Elevated CSF beta-endorphin immunoreactivity in Rett's syndrome: report of 158 cases and comparison with leukemic children.

Because some symptoms of Rett's syndrome are suggestive of excessive endogenous opioid activity, we measured the levels of beta-endorphin-like immunoreactivity in lumbar CSF from 158 affected female patients and from 13 female controls. The mean (+/- SE) control level of beta-endorphin immunoreactivity in CSF was 35.3 +/- 2.8 pg/ml (range, 23 to 48 pg/ml), whereas those with Rett's syndrome had a mean level of 95.3 +/- 3.6 pg/ml (range, 31 to 293 pg/ml). The levels of beta-endorphin immunoreactivity in initial CSF samples exceeded the control range in 90% of the patients with Rett's syndrome. The mean beta-endorphin immunoreactivity was also elevated in CSF from leukemic children (119.2 +/- 16.9 pg/ml; range, 40 to 159 pg/ml), relative to the control group. These results are consistent with the hypothesis that some symptoms of Rett's syndrome may be associated with excessive endogenous opioid levels in the CNS.

Comparison of the effects of diisopropylfluorophosphate, sarin, soman, and tabun on toxicity and brain acetylcholinesterase activity in mice.

The LD50s and ED50s for inhibition of acetylcholinesterase (AChE) in whole mouse brain by DFP (diisopropylfluorophosphate), sarin (methylphosphonofluoridic acid 1-methyl ethyl ester), soman (methylphosphonofluoridic acid 1,2,2-trimethyl propyl ester), and tabun (dimethylphosphoramidocyanidic acid ethyl ester) were compared after iv administration. The LD50s of DFP, sarin, soman, and tabun in ICR (Institute for Cancer Research) mice were 3.40, 0.109, 0.042, and 0.287 mg/kg, respectively. The recovery of AChE activity in whole mouse brain after sub-LD50 doses of these agents was slow and did not reach control values by 14 d after iv administration. AChE activity was inhibited in a dose-dependent manner in whole mouse brain, as well as in six brain regions (cortex, hippocampus, striatum, midbrain, medulla-pons, and cerebellum). None of these brain areas appeared to be particularly sensitive to AChE inhibition. The ED50s for DFP, sarin, soman, and tabun for inhibition of AChE in whole mouse brain were approximately 19, 38, 69, and 66% of their respective LD50s. Because of the differential potencies between lethality and inhibition of AChE, it is concluded that the lethality of these agents is due to more factors than simply the inhibition of AChE within the brain.

Relationship of the biodisposition of the stereoisomers of nicotine in the central nervous system to their pharmacological actions.

The stereoisomers of nicotine were evaluated for their effectiveness in producing antinociception and altering spontaneous activity and Rotarod performance in rats. (-)-Nicotine was found to be 6, 15 and 30 times more active than its unnatural enantiomer, (+)-nicotine, in the spontaneous activity, Rotarod and antinociceptive tests, respectively. Biodispositional studies revealed that the time course (-)-[3H]nicotine closely paralleled the time course of effects on spontaneous activity and Rotarod performance but not antinociception, which suggested that multiple mechanisms were involved in the actions of nicotine. In addition, the distribution studies showed the brain and plasma levels of (-)-[3H]nicotine were higher than those of (+)-[3H] nicotine, which indicate that the pharmacological stereoselectivity of nicotine is less than originally determined. Finally, the greatest difference in the regional localization in brain of the stereoisomers was found in cerebral cortex, hippocampus and corpus striatum.

Nicotine-induced antinociception in rats and mice: correlation with nicotine brain levels.

Nicotine was found to be potent in producing antinociception in mice and rats as measured by tail-flick latency but its action was of short duration. Nicotine's ED50 values (confidence limits) were 0.7 (0.4-1.1) and 2.0 (1.2-3.4) mg/kg in rats and mice, respectively, at the time of maximum effect. Brain levels of nicotine reached a maximum at 10 min, whereas antinociception was maximal within 2 min in rats. However, there was a good correlation between the time courses of antinociception and brain levels of nicotine in mice with both attaining maximal levels at 5 min. It was found that tachyphylaxis developed to the antinociception in rats within 10 min and lasted for up to 14 h, but tachyphylaxis did not develop to nicotine-induced antinociception in mice. The effect of nicotine appeared to be central in both rats and mice inasmuch as mecamylamine antagonized completely but hexamethonium (5 mg/kg) antagonized partially. Nicotine-induced antinociception was not blocked in either rats or mice by atropine in doses up to 10 mg/kg. Naloxone did not block nicotine in rats but did antagonize the antinociception in mice. In addition, yohimbine, a selective alpha-2 antagonist, blocked the antinociception in both species. These data implicate several different mechanisms in the antinociceptive action of nicotine.

Synthesis of 4,4-ditritio-(+)-nicotine: comparative binding and distribution studies with natural enantiomer.

The preparation of 4,4-ditritio-(+)-nicotine (Vb) (specific activity 10.3 Ci/mmole)from (+)-nicotine (Ib) via (-) 4,4-dibromocotinine (IIIb) is described. Although Ib is 10-30 times less potent than (-)-nicotine (Ia) in the CNS, its binding affinity for the crude mitochondrial or nuclear fraction of whole rat brain is only three times less than that of Ia. However, distribution studies showed that the maximum brain levels of (-)-[3H] nicotine are nearly twice those of (+)-[3H]-nicotine following administration of a 2-micrograms/kg dose. Binding affinity and disposition of the stereoisomers account for a portion of the pharmacological stereospecificity of nicotine.