Faculty Bibliography

Norcocaine (NC) and N-hydroxynorcocaine (NHNC), products of the oxidative metabolism of cocaine, were examined in plasma, brain, and liver of mice injected intraperitoneally with cocaine. Plasma levels of NHNC were altered in vivo by inhibiting esterase activity with diazinon and chloral hydrate or activating esterase activity with phenobarbital, and activating the microsomal P-450 system with phenobarbital. Changes in plasma concentrations of NHNC resulted in similar changes in brain, which were often different from those in liver. After intracisternal administration of cocaine to mice, no appreciable amount of NC or NHNC could be detected in brain; the same results were obtained upon intracisternal and intraventricular administration to rats. Microsomal preparations from mouse brain were found to be considerably less active than those from liver in converting NC to NHNC. We conclude that the cerebral oxidative metabolism of cocaine is not appreciable and that most of the NC and NHNC found in the brain after systemic cocaine administration is derived from plasma rather than formed centrally by brain microsomal enzymes

Chronic administration of caffeine to mice did not alter cellular (low-affinity) transport as measured in brain slices of the amino acids ?-aminobutyric acid, glutamic acid, and glycine. Chronic caffeine administration did, however, increase the long-term (60-min) uptake of ?-aminoisobutyric acid and valine into brain slices. A similar tendency, although not statistically significant, towards increased amino acid uptake was also seen in the transport of phenylalanine and lysine across the blood-brain barrier in chronically treated rats. The increase in neutral amino acid uptake seems unrelated to changes in brain protein metabolism, since chronic caffeine administration did not significantly alter brain protein synthesis rates. In vitro, caffeine (0.01-1 mM) did not alter brain slice transport of the amino acids ?-aminobutyric acid, glutamic acid, glycine, valine, and the amino acid analog ?-aminoisobutyric acid. Caffeine (1-100 ?M) was also ineffective in altering the synaptosomal (high-affinity) transport of the neurotransmitter amino acids ?-aminobutyric acid, glutamic acid, and glycine. These data support the idea that caffeine is a mildly stimulating drug with no significant effect on neurotransmitter amino acid transport systems in rodent brain