Tetrahydroaminoacridine and physostigmine have opposing effects on probability of transmitter release at the frog neuromuscular junction

Provan, Spencer D.; Miyamoto, Michael D.

doi:10.1016/0304-3940(91)90174-r

Cited by 8 publications

(4 citation statements)

References 18 publications

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“…However, chronic administration of antiChEs may produce receptor desensitization, so an alternative is to increase ACh release at the remaining nerve terminals, using agents such as DuP 996. The finding of an increase in quantal ACh release with DuP 996 affirms that the increase in ACh output is not due to interference with quantal packaging and overflow of non-quantal ACh, as may occur with physostigmine (Alderdice, 1979;Provan & Miyamoto, 1991). …”

Section: Comparison Of Results With Neurochemical Studiesmentioning

confidence: 53%

“…This lack of effect differs from the increases in m.e.p.p. amplitude found with 3 jM THA (22%), physostigmine (46.5%) and neostigmine (79.2%) (Provan & Miyamoto, 1991), all of which are known antiChEs. This again implies that the facilitatory action of DuP 996 on cholinergic transmission must be due to pre-and not postsynaptic effects.…”

Section: Comparison Of Results With Neurochemical Studiesmentioning

confidence: 96%

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Effect of the putative cognitive enhancer, linopirdine (DuP 996), on quantal parameters of acetylcholine release at the frog neuromuscular junction

Provan

Miyamoto

1994

British J Pharmacology

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The subcellular mechanism and site of action of linopirdine or DuP 996 (3,3‐bis(4‐pyridinylmethyl)‐1‐phenylindolin‐2‐one) was investigated at the frog neuromuscular junction, using miniature endplate potential (m.e.p.p.) counts and a new method for obtaining unbiased estimates of n (number of functional release sites), p (probability of release), and varsp (spatial variance in p). DuP 996 produced an increase in m (no. of quanta released), which was due to an increase in n and p. The increase in m was concentration‐dependent over a range of 0.1–100 μm and completely reversible with 15 min of wash. There was a saturation in the increase in p, but not in the increase in m and n, for [DuP 996] >10 μm. By contrast, there was no major change in varsp. Block of presynaptic Na+‐ and Ca2+‐channels with 3 μm tetrodotoxin and 1.8 mm Co2+prevented the m.e.p.p. frequency increase to DuP 996, and this effect was completely reversed by washing. Application of the neuronal Ca2+‐channel blocker, ω‐conotoxin GVIA (1 μm) brought about a rapid and profound decrease in the m.e.p.p. frequency increase produced by DuP 996. The effect of the toxin was not reversed by prolonged washing. Block of voltage‐gated K+‐channels with 100 μm 4‐aminopyridine (4‐AP) resulted in only a small (28%) increase in m. The combination of 4‐AP (100 μm) and DuP 996 (10 μm) produced an increase in m (189%) which was much greater than the sum of the responses to each agent alone. This increase in m was due solely to an increase in n, as p and varsp were unchanged. For [DuP 996] up to 100 μm, there was no apparent change in the mean size, amplitude distribution, or time course of m.e.p.ps, signifying that it had no anticholinesterase activity. It is concluded that DuP 996 increases the release of quantal transmitter but not the postsynaptic response to the quanta. This appears to involve an effect at the nerve terminal membrane, most likely an increase in Ca2+‐conductance, and not an action to block K+‐conductance or to release Ca2+from intraterminal organelles.

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Section: Comparison Of Results With Neurochemical Studiesmentioning

confidence: 53%

Section: Comparison Of Results With Neurochemical Studiesmentioning

confidence: 96%

Effect of the putative cognitive enhancer, linopirdine (DuP 996), on quantal parameters of acetylcholine release at the frog neuromuscular junction

Provan

Miyamoto

1994

British J Pharmacology

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“…Tacrine potentiated neuromuscular transmission in isolated rat and chick skeletal muscle preparations (Bosch et al 1992;Braga et al 1991;Provan & Miyamoto 1991). Fast excitatory postsynaptic potentials were augmented by tacrine in rat neuromuscular preparations, and slow inhibitory postsynaptic potentials were blocked (Dutar et al 1990).…”

Section: Neuromuscular Transmissionmentioning

confidence: 99%

“…Fast excitatory postsynaptic potentials were augmented by tacrine in rat neuromuscular preparations, and slow inhibitory postsynaptic potentials were blocked (Dutar et al 1990). Tacrine increased miniature endplate potential amplitude (Braga et al 1991;Thesleff et al 1990) and frequency (Provan & Miyamoto 1991) and prolonged the decay phase (Braga et al 1991) in various isolated neuromuscular preparations.…”

Section: Neuromuscular Transmissionmentioning

confidence: 99%

Tacrine

Wagstaff¹,

McTavish²

1994

Drugs & Aging

124

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Tacrine is a centrally acting cholinesterase inhibitor with additional pharmacological activity on monoamine levels and ion channels. It has been postulated that some or all of these additional properties may also be relevant to the mode of action of the drug. There are wide interindividual variations in pharmacological and clinical response to tacrine, possibly related to interindividual variation in bioavailability. Tacrine appears to improve cognitive function and behavioural deficits in a proportion of patients with Alzheimer's disease, at dosages of 80 to 160 mg/day. In the best designed trials, 30 to 51% of evaluable patients showed an improvement of at least 4 points on the cognitive subscale of the Alzheimer's Disease Assessment Scale, versus 16 to 25% of placebo recipients. A similar proportion of tacrine recipients were judged to have improved when global assessment scales were used. There was a significant dose-response relationship up to 160 mg/day. However, large numbers of patients were withdrawn during the trials, many because of tacrine-associated increases in transaminase levels. Elevated liver enzyme levels occurred in about 50% of tacrine recipients (reaching clinical significance in about 25%). Cholinergic symptoms also occurred more often in tacrine recipients than in those receiving placebo. A gradual increase in tacrine dosage, at 6-week intervals, is recommended when initiating therapy, and weekly serum transaminase monitoring is required for 6 weeks after each dosage increase. Despite the limitations implied by the low proportion of responders and high incidence of hepatic adverse effects associated with therapy, tacrine appears to make a measurable difference in both cognitive and behavioural function in a proportion of patients with Alzheimer's disease--a welcome advance in an area previously devoid of acceptable treatment options.

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Neuropharmacology of potassium ion channels

Harvey

1993

Medicinal Research Reviews

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Tetrahydroaminoacridine and physostigmine have opposing effects on probability of transmitter release at the frog neuromuscular junction

Cited by 8 publications

References 18 publications

Effect of the putative cognitive enhancer, linopirdine (DuP 996), on quantal parameters of acetylcholine release at the frog neuromuscular junction

Effect of the putative cognitive enhancer, linopirdine (DuP 996), on quantal parameters of acetylcholine release at the frog neuromuscular junction

Tacrine

Neuropharmacology of potassium ion channels

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