Pbs. Clarke et al., BLOCKADE OF NICOTINIC RESPONSES BY PHYSOSTIGMINE, TACRINE AND OTHER CHOLINESTERASE-INHIBITORS IN RAT STRIATUM, British Journal of Pharmacology, 111(3), 1994, pp. 695-702
1 The acetylcholinesterase inhibitors physostigmine, neostigmine, tetr
ahydroaminoacridine (tacrine; THA) and diisopropylfluorophosphate (DFP
) were tested for possible direct nicotinic actions in rat striatal sy
naptosomes preloaded with [H-3]-dopamine. In this preparation, nicotin
ic cholinoceptor activation evoked [H-3]-dopamine release. 2 Antagonis
t activity was examined by giving a brief nicotine (1 mu M) challenge
after 30 min superfusion with an acetylcholinesterase (AChE) inhibitor
(0.3-300 mu M). Physostigmine, neostigmine and tacrine produced a con
centration-dependent blockade. Physostigmine and tacrine were particul
arly potent (IC(50)s approx. 10 mu M and 1 mu M, respectively). DFP re
duced nicotinic responses only at the highest concentration tested (30
0 mu M). 3 Nicotinic blockade produced by superfusion with physostigmi
ne (30 mu M) was insurmountable when tested against nicotine (0.1-100
mu M). 4 Physostigmine (30 mu M) also reduced responses to the nicotin
ic agonists 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) and cytisi
ne, but did not alter responses to high K+ or (+)-amphetamine. A highe
r concentration of physostigmine (300 mu M) completely blocked respons
es to nicotine, somewhat reduced responses to amphetamine, and did not
alter responses to high K+. Tacrine (3 mu M) reduced responses to nic
otine and to high K+ but did not affect responses to amphetamine. 5 Ph
ysostigmine (0.3-300 mu M), given as a brief pulse, did not produce a
nicotinic agonist-like effect. 6 Physostigmine, neostigmine, tacrine a
nd DFP (all at 30 mu M) each produced near-total (>96%) inhibition of
AChE activity. However, DFP at a concentration (60 mu M) that produced
a degree of AChE inhibition equal to that of physostigmine 30 mu M, d
id not significantly reduce nicotine-induced dopamine release. 7 It th
us appears that physostigmine blocks CNS nicotinic receptors in an ins
urmountable and pharmacologically selective manner, independent of its
ability to inhibit acetylcholinesterase. Tacrine reduced nicotinic re
sponses, quite possibly by an indirect mechanism. The possibility of d
irect or indirect blockade of nicotinic receptor-mediated actions may
complicate the interpretation of preclinical studies that have employe
d physostigmine and tacrine.