Cholinergic drugs and 4-aminopyridine alter hypoxic-induced behavioral deficits

To test the hypothesis that decreased acetylcholine (ACh) metabolism during hypoxia is behaviorally important, the effects of cholinergic drugs and 4-aminopyridine, an enhancer of ACh release, were examined in hypoxic mice. Chemical hypoxia (150 mg/kg NaNO2) reduced tight rope test scores from 13.2 +/- 0.2 to 2.8 +/- 0.3. 4-Aminopyridine partially reversed the scores of hypoxic mice (7.3 +/- 0.7). Physostigmine improved performance by hypoxic mice (7.9 +/- 0.4) when it was given before NaNO2 and this effect was blocked by pretreatment with atropine (3.5 +/- 0.4) or mecamylamine (2.4 +/- 0.6). Neostigmine (0.002-0.2 mg/kg) was ineffective. Performance also improved if atropine (7.0 +/- 0.5) or mecamylamine (7.2 +/- 0.5) was given before NaNO2. Nicotine (5.5 +/- 0.7) or the muscarinic agonist arecoline (5.4 +/- 0.5) improved performance when given during the hypoxic episode, and when the drugs were combined, the score was even higher (8.2 +/- 1.0). Neither epinephrine (0.002-2.0 mg/kg) nor norepinephrine (0.00002-2.0 mg/kg) improved performance by hypoxic mice. These results suggest that hypoxia produces a behaviorally important impairment of the cholinergic system perhaps through a primary alteration of acetylcholine release.