Pharmacokinetics of cocaine: basic studies of route, dosage, pregnancy and lactation.

As a preface to the pharmacokinetic analysis of cocaine in pregnant and lactating rats (using oral administration of drug), young Long-Evans rats were used to compare the relative concentrations of cocaine in blood, brain, and liver after administering cocaine by iv or oral routes. Cocaine and its metabolites were determined using 3H-cocaine as a tracer, followed by homogenization and solvent extraction of tissues, and quantitative analysis by HPTLC and LSC. From 30 min postinjection to several hrs later, the concentration of cocaine was higher in brain (3-4 fold) and liver (3-5 fold) than in blood, using the iv route. Using the oral route, the concentration in brain was 2-3 fold higher than in blood, and in liver, 10-20 fold higher. The metabolites of cocaine were largely excluded from entry into brain tissue, whereas the accumulation of metabolites in liver was typically an order of magnitude higher, or more, than in blood (iv or oral route). The ratio of cocaine to metabolites increased in all three tissues, as the dosage increased, indicating that more and more of an administered dose actually reaches the tissues as cocaine as the dosage level increases. During the period from 30 to 90 min following the administration of cocaine to pregnant dams, cocaine appeared in fetal brain at a rate of 50-90% of the concentration in the dam's brain (presumably because of the lower lipid content in fetal brain compared to adult), but still at a rate of 109-151% of the concentration in the dam's blood. Cocaine is sufficiently stable in milk to assume that any cocaine entering breast milk from the blood stream will be available to the suckling infant, and after administering radioactive cocaine to lactating dams, the milk/blood ratio for cocaine averaged 7.8. These data indicate that both the fetus and suckling infant are at considerable risk from cocaine use by the mother.

Effects of aging and alcohol on the biochemical composition of histologically normal human brain.

Human brains were removed at autopsy and examined grossly and histologically for any abnormality or evidence of disease. Sixty-two brains appearing normal by these criteria were examined further. First, a detailed record of alcohol consumption was obtained. Second, frozen punches of gray and white matter were used to determine the compositional change associated with age and drinking patterns. Increased age was associated with an increase in the water content, particularly in the white matter, a decline in RNA content in gray matter, a decline in total protein in white matter, and a decline in both myelin and the myelin-like subfraction. The loss of myelin membrane in white matter corresponded to a similar increase in water content, although there was an additional loss of some nonmyelin protein. There was no significant shift in the density between the myelin and the myelin-like membranes, and the protein composition of myelin was not significantly altered by age. A history of heavy alcohol consumption was associated with a relative increase in total protein in white matter even though heavy drinking accelerated the age-related loss of myelin. Presumably, alcohol produced a lag in the rate at which nonmyelin proteins are lost or accelerated the accumulation of abnormal protein. Alcohol consumption did not influence the myelin composition or the ratio of myelin and myelin-like membranes. The interval between patient death and autopsy was shown to have little or no effect on the samples used in this study. These data show that normal aging, uncomplicated by other disease processes, can have a significant effect on the composition of brain tissue, particularly the white matter, and that heavy alcohol consumption accelerates degenerative change, even in tissue appearing normal by histology.

Voluntary wheel running exercise and monoamine levels in brain, heart and adrenal glands of aging mice.

The goals of this study were to examine the effects of three months of voluntary wheel-running exercise on life span, whole body and brain, heart and adrenal weights and biogenic amine content (norepinephrine, dopamine, epinephrine and serotonin) in three age groups of male mice. The three groups consisted of mature (9 months), middle-aged (19 months), and old (27-29 months) mice. No significant differences in weight were found between control and exercise or age. The oldest mice had a survival rate of 69% for the exercise group and 43% for the age matched controls when the exercise phase was completed. Locomotor activity was significantly reduced for the old mice compared to the middle-age and mature mice. Only the mature (12 months of age at sacrifice) exercised mice showed a cardiac and adrenal hypertrophy (about 10%). There was a moderate increase in norepinephrine content in the ventral hypothalamus of the brain with exercise (significant at 12 months of age). Biogenic amine content in other regions of the brain (brain stem and forebrain minus hypothalamus) was not affected by age and/or exercise. There was a significant decrease in heart norepinephrine content with exercise in old mice (30-32 months). Adrenal gland norepinephrine content was significantly increased by exercise at 12 months of age and decreased at 22 months of age. Our results suggest that an increase in norepinephrine content in the hypothalamus might be a manifestation of an adaptation to the increased demands upon hypothalamic noradrenergic terminals imposed by prolonged exercise. It is also apparent that aging and exercise alters the amounts of sympathetic transmitter of the heart and adrenal glands. Such alteration may be beneficial to the aging brain by retaining norepinephrine stores that normally decline with age.

Age-related changes in rat brain capillaries.

We have measured several morphological parameters by electron microscopy of the frontal cortex (FC) and hippocampal CA1 (HC) capillaries in male Fischer 344 rats 3-, 9- and 24-months old. The results indicate that with increasing age there is an increase in the cross-sectional area of the basement membrane, increase in the fraction of endothelial cell and pericyte cytoplasmic area occupied by mitochondria in the FC, increase in the size of the pericyte mitochondria in both the FC and HC, increased capillary lumen area in the FC and decreased capillary lumen area in the HC. Also, the cytoplasmic area occupied by mitochondria in capillary pericytes is larger than in the endothelial cells of both FC and HC. These results suggest that there is regional variation in the age-associated changes in capillary morphometrics.

Regional uptake of [35S]-cysteine in rat brain after arterial injection.

The brain uptake index of [35S]-cysteine in ten rat brain regions and in the eye was determined by measuring [35S]-cysteine remaining in the brain regions and in the eye, five seconds after carotid injection, relative to a simultaneously injected diffusible internal standard, 3H2O and a non-diffusible internal standard Tc99m-Sn-DTPA. A statistical comparison for the regions that receive their blood supply from the internal carotid artery was done. Only the diencephalon and the septum-nucleus accumbens were found significantly higher than cortex.

Dihydroergotoxine(Hydergine) and ethanol-induced aging of C57BL/6J male mice.

The residual effects of dihydroergotoxine (Hydergine), ethanol, and Hydergine-plus-ethanol were investigated in old male mice of the C57BL/6J strain. Prolonged 10% v/v ethanol, concomitant with adequate nutrition, produced a significant decrease in life-span, decreased spontaneous locomotor activity and reduced lipofuscin accumulation in neurons of the reticularis gigantocellularis. These effects were not apparent in mice treated with Hydergine or alcohol combined with Hydergine.

Nerve fiber hypertrophy in posterior tibial nerves of mice in response to voluntary running activity during aging.

Three-month-old male C57BL/10 mice were exercised by voluntary running activity in vertically revolving wheels for two hours each day until 24 months of age. Activity scores were recorded each day and the animals were regularly weighed and inspected for abnormalities. Control animals were similarly treated except that the activity wheels were immobilized. At the end of the exercise period, survival was 84% for the exercise group and 64% for the controls. Light microscopic examination of the posterior tibial nerve of the surviving animals showed a significant fiber hypertrophy in response to the exercise. The number of myelinated fibers in nerves from exercised animals did not differ from those of the controls. On the basis of these data, it is suggested that prolonged exercise does not prevent the loss of peripheral nerve fibers associated with age but rather, may exert an effect on the nervous system by modifying the surviving cells.