Role of ornithine decarboxylase in cardiac growth and hypertrophy.

Inhibition of cardiac ornithine decarboxylase (ODC) by alpha-difluoromethylornithine (DFMO) did not prevent normal cardiac growth in mature rats but attenuated isoproterenol-induced hypertrophy. Hypertrophy caused by triiodothyronine was not prevented by DFMO. There appear to be both ODC-dependent and ODC-independent processes contributing to the subcellular mechanisms associated with growth, which must be considered in the potential laboratory and clinical use of DFMO.

Overexpression of the high affinity choline transporter in cortical regions affected by Alzheimer's disease. Evidence from rapid autopsy studies.

Cholinergic deficits in Alzheimer's disease are typically assessed by choline acetyltransferase, the enzyme that synthesizes acetylcholine. However, the determining step in acetylcholine formation is choline uptake via a high affinity transporter in nerve terminal membranes. Evaluating uptake is difficult because regulatory changes in transporter function decay rapidly postmortem. To overcome this problem, brain regions from patients with or without Alzheimer's disease were frozen within 4 h of death and examined for both choline acetyltransferase activity and for binding of [3H]-hemicholinium-3 to the choline transporter. Consistent with the loss of cholinergic projections, cerebral cortical areas exhibited marked decreases in enzyme activity whereas the putamen, a region not involved in Alzheimer's disease, was unaffected. However, [3H]hemicholinium-3 binding was significantly enhanced in the cortical regions. In the frontal cortex, the increase in [3H]hemicholinium-3 binding far exceeded the loss of choline acetyltransferase, indicating transporter overexpression beyond that necessary to offset loss of synaptic terminals. These results suggest that, in Alzheimer's disease, the loss of cholinergic function is not dictated simply by destruction of nerve terminals, but rather involves additional alterations in choline utilization; interventions aimed at increasing the activity of cholinergic neurons may thus accelerate neurodegeneration.

Marked reduction in the number of platelet-tritiated imipramine binding sites in geriatric depression.

The number (Bmax) and affinity (Kd) of platelet-tritiated imipramine binding sites was determined in young and middle-aged controls 50 years of age and younger (n = 25), elderly normal controls over 60 years of age (n = 18), patients who fulfilled DSM-III criteria for major depression who were under 50 years of age (n = 29), patients who fulfilled DSM-III criteria for major depression who were 60 years of age and older (n = 19), and patients who fulfilled both DSM-III criteria for primary degenerative dementia and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer's disease (n = 13). Both groups of depressed patients (under 50 and over 60 years of age) exhibited significant reductions (decreases 42%) in the number of platelet-tritiated imipramine binding sites with no change in affinity, when compared with their age-matched controls. There was little overlap in Bmax values between the elderly depressed patients and their controls. The patients with probable Alzheimer's disease showed no alteration in platelet-tritiated imipramine binding. There was no statistically significant relationship between postdexamethasone plasma cortisol concentrations and tritiated imipramine binding. These results indicate that platelet-tritiated imipramine binding may have potential utility as a diagnostic adjunct in geriatric depression, and moreover that the reduction in the number of platelet-tritiated imipramine binding sites is not due to hypercortisolemia.

Dendritic development of Purkinje and granule cells in the cerebellar cortex of rats treated postnatally with alpha-difluoromethylornithine.

Postnatal administration of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), is known to curtail replication of granule cells in the cerebellum of the rat, but its effects on post-proliferative neurons is unknown. This Golgi study assessed the influence of daily postnatal injections of DFMO on dendritic development of the Purkinje and granule cells. Although the overall appearance of the Purkinje cells was normal, DFMO affected morphogenesis by causing: 1) a reduction in somatic growth, 2) an elongation of the primary dendrite, 3) a lengthening of the distance between the soma and the pial surface, 4) a reduction in the number of tertiary dendrites, and 5) a disruption of the distribution of the tertiary branches. Many of these effects of DFMO may be mediated via the reduction of granule cells rather than representing a direct effect on dendritogenesis. In addition to reducing the number of granule cells, the distribution and morphology of these cells in the DFMO-treated rats were severely affected. Many granule cells did not complete their migration and remained trapped in the molecular layer, and many of those trapped had greatly elongated dendrites that extended into the internal granule cell layer. These results suggest that ornithine decarboxylase is involved in the postproliferative processes of neuronal migration and differentiation.

Release of corticotropin-releasing factor from rat brain regions in vitro.

In addition to its endocrine action in the anterior pituitary, corticotropin-releasing factor (CRF) also appears to play a role in regulating higher central nervous system function(s). To investigate further the role of CRF in brain, a specific RIA was used to measure in vitro CRF release during incubation of various rat brain regions in Krebs-Henseleit buffer. Increasing the potassium concentration to 56 mM resulted in a 10-fold increase in CRF release from minced hypothalamus. However, the high K+ concentrations had no effect in the presence of calcium-free buffer containing 1 mM EGTA. Scorpion venom also stimulated CRF release in a calcium-dependent manner. CRF-like immunoreactivity was detected in extrahypothalamic brain regions using RIA and HPLC. Significant calcium-dependent CRF release from the rat amygdala and midbrain was observed in response to 56 mM K+ or scorpion venom. These results indicate that depolarizing agents induce the release of CRF-like immunoreactivity not only from the hypothalamus but also from other rat brain regions and lend further support to the hypothesis that CRF may be a neurotransmitter or neuromodulator in the central nervous system.

Do glucocorticoids contribute to the abnormalities in serotonin transporter expression and function seen in depression? An animal model.

Adrenocorticosteroids and serotonergic neurons exert reciprocal regulatory actions, and both are abnormal in depression. We evaluated whether glucocorticoids influence the serotonin transporter in rat platelets and brain by infusing dexamethasone for 26 days, sufficient for replacement of the entire platelet population. Effectiveness was verified by measurement of plasma dexamethasone levels, adrenal atrophy, and growth inhibition. At the end of the infusion, we examined [3H]paroxetine binding to platelet, hippocampal, and cerebrocortical membranes, and [3H]serotonin uptake into platelets and synaptosomes. Dexamethasone slightly reduced platelet [3H]paroxetine binding (12%) and had no effect on binding in brain. Platelet [3H]serotonin uptake was unaffected, but synaptosomal uptake was significantly reduced. In neither platelets nor synaptosomes did dexamethasone alter imipramine's ability to inhibit uptake. Thus, elevated glucocorticoids are not responsible for reduced platelet serotonin transporter expression in depression, nor for resistance to imipramine's effect in platelets in elderly depression; however, reduced synaptosomal [3H]serotonin uptake indicates that glucocorticoids can affect transport efficiency, even when the number of transporter molecules is unaltered.

Serotonin transporter expression in rat brain regions and blood platelets: aging and glucocorticoid effects.

Hyperactivity of the hypothalamus-pituitary-adrenal axis is more common in elderly depression than in younger cohorts and glucocorticoids are known to influence serotonergic systems. The current study explores the interaction of glucocorticoids with aging on serotonin transporter expression and function. Continuous infusions of dexamethasone (26 days) reduced transporter expression in the aged brain but the ability of imipramine to inhibit synaptosomal [3H]serotonin uptake was unimpaired. These effects were unique to aged animals, as prior work with young adults found no effects of dexamethasone on transporter expression. In contrast to the effects in the brain, there were no differences in platelet transporter expression between young and old rats nor did dexamethasone treatment affect the values in the aged group: thus, the platelet may not reliably model these aspects of CNS function. The results suggest that there are basic biologic differences in the effects of glucocorticoids in aged vs. young brain that could contribute to lowered effectiveness to antidepressants in elderly depression; if transport capacity is already reduced by the effects of increased glucocorticoids, further inhibition of transport by antidepressants would have proportionally less impact on synaptic serotonin concentrations.

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.

Ontogenetic changes in laminar distribution of ornithine decarboxylase during development of cerebellar cortex: autoradiographic localization with [3H]alpha-difluoromethylornithine.

Ornithine decarboxylase is the first enzyme in the biosynthesis of the polyamines, which control macromolecule synthesis during cellular development. Polyamines appear to play a critical role in the development of the rat cerebellar cortex, since postnatal treatment with the specific irreversible ornithine decarboxylase inhibitor, alpha-difluoromethylornithine, arrests cell division and migration in this region. To determine whether the distribution of ornithine decarboxylase within the developing cerebellar cortex correlates with specific maturational events, [3H]alpha-difluoromethylornithine, a specific marker for ornithine decarboxylase activity, was localized autoradiographically in 3-13-day-old rats. The density of autoradiographic grains within the cerebellar cortex as a whole paralleled the postnatal rise and fall of biochemically determined ornithine decarboxylase activity. Superimposed on this pattern was a selective laminar distribution of label which indicated specific association of ornithine decarboxylase with cell replication, as shown by preferential labeling of the superficial (mitotic) zone of the external granule cell layer. In addition, ornithine decarboxylase activity was temporally associated with regions in which post-mitotic cells were undergoing migration, axonogenesis and dendritic arborization, as shown by the patterns obtained in deeper layers. In contrast, there was no evidence for an association between ornithine decarboxylase activity and synaptogenesis, gliogenesis or myelination. These results, in combination with previous biochemical and morphological data, support the view that the ornithine decarboxylase/polyamine system plays an important role in both mitotic and post-mitotic events within the nervous system.

Impaired morphological development of the dorsal cochlear nucleus in hamsters treated postnatally with alpha-difluoromethylornithine.

The dorsal cochlear nucleus is a highly organized nucleus in the auditory system in which the ramifications of depletion of specific cell types during development can be studied. Granule cells, small interneurons that are located in all layers of the DCN in the adult hamster, proliferate postnatally and are, therefore, potentially vulnerable to anti-mitotic agents that are administered after birth. The present experiments describe the effects of alpha-difluoromethylornithine, a drug that inhibits proliferation of cerebellar granule cells, on the granule cells in the dorsal cochlear nucleus. As in the cerebellum, the density of granule cells in the dorsal cochlear nucleus is reduced after alpha-difluoromethylornithine treatment. In hamsters treated with alpha-difluoromethylornithine (200 or 500 mg/kg subcutaneously (s.c.), twice daily on postnatal days 4-14), the numerical density of granule cells was reduced in the superficial dorsal cochlear nucleus at 15 days; by 40 days this effect was also apparent in the deep layer, suggesting that cells located superficially that would have migrated into the deep dorsal cochlear nucleus had either failed to develop or did not arrive at their final location. This evidence suggests that the cells normally migrate down from the superficial proliferative zone into the deeper layers. In the drug-treated animals, a layer of mixed granule cells and fusiform cells was thinner than in controls probably due to the reduction in interspersed granule cells since the number of fusiform cells was unaffected. There was also a dose-dependent effect on cell growth; fusiform cells were affected at both doses, while giant cells were only affected at the highest dose. Granule cells form a major input to the fusiform cells and their depletion may account for some of the effects on fusiform cell growth. There could also be additional direct actions of alpha-difluoromethylornithine on this population.

Development of sympathetic ganglionic neurotransmission in the neonatal rat. Pre- and postganglionic nerve response to asphyxia and 2-deoxyglucose.

To determine the time course of development of neurotransmission in the sympathetic ganglion of the rat, pre- and postganglionic activity was recorded from the cervical sympathetic trunk in anesthetized neonatal and mature preparations. Tonic activity and responses to two stimuli, cellular hypoglycemia induced by 2-deoxyglucose and asphyxia, which are known to evoke CNS-mediated sympathetic activation in mature rats were measured. In 2-11-day-old neonates, tonic preganglionic activity recorded from the cervical sympathetic nerve and responses to hypoglycemia and asphyxia were comparable to or greater than that in mature rats. In 17-19-day-old neonates these variables were elevated to twice the adult value. In contrast, tonic postganglionic activity recorded from the internal carotid nerve was barely detectable through 5 days of age and there was no response to hypoglycemia. During asphyxia, maximum postganglionic impulse frequency and total number of impulses discharged were 10-20% of the mature value through the 5th postnatal day and the duration of the postganglionic response was only 25% of the preganglionic response. Tonic postganglionic activity and response to stimuli were equivalent to those in mature rats by the 10th postnatal day. The compound action potential evoked in the postganglionic axons by direct electrical stimulation was comparable in 4-5 and 10-13 day-old rats. In the concluded that functional ganglionic neurotransmission is established in the neonatal rat between the 5th and 10th postnatal day. The relation between biochemical changes associated with maturation of the postganglionic neuron, ganglionic synaptogenisis and neurotransmission is discussed. It is concluded that synaptogenisis and onset of neurotransmission are causally associated with development of CNS regulation of postganglionic activity and end organ response rather than with maturation of the postganglionic neuron and that cholinergic excitation of the postganglionic neuron adequate to evoke action potentials is not essential to initiate maturation of the neuron.

Autoradiographic localization of ornithine decarboxylase in cerebellar cortex of the developing rat with [3H]alpha-difluoromethylornithine.

Ornithine decarboxylase was autoradiographically localized in the developing rat cerebellar cortex after intracisternal injection of [3H]alpha-difluoromethylornithine, a specific, irreversible inhibitor of the enzyme. At nine days of age, when cerebellar ornithine decarboxylase activity is maximal, autoradiographic grains were distributed over all layers of the cerebellar cortex and throughout the brain stem. Within cerebellar folia, the highest grain density was associated with the molecular layer, whereas the internal and external granule cell layers were less densely labeled. Enhancement of ornithine decarboxylase activity by intracisternally-administered isoproterenol correspondingly increased the autoradiographic grain density over each layer. Thus much of the polyamine biosynthetic capability needed to support neuronal and/or glial differentiation appears to be associated with the developing cell processes. The combination of [3H]alpha-difluoromethylornithine autoradiography with localized injection techniques provides a potentially powerful tool for the study of the involvement of polyamine biosynthesis in brain development.

Critical development periods for inhibition of ornithine decarboxylase by alpha-difluoromethylornithine: effects on ontogeny of sensorimotor behavior.

The roles of ornithine decarboxylase and the polyamines in behavioral development were examined through the use of alpha-difluoromethylornithine, a specific irreversible inhibitor of ornithine decarboxylase. alpha-Difluoromethylornithine was administered either prenatally during gestation (days 15-17) or postnatally (days 1-20) to examine critical periods of sensitivity. Prenatal alpha-difluoromethylornithine administration resulted in a deficit in early sensorimotor ontogeny: latencies in surface righting reflex (postnatal days 1-5) and negative geotaxis (postnatal days 5-8) were prolonged, and time spent pivoting (postnatal days 7, 9, and 11) was reduced. In contrast, postnatal alpha-difluoromethylornithine primarily influenced later maturing, complex integrative behaviors such as swimming and open field activity. Thus, the behavioral effects of alpha-difluoromethylornithine exposure are highly dependent upon the age at which the drug is administered, a finding in keeping with the participation of the ornithine decarboxylase/polyamine system in cell replication and differentiation during discrete periods of neural development. The behavioral consequences of ornithine decarboxylase inhibition during these critical periods are thus related primarily both to the timetable for cellular maturation in each brain region.

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)

Non-neurogenic mechanism for reserpine-induced release of catecholamines from the adrenal medulla of neonatal rats: possible modulation by opiate receptors.

Neonatal rats do not have functional splanchnic nerve connections to the adrenal medulla until approximately one week of postnatal age, yet they are able to respond to some drugs or stresses by releasing adrenal catecholamines. Reserpine (5 mg/kg s.c.) resulted in significant loss (20-40%) of neonatal catecholamines within 4 h; unlike the acute effects of reserpine in the adult, depletion was not prevented by pretreatment with a nicotinic blocking agent, demonstrating that the effect in the neonate is non-neurogenic. Depletion did not result simply from inhibition of catecholamine storage by reserpine, but rather, the non-neurogenic depletion represented net movement of the amines from the storage granules into the extracellular space, as evaluated by the subcellular distribution of catecholamines. These results suggest that the non-neurogenic mechanism represents release of catecholamines. The immature response mechanism disappeared by 11 days of age and was replaced by a completely neurogenic release, demonstrating that the special mechanism is lost within several days of the onset of functional innervation of the adrenal. Experiments also were carried out to test whether endogenous opioids and/or opiate receptors are involved in the non-neurogenic mechanism. Naloxone (5 mg/kg s.c.) potentiated the depletion of catecholamines by reserpine, while methadone (2.5 mg/kg s.c.) inhibited the non-neurogenic response. In contrast, no potentiation of release by naloxone or inhibition by methadone was seen in adult rats. Thus, opiate receptors may modulate only the immature secretory mechanism.

Impaired development of cerebellar cortex in rats treated postnatally with alpha-difluoromethylornithine.

alpha-Difluoromethylornithine specifically and irreversibly inhibits the enzyme ornithine decarboxylase. Ornithine decarboxylase catalyses the initial step in the synthesis of polyamines, which are thought to play an essential role in growth and development of mammalian tissues. The current study examined the effects of alpha-difluoromethylornithine on the ontogenic development of the rat cerebellar cortex. Animals injected daily with alpha-difluoromethylornithine on postnatal days 1-21 suffered a deficit in the number of granule cells and many of the remaining granule cells became trapped in the molecular layer during migration. Purkinje cells were also scattered throughout the molecular layer and their mean diameter was 38% smaller than in controls. In general, the cerebellar cortex of alpha-difluoromethylornithine-treated rats failed to progress much beyond the stage of development reached in control rats during the first postnatal week. These effects of alpha-difluoromethylornithine were already clearly visible at 10-15 days of age. The final size of the cerebellum as a whole and of individual folia was markedly subnormal. These data indicate that polyamines play an obligatory role in cerebellar neurogenesis and histogenesis.

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.

Postnatal development of brain alpha 1-adrenergic receptors: in vitro autoradiography with [125I]HEAT in normal rats and rats treated with alpha-difluoromethylornithine, a specific, irreversible inhibitor of ornithine decarboxylase.

The postnatal development of brain alpha 1-adrenergic receptors was studied in the rat brain using in vitro autoradiography. In some regions, such as the globus pallidus, receptor-binding sites were present at birth and increased during the first week but then decreased to very low levels by adulthood. In contrast, other regions such as the olfactory bulb and cerebral cortex exhibited little binding at birth, with a subsequent increase in receptors during the second week of life that persisted into the mature stage. Several regions had an intermediate pattern with significant labelling at birth, an increase in the first few weeks and a smaller decrement in binding sites as adulthood was approached. The data suggested that there were two archetypal development patterns, one of which was potentially related to the arrival of noradrenergic nerve projections (olfactory bulb) and the other of which was determined intrinsically by differentiation (globus pallidus). The two patterns could be distinguished by their sensitivity to alpha-difluoromethylornithine, a drug that inhibits ornithine decarboxylase, leading to a slowing of cellular replication, differentiation and migration. Drug treatment dramatically delayed the developmental fall-off of binding in the globus pallidus such that receptor sites remained in high concentration well past the point at which they disappeared in control animals. In the olfactory bulb, however, alpha-difluoromethylornithine had little or no effect on the ontogeny of receptor binding. These studies provide evidence that alpha 1-adrenergic receptors in various brain regions develop at different rates and with at least two characteristic patterns. Autoradiographic techniques provide important insights into receptor development that cannot be garnered from biochemical methods using isolated membrane preparations.

Effects of reserpine on the adrenal medulla of the spontaneously hypertensive rat.

1. Reserpine administration resulted in a larger initial decline in adrenal catecholamines in spontaneously hypertensive rats (SHR) than in normotensive Wistar rats (NWR); the difference was eliminated by pretreatment with cholisdondamine. 2. Reserpine also produced a larger increase in SHR catecholamines and dopamine beta-hydroxylase several days later; chlorisondamine pretreatment did not prevent the increases, although it did slightly slow the increases. 3. Vesicles from SHR, or NWR incubated with reserpine in vitro demonstrated equivalent inhibition of adenosine 5'-triphosphate (ATP)-Mg-2+-stimulated adrenaline uptake. 4. Recovery of uptake was more rapid in SHR than in NWR after reserpine inhibition, and this was associated with a burst of new vesicle synthesis in the SHR; chlorisondamine pretreatment reduced the number of new, immature vesicles in reserpine-treated SHR. 5. Both SHR and NWR secreted equal proportions of their adrenal catecholamine contents after nicotine administration. 6. These data suggest that the sympatho-adrenal system of the SHR exhibits an enhanced reflex response to reserpine but that reserpine is equally effective in SHR and NWR in producing blockade of vesicular catecholamine transport; these alterations can affect markedly the actions of autonomic drugs in the SHR.

Concomitant development of [3H]-dopamine and [3H]-5-hydroxytryptamine uptake systems in rat brain regions.

1 Synaptosomal uptake mechanisms of 5-hydroxytryptamine and dopamine were examined in cerebral cortex, corpus striatum and midbrain plus brainstem of developing rats. 2 In all regions, there was generally a parallel biphasic development of both uptake systems; the most rapid increases occurred in the first two weeks postpartum, followed by a slower rate of increase. 3 Kinetic studies with dopamine indicated that the maturation involved increases in maximal uptake without a change in the substrate Km, suggesting that there is a change in the number or terminals but not in the uptake system per se.