Faculty Bibliography

We assayed calpain activity in 27 human brain regions from adult (43-65 years of age) and aged (66-83 years of age) postmortem tissue samples. Calpain I (microM Ca-requiring) activity was 10% or less of the total activity; it was below detectable levels in a number of areas, and so data are are expressed as total (microM + mM Ca-dependent) calpain activity. The distribution of the enzyme was regionally heterogeneous. Highest activity was found in the spinal cord, followed by the amygdala, and levels in mesencephalic areas and in cerebellar grey matter were also high. Levels in cerebellar white matter, tegmentum, pons, and putamen were low, and activity in cortical areas was also relatively low. Although in some areas activity seemed higher with aging, the differences were not statistically significant. We previously found that the regional distribution of cathepsin D in human and in rat brain is similar, this seems to be true for calpain activity as well. The increase of protease activity with age found in rat brain is not found in human areas, as was shown previously with cathepsin D, and in the present study with calpain

A fragment (11-19) of thymosin beta 4 was found to stimulate phosphodiesterase activity even in the absence of calcium and calmodulin. Half-maximal enzyme activation occurred with 10 nM peptide, and was further increased by phospholipids such as phosphatidylserine. The mechanism of stimulation is an increase in the Vmax of cAMP degradation without a substantial change in the Km for the substrate. In the presence of calcium ions and calmodulin the peptide was also stimulatory

Brain microdialysis and high-performance liquid chromatography with electrochemical detection were utilized to study the effect of the selective non-competitive NMDA antagonist MK-801 (dizocilpine) on striatal dopamine (DA) release in the anesthetized rat. Perfusion of 100 microM and 300 microM (+/-)-MK-801 through the probe did not significantly change the basal release of DA. These results suggest that excitatory amino acids do not exert a tonic excitatory influence on striatal DA release through NMDA receptors. 1 mM and 3 mM (+/-)-MK-801 caused a significant increase (398% and 580%, respectively), while there was no change in the level of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). To clarify the mechanism of the (+/-)-MK-801-induced increase, the differential effect of its enantiomers (the active (+)-MK-801 and the less active (-)-MK-801) was determined. There was no difference in the action of these compounds: both drugs increased the striatal DA release with the same efficacy. Our data suggest that the MK-801-induced increase of striatal DA release is not an NMDA receptor-mediated effect

After a period of forced exposure to 300 mg/l cocaine HCl in drinking water for a period of one week, followed by forced exposure to 200 mg/l cocaine for an additional week, male C57BL/6By mice developed a preference for cocaine when given a choice of drinking either water or a solution containing cocaine (200 mg/l). The mean daily intake of cocaine during the choice period was 26 +/- 1 mg/kg or, when expressed as the ratio of cocaine over total fluid intake, represented a cocaine preference of 71 +/- 2%. Administration of ibogaine HCl (40 mg/kg, two injections 6 h apart) two weeks after the beginning of the choice period reduced the cocaine preference for at least five days; the mean daily intake of cocaine was reduced by 38% (to 16 +/- 1 mg/kg per day; p < 0.05) and cocaine preference was reduced to 41 +/- 2% (cocaine fluid consumption/total fluid intake). An acute challenge injection of cocaine (25 mg/kg SC) produced a significant increase in cocaine-induced locomotor activity and stereotypy in mice previously exposed to cocaine in their drinking water (cocaine choice group). Five days after ibogaine administration, locomotor and stereotypy activity were significantly lower after a challenge injection of cocaine (25 mg/kg SC). Brain levels of cocaine 35 min after the challenge injection of cocaine were approximately 25% higher in ibogaine-treated mice (7.2 +/- 0.5 and 9.3 +/- 0.8 micrograms/g wet wt for water vs. mice treated with water plus ibogaine and 9.3 +/- 0.2 and 11.8 +/- 0.7 micrograms/g wet wt for cocaine drinking vs. cocaine drinking plus ibogaine treatment).(ABSTRACT TRUNCATED AT 250 WORDS)