The reversible anticholinesterase pyridostigmine does not readily cross the blood-brain barrier. However, administration of this drug for 6 days in guinea-pigs caused delayed changes in the activity of brain acetylcholinesterase (AChE) which were still manifest long after the inhibitory effect had worn off (Lintern et al. 1998). The effects of pyridostigmine administration on brain choline acetyltransferase (ChAT) in that study are now reported.

ChAT activity was determined in the striatum, hippocampus, mid-brain, cortex, medulla pons and cerebellum of guinea-pigs, using the method of Fonnum (1974). In untreated animals ChAT activity (DPM X 10³ (mg tissue)^-1) was over 3-fold higher in striatum (19.4 ± 1.8 (S.E.M.), n = 6, P < 0.001, ANOVA and Fisher’s post hoc test), and significantly lower in cerebellum (0.3 ± 0.1 (S.E.M.), n = 6, P < 05), than any other region examined. The relative distribution resembled that of acetylcholine (Wetherell et al. 1989). Pyridostigmine (5.1 µg h^-1) or saline (0.9 %) was delivered via a mini osmotic pump, implanted under halothane anaesthesia (3 % in O₂). Animals were killed by cervical dislocation on day 6 (prior to pump removal) or 1, 7 or 13 days after pump removal under halothane anaesthesia. Some animals had anaesthetic alone. The experiments were performed according to UK legislation. The effects of pyridostigmine treatment were determined in striatum and cerebellum.

At 6 days ChAT activity in the striatum (32.7 ± 6.3, n = 6) was approximately double that seen in saline-treated (16.3 ± 4.5, n = 6) or untreated controls. At 1 day after pump removal it had declined to below control levels, but by 7 days after pump removal it had increased again to significantly higher even than at 6 days (P < 0.05). There were also small changes in the saline-treated controls after pump removal. Anaesthetic alone had no effect. There were no significant effects of pyridostigmine on ChAT activity in cerebellum at any time point tested.

The changes in the striatum could be secondary to a peripheral action of pyridostigmine but it is also possible that the drug had permeabilised the blood-brain barrier, or that the stress of the procedures was responsible. The cerebellum is low in acetylcholine and ChAT, but high in AChE, whereas the striatum is high in acetylcholine, ChAT and AChE. The different effects in the two brain regions could be related to differences in the levels of acetylcholine following inhibition of AChE by the drug.

This work was supported by Dstl. C. British Crown copyright 2001/Dstl. Reproduced with the permission of her Britannic Majesty’s Stationery Office.