by direct measurement of norepinephrine levels and turnover. Despite the denervation, no evidence of beta-receptor up-regulation was found; in fact, receptor binding sites tended to be reduced throughout development. The cyclic AMP response to isoproterenol challenge was initially suppressed in the lesioned animals, but became supersensitive even in the face of reduced receptor binding capabilities. Evidence was also obtained for ontogenetic abnormalities in the ornithine decarboxylase/polyamine system, which is partially controlled by beta-adrenergic input and which regulates macromolecule synthesis in replicating and differentiating cells. Eventually, the alterations were reflected in aberrant developmental patterns of DNA, RNA and protein in the lung. These results indicate that sympathetic neurons influence the biochemical development of the lung and may serve to program permanently the relationships among receptor sites, receptor coupling to cellular function, and control of cell maturation.

Adrenergic control of DNA synthesis in developing rat brain regions: effects of intracisternal administration of isoproterenol.

Catecholamines are hypothesized to control cellular development in the central nervous system. In the current study, isoproterenol administered intracisternally to neonatal rats was found to inhibit DNA synthesis [( 3H]thymidine incorporation) in brain regions. The regional selectivity of effect corresponded to the sequence of cellular maturation, namely midbrain + brainstem greater than cerebral cortex greater than cerebellum, suggesting that the specific linkage of beta-adrenergic receptors to cessation of cell replication occurs during a specific maturational stage.

Effects of prenatal dexamethasone on development of ornithine decarboxylase activity in brain and peripheral tissues of rats.

The use of glucocorticoids in the management of neonatal respiratory distress syndrome may be associated with abnormalities of growth and neurologic development. In our study, pregnant rats received either 2 or 0.2 mg/kg of dexamethasone on gestational days 17, 18, and 19 and tissues of the offspring were examined for ornithine decarboxylase activity, a marker enzyme for perturbations of cellular maturation. Acutely, the higher dose of dexamethasone suppressed ornithine decarboxylase activity in all tissues except lung, where a short-term stimulation was obtained. Repeated administration of 2 mg/kg resulted in an ornithine decarboxylase pattern consistent with delayed cellular development in all tissues (suppressed activity followed by prolonged postnatal elevations), accompanied by impaired viability and general growth. Lowering the dose of dexamethasone to 0.2 mg/kg eliminated all the adverse effects on viability but still produced perturbations of tissue ornithine decarboxylase, most notably a prolonged suppression of activity across all brain regions. These data suggest that administration of glucocorticoids even at the threshold for effects on respiratory function, may compromise neural development.

Neonatal nutritional deprivation or enhancement: the cardiac-sympathetic axis and its role in cardiac growth and stress responses.

To determine the mechanisms by which neuronal input influences cardiac growth during altered neonatal nutritional status, rats were reared in small, standard, or large litter sizes and the adrenergically mediated stimulation of cardiac ornithine decarboxylase was determined; ornithine decarboxylase provides a mechanistic link connecting adrenergic input to cardiac growth. Nutritionally deprived pups showed impaired development of sympathetic reflex stimulation as shown by the attenuation of the cardiac ornithine decarboxylase response to hydralazine-induced hypotension throughout the preweanling period. The subnormal reactivity to hydralazine reflected a defect in neurotransmission, as a full response was obtained with direct beta-receptor stimulation (isoproterenol). Nevertheless, cardiac hypertrophy in response to repeated isoproterenol administration was markedly suppressed in nutritionally deprived animals, suggesting that the beta-receptor/ornithine decarboxylase pathway had become uncoupled from growth. Because maturation of neural connections to peripheral tissues causes a loss of hypoxia tolerance, nutritional status also influenced the ability of neonatal rats to survive hypoxia. These data indicate that cardiac growth suppression or enhancement caused by nutritional manipulations may be mediated, in part, through alterations in the development of neuronal input to the tissue, and that similar factors influence survival during hypoxic stress.

Prenatal exposure to nicotine via maternal infusions: effects on development of catecholamine systems.

The effects of a continuous 16-day gestational exposure to nicotine on development of central and peripheral catecholaminergic pathways were examined in the offspring of dams who received a minipump implant on the 4th day of gestation. Prenatal nicotine exposure resulted in a selective suppression of maturational increases in norepinephrine and dopamine levels and utilization rates in the cerebral cortex and also reduced transmitter levels in sympathetic pathways to the lung and kidney. The regional selectivity of the effect, combined with measurements of synaptosomal uptake of [3H]norepinephrine and of tyrosine hydroxylase activity, all suggested that the alterations in transmitter disposition reflected reduced neural activity as opposed to actions on general cellular development or synaptogenesis. Although the lag in development was largely made up by weaning, deficits in norepinephrine utilization reappeared in young adulthood in the cerebral cortex and midbrain + brainstem, suggesting that lasting functional alterations may occur as a consequence of prenatal nicotine exposure. Comparisons with the results obtained with maternal nicotine injections (which produce largely stimulatory effects on norepinephrine levels and turnover) suggest that the hypoxia/ischemia associated with injected nicotine causes a reactive hyperinnervation; the adverse actions of nicotine on neurotransmitter development are thus highly dependent upon the route of drug administration.

Biochemical determinants of growth sparing during neonatal nutritional deprivation or enhancement: ornithine decarboxylase, polyamines, and macromolecules in brain regions and heart.

In order to elucidate the biochemical mechanisms operating to protect the brain from growth retardation in response to nutritional deprivation, comparisons were made of markers of cellular development in brain regions (cerebellum, cerebral cortex, midbrain + brainstem) and in a tissue which is not spared (heart). Nutritional status of neonatal rats was manipulated by increasing or decreasing the litter size beginning at birth, and development of DNA, RNA, and proteins followed throughout the neonatal period. In addition, we assessed the activity and levels of ornithine decarboxylase and its metabolic products, the polyamines, which are known to coordinate macromolecule synthesis in immature tissue and to provide an early index of perturbed development. Cardiac ornithine decarboxylase and polyamines were altered within 48 h of initiating the changes in litter size, and the direction and magnitude of these biochemical effects were predictive of subsequent impairment or enhancement of organ growth and of cellular development. All three brain regions were buffered from growth alterations relative to the heart, but the cerebellum, which undergoes major phases of cell replication later than the other two regions, was somewhat less protected. The spared brain regions also showed evidence of compensatory hypertrophy in nutritional deprivation (increased protein/DNA ratio) which accounts for maintenance of growth in the presence of reduced cell numbers. Thus, brain growth sparing involves specific cellular responses which are dependent on the maturational profile of each brain region.

Beta adrenergic control of macromolecule synthesis in neonatal rat heart, kidney and lung: relationship to sympathetic neuronal development.

The sympathetic nervous system has been hypothesized to coordinate the timing of cellular development in peripheral tissues. In the current study, we evaluated the relationships among the ontogeny of sympathetic projections to peripheral organs, the patterns of macromolecule synthesis in those organs and the reactivity of synthetic processes to beta adrenergic stimulation by isoproterenol. The major developmental rise in norepinephrine concentration and turnover, as well as in numbers of beta receptors, occurred during the second to fourth postnatal weeks in renal and lung sympathetic pathways and slightly earlier in the cardiac-sympathetic axis. The developmental decline in DNA synthesis in heart, kidney and lung coincided with the maturation of sympathetic projections. Direct stimulation of beta receptors by the in vivo administration of isoproterenol caused acute reductions in DNA synthesis in an age-dependent manner. In the heart, isoproterenol was first able to suppress DNA synthesis at 5 days of age and a maximal effect was seen at 9 days; this early phase was characterized by a rapid time constant of coupling of beta receptors to the DNA effect (maximal effect at 6 h after isoproterenol). Reactivity was lessened by 12 days of age and thereafter displayed a longer time constant (maximal effect at 12-24 h). Reactivity of DNA synthesis to isoproterenol challenge was slightly different in kidney and lung (detectable by 2 days of age), but bore similar developmental characteristics to the pattern in the heart (peak of reactivity at 9 days and a decline in reactivity and lengthening of the time constant after 16 days).(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of adrenal chromaffin cell development by the central monoaminergic system: differential control of norepinephrine and epinephrine levels and secretory responses.

In the mature rat, reflex sympathetic stimulation by insulin-induced hypoglycemia resulted in profound depletion of adrenal epinephrine, and to a lesser extent, norepinephrine. In the developing rat, insulin evoked little or no secretory response from the adrenals prior to 1 week of age. By 7 days, a moderate depletion of epinephrine was seen and the magnitude of the response increased with age. In contrast, during the first 3 weeks of postnatal life, insulin failed to deplete norepinephrine from the adrenal medulla and in fact, produced an increase. This chiefly resulted from de novo biosynthesis of the amine, as the rise was blocked by alpha-methyl-p-tyrosine. These results suggest that the ontogeny of the two chromaffin cell types (norepinephrine and epinephrine-containing) in the adrenals and the maturation of their secretory responses are under differential regulation. Because descending supraspinal catecholaminergic and serotonergic systems have been implicated to play key roles in regulating adrenomedullary function, the ontogeny of the sympatho-adrenomedullary axis was evaluated after neonatal central lesioning with 6-hydroxydopamine or 5,7-dihydroxytryptamine. 6-Hydroxydopamine resulted in a preferential elevation of epinephrine in the developing adrenals as well as an increase in the responsiveness of the adrenals to reflex stimulation by insulin; the mature secretory pattern was obtained as early as at 4 days postnatally for epinephrine and 9 days for norepinephrine. In contrast, 5,7-dihydroxytryptamine led to a preferential reduction of basal adrenal norepinephrine content.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of prenatal nicotine exposure on neuronal development: selective actions on central and peripheral catecholaminergic pathways.

The effects of prenatal nicotine exposure on development of catecholaminergic pathways were examined through measurements of transmitter turnover and levels in both the central and peripheral nervous system. Administration of nicotine (3 mg/kg SC, twice daily) to pregnant rats on gestational days 3 through 20 resulted in growth retardation which did not spare the brain and which did not resolve until after weaning. Nicotine exposure produced an elevation in transmitter turnover in central noradrenergic pathways with a regional selectivity reflecting the timetable of cellular development: the most profound effects were seen in late-developing regions (cerebellum), intermediate effects were found in earlier-developing areas (cerebral cortex) and the least effect was obtained where maturation occurs earliest (midbrain + brainstem). Dopaminergic pathways were much less vulnerable than was the noradrenergic system. Effects on the peripheral sympathetic nervous system also were targeted toward specific neuronal populations: renal, cardiac and adrenal pathways were activated by prenatal nicotine exposure, whereas sympathetic innervation of the lung showed reduced activity. All the peripheral effects appeared only after the second postnatal week. These results indicate that prenatal nicotine exposure produces profound alterations in transmitter disposition which are targeted toward specific neuronal populations and which may depend upon generalized effects on cellular development of specific brain regions. Because altered peripheral nerve activity was seen only after the onset of central control of sympathetic tone, actions on central regulation may play a role in the relatively more profound effects in the autonomic nervous system.

Effects of prenatal nicotine exposure on biochemical development of rat brain regions: maternal drug infusions via osmotic minipumps.

The effects of a continuous 16-day gestational exposure to nicotine on brain development were examined in the offspring of dams who received a minipump implant on the 4th day of gestation. Maternal viability was unaffected and weight gain was only reduced slightly, but nearly half the dams failed to give birth; dams delivering pups had normal litter sizes. Examination of fetal macromolecules on the 18th day of gestation revealed specific deficits in cell number (DNA) in developing brain tissue as opposed to the rest of the fetus, accompanied by parallel shortfalls in other macromolecules (RNA, protein). After birth, brain development in the nicotine-exposed animals showed persistent abnormalities in the timing of maturational events, with elevated levels of ornithine decarboxylase (an enzymatic marker related to cellular maturation) detectable in all brain regions. Subsequent effects on macromolecules were highly selective regionally, with clear distinctions between areas in which neuronal replication occurs relatively late (cerebellum) compared to early-developing regions (midbrain plus brainstem). Differences apparent between the effects of infused maternal nicotine and those noted previously in studies with nicotine injections indicate that the drug does exert primary effects on developing neural tissues, but that other factors associated with the injection route (such as hypoxia and ischemia consequent to acute effects of nicotine) can interact with the drug to influence brain cell maturation.

Effects of neonatal methylmercury exposure on adrenergic receptor binding sites in peripheral tissues of the developing rat.

Neonatal exposure to methylmercury produces changes in patterns of tissue growth and function, in part, due to alterations in adrenergic neuronal input. To explore the mechanisms by which these changes come about, newborn rats were exposed to methylmercury (1 or 2.5 mg/kg per day) throughout the preweaning stage and the ontogeny of adrenergic receptor binding sites evaluated in liver, kidney, heart and lung, using [3H]prazosin (alpha 1-receptors), [3H]rauwolscine (alpha 2-receptors) and [125I]pindolol (beta-receptors). In the kidney, methylmercury caused decreases in beta- and alpha 1-receptor binding and increases in alpha 2-binding; previous work has shown that beta-receptor-mediated responses are generally enhanced in methylmercury-exposed pups, and the down-regulation of beta-receptor binding thus probably represents a compensatory action secondary to alterations in post-receptor coupling mechanisms. The effects of methylmercury on hepatic adrenergic receptors were different from those seen in the kidney, with substantial elevations in beta- and alpha 1-receptor binding apparent in the preweaning stage; this agrees also with the differences in effects of the mercurial on trophic reactivity and growth in the 2 tissues. Despite the fact that methylmercury causes activation of neonatal cardiac sympathetic nerves, beta-receptor binding sites in the heart were unaffected by methylmercury exposure; the failure to down-regulate cardiac postsynaptic receptors in the face of increased nerve activity again represents an anomaly of synaptic regulatory function. These results indicate that methylmercury alters adrenergic responsiveness, in part, through actions on the development of receptor binding sites, and further, that the organ-specificity and receptor subtype-selectivity are consistent with subsequent effects of the organomercurial on adrenergic participation in target organ growth; however, changes in receptor binding alone do not account for all of the effects of methylmercury on synaptic activity or trophic responses.

Perinatal dietary supplementation with a soy lecithin preparation: effects on development of central catecholaminergic neurotransmitter systems.

Previous work has shown that exposure of developing rats to soy lecithin preparations (SLP) influences macromolecular constituents of immature brain cells and causes abnormal behavioral patterns. To determine if synaptic mechanisms are adversely affected by SLP, we examined the developmental characteristics of noradrenergic and dopaminergic pathways in discrete brain regions. Although transmitter levels were unaffected, the utilization rates of both catecholamines were profoundly disturbed in an age-dependent, regionally-selective manner. Utilization tended to be subnormal in the preweanling stage, but demonstrated a postweaning elevation in cerebellum and midbrain + brainstem. Enhanced utilization persisted in the latter region only, and cerebral cortex actually showed a lowered utilization rate in adulthood (60 days of age). Transmitter uptake capabilities were also affected by developmental exposure to SLP, as was tyrosine hydroxylase activity. The patterns of effects on these two variables indicated that the altered transmitter utilization rate probably reflected a change in impulse activity in the affected neuron populations, with promotion of activity in the midbrain + brainstem and reduced activity in the cerebral cortex. These data indicate that dietary supplementation with SLP throughout perinatal development alters synaptic characteristics in a manner consistent with disturbances in neural function.

Uptake of serotonin into rat platelets and synaptosomes: comparative structure-activity relationships, energetics and evaluation of the effects of acute and chronic nortriptyline administration.

In order to establish whether the uptake systems in platelets and synaptosomes are equivalent, the structure-activity relationships for drug-induced inhibition of serotonin uptake were examined in vitro. The rank order for potency of inhibitors was the same in platelets as in synaptosomes, namely imipramine greater than nortriptyline greater than desmethylimipramine much much greater than norepinephrine greater than histamine; in addition, serotonin uptake was clearly distinguishable from the norepinephrine synaptic uptake mechanism, which displayed a different rank order. The synaptosomal uptake of serotonin was, however, much more dependent upon maintenance of Na+-K+-ATPase activity for its energy source than was the platelet uptake mechanism. Acute administration of nortriptyline produced substantial inhibition of platelet serotonin uptake and a smaller degree of inhibition of synaptosomal uptake; inhibition was detectable even after extensive washing of the platelet and synaptosome preparations, and was associated with persistent binding of the drug to the organelles. Chronic infusion of nortriptyline (20 mg/kg for 21 days, followed by a 24 hr washout period to dissipate persistent binding) did not alter the uptake capacity of synaptosomal or platelet preparations, but did cause a shift in the drug specificity of inhibitors. The latter effect was in opposite directions in platelets vs. synaptosomes. These data indicate that the platelet uptake mechanism does bear some resemblance to that seen in serotonergic neurons, but that the energy source for transport differs and the two mechanisms respond differently to prolonged drug administration in vivo. The use of uptake as a marker during the course of antidepressant administration is likely to be confounded by persistent direct drug effects on these organelles.

Effects of neonatal hypoxia on brain development in the rat: immediate and long-term biochemical alterations in discrete regions.

To evaluate the sensitivity of immature brain tissue to hypoxic insult, neonatal rats were exposed to 7% O2 for 2 h at critical stages of development (1, 8, 15, 23 days of postnatal age); the immediate and long-term impact of hypoxia was then assessed in cerebellum, cerebral cortex and midbrain through measurement of ornithine decarboxylase (ODC) activity, a biochemical determinant of cellular injury and subsequent maturation, and through measurements of protein synthesis, growth and synaptosomal uptake of norepinephrine (an index of noradrenergic synaptogenesis). In one-day-old rats, hypoxia caused stimulation of protein synthesis and short-term suppression of ODC activity which persisted for several hours after termination of low O2 exposure; over the ensuing days, there was a prolonged elevation of enzyme activity and a subsequent, regionally selective increase in synaptosomal uptake of norepinephrine without changes in brain growth. In contrast, hypoxia in 8-day-old rats produced signs of metabolic injury, with a short-term elevation of ODC throughout the brain and reduced protein synthetic rates, eventual shortfalls in brain regional growth and no net increase in synaptosomal uptake. The effects of hypoxia on brain regional growth in 8-day-old animals appeared to represent an age-specific effect, as low as O2 conditions in older animals did not affect growth (animals made hypoxic at 15 or 23 days), but did produce an eventual reduction in synaptosomal uptake (hypoxia at 15 days). Differences between one-day-old and 8-day-old rats were also apparent in cerebral responses simply to a 2-h separation from the dam under normoxic conditions. These results support the view that cellular development and synaptogenesis are compromised when neonatal brain tissue is exposed to hypoxic conditions, and that there are critical periods of sensitivity in which processes undergoing rapid maturational change are particularly vulnerable.

Effects of alpha-difluoromethylornithine, a specific irreversible inhibitor of ornithine decarboxylase, on nucleic acids and proteins in developing rat brain: critical perinatal periods for regional selectivity.

Ornithine decarboxylase and its metabolic products, the polyamines, are known to coordinate macromolecule synthesis in developing neural tissues; consequently, inhibition of this enzyme by alpha-difluoromethylornithine interferes with cellular replication and differentiation. We examined the regional selectivity of the effect of alpha-difluoromethylornithine administered either postnatally (days 1-19) or during gestation (days 15-17), in order to determine whether specific phases of maturation are particularly sensitive to polyamine depletion. In the cerebellum, which undergoes major phases of replication and differentiation after birth, postnatal alpha-difluoromethylornithine administration caused a profound and progressive deficit in tissue weight gain as well as in DNA, RNA and protein content. Although regions which develop earlier (cerebral cortex, midbrain + brain stem) also showed adverse effects of postnatal alpha-difluoromethylornithine, the deficits were of much smaller magnitude and were comparable to the effect of the drug on general body growth. Despite these regional differences, inhibition of DNA synthesis ([3H]thymidine incorporation) was similar in cerebellum and in midbrain + brain stem, indicating that the direct impact of alpha-difluoromethylornithine-induced polyamine depletion is exerted in both; DNA synthesis in cerebral cortex was spared relative to the other two regions. These data suggested that the impact of alpha-difluoromethylornithine on development depends, in part, upon the relative degree of maturation of each brain region at the time of drug exposure. In confirmation of this hypothesis, prenatal alpha-difluoromethylornithine given on gestational days 15-17 resulted in loss of the specificity toward cerebellar development and enhancement of effects on cerebral cortex, the region which had displayed the least sensitivity to postnatal alpha-difluoromethylornithine.

Perinatal dietary exposure to soy lecithin: altered sensitivity to central cholinergic stimulation.

The effects of perinatal exposure to soy lecithin preparation (SLP) on the development of cholinergic responses in the rat brain were examined by assessing the ability of intracisternally administered carbachol to stimulate 33Pi incorporation into phospholipids in vivo, an effect of carbachol mediated by muscarinic cholinergic receptors. Maternal intake of SLP produced a suppression of the cholinergic response in the offspring, an effect which was specific in that basal (unstimulated) incorporation rates were not reduced (in fact, they eventually became elevated), nor was the response to another neurotransmitter (dopamine) compromised. The effect occurred early in the preweanling stage, a period in which SLP exposure also enhances development of cholinergic nerve terminals. These results suggest that SLP exposure has a major effect on cholinergic synaptic development and reactivity, followed by secondary changes in other neurotransmitter pathways and by more generalized effects on basal membrane phospholipid turnover.

A simplified method for isocratic HPLC analysis of polyamines.

A simple technique is described for the separation and analysis of polyamines in tissues and body fluids, utilizing precolumn clean-up on disposable CM-cellulose columns, followed by an automatable HPLC procedure. Complete separation and analysis takes 12-15 min per sample with sensitivity in the pmole range.

Polyamines in brain and heart of the neonatal rat: effects of inhibitors of ornithine decarboxylase and spermidine synthase.

Daily administration of dicyclohexylamine (DCHA), an inhibitor of spermidine synthase, to neonatal rats produced a dose-dependent depletion of brain spermidine, accompanied by a rise in putrescine and spermine. Despite continued DCHA treatment, levels of all three polyamines returned toward normal within two weeks. alpha-Difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, had a much more profound and persistent effect on spermidine and also depleted putrescine throughout drug administration; furthermore, DFMO prevented both the elevation of putrescine caused by DCHA and the eventual restitution of spermidine levels. Although a similar pattern of effects was seen in the heart, the time course of onset of DCHA-induced alterations in polyamine levels and the rapidity of subsequent adaptation were considerably different from those in brain. The net activity of DCHA toward polyamines in developing tissues thus involves the direct actions of the drug on spermidine synthesis in combination with compensatory metabolic adjustments made by each tissue to polyamine depletion.

Exposure to methylmercury in utero: effects on biochemical development of catecholamine neurotransmitter systems.

Administration of methylmercury to pregnant rats resulted in major alterations in synaptic dynamics of brain dopamine systems in the offspring which were prominent even at doses of the organomercurial which did not produce acute toxicity, fetal or neonatal death, low birth weight or reduced litter sizes. The abnormalities were typified by shortfalls in both the levels and turnover rate of the transmitter in vivo, accompanied by elevations in synaptic uptake as assessed in synaptosomal preparations in vitro. These effects were not apparent in the immediate postnatal period but instead showed a delayed onset beginning at about the time of weaning. Methylmercury exposure displayed selectivity in that central noradrenergic systems showed only the synaptic uptake alterations without changes in transmitter levels or turnover; targeted interactions were also apparent in peripheral sympathetic pathways to the heart and kidney. The threshold dose required to elicit damage to biochemical development of neurotransmitter systems was the same as that to alter more generalized cellular development, as assessed through measurements of brain ornithine decarboxylase activity. These studies indicate that neurochemical damage produced by prenatal exposure of the developing organism to methylmercury involves transmitter-selective alterations in synaptic dynamics and function which may contribute to adverse behavioral outcomes; the underlying mechanisms, however, do not necessarily reflect actions of the organomercurial which are primary or specific to these particular neuronal tissues.