Neuronal bungarotoxin blocks the nicotinic stimulation of endogenous dopamine release from rat striatum

doi:10.1016/0304-3940(89)90420-5

Neuroscience Letters

Volume 98, Issue 3, 10 April 1989, Pages 310-316

https://doi.org/10.1016/0304-3940(89)90420-5 Get rights and content

Abstract

Nicotinic receptors in the brain are receiving increased attention due in part to the recent cloning of receptor subunits and to postmortem studies revealing alterations in receptor density associated with Alzheimer's disease. The peptide neurotoxin neuronal bungarotoxin (NBT) has been shown to block nicotinic cholinergic responses in autonomic ganglia and in retinal ganglion cells. These findings suggest that NBT may be a useful probe for studying nicotinic receptors in the brain. Therefore, we have investigated the effects of NBT on the nicotine-mediated enhancement of endogenous dopamine release from rat striatal slices. It was found that the transient increase in dopamine release caused by 100 μM nicotine was completely blocked by 100 nM NBT, indicating that NBT is a functional nicotinic antagonist in this system.

References (26)

Y. Arimatsu et al.
Localization of α-bungarotoxin binding sites in mouse brain by light and electron microscopic autoradiography
Brain Res.
(1978)
L. Arqueros et al.
Nicotine-induced release of catecholamines from rat hippocampus and striatum
Biochem. Pharmacol.
(1978)
D.A. Brown et al.
Dissociation of α-bungarotoxin binding and receptor block in the rat superior cervical ganglion
Brain Res.
(1977)
P.B.S. Clarke et al.
Autoradiographic distribution of nicotine receptors in rat brain
Brain Res.
(1984)
P.B.S. Clarke et al.
Autoradiographic evidence for nicotine receptors on nigrostriatal and mesolimbic dopaminergic neurons
Brain Res.
(1985)
J. DeBelleroche et al.
Biochemical evidence for the presence of presynaptic receptors on dopaminergic nerve terminals
Brain Res.
(1978)
F.R. Goodman
Effects of nicotine on distribution and release of [¹⁴C]-norepinephrine and [¹⁴C]-dopamine in rat brain striatum and hypothalamus slices
Neuropharmacology
(1974)
S. Hunt et al.
Some observations on the binding patterns of α-bungarotoxin in the central nervous system of the rat
Brain Res.
(1978)
R.H. Loring et al.
Characterization of a snake venom neurotoxin which blocks nicotinic transmission in the avian ciliary ganglion
Neuroscience
(1984)
R.H. Loring et al.
Characterization of neuronal nicotinic receptors by snake venom neurotoxins
Trends Neurosci.
(1988)

R.H. Loring et al.

The ultrastructural distribution of putative nicotinic receptors on cultured neurons from the rat superior cervical ganglion

Neuroscience

(1988)

O.H. Lowry et al.

Protein measurement with the Folin phenol reagent

J. Biol. Chem.

(1951)

Y. Sakurai et al.

Enhancement of [³H]dopamine release and its [³H]metabolites in rat striatum by nicotinic drugs

Brain Res.

(1982)

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Neuronal bungarotoxin blocks the nicotinic stimulation of endogenous dopamine release from rat striatum

Abstract

Brain Res.

Biochem. Pharmacol.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Neuropharmacology

Brain Res.

Neuroscience

Trends Neurosci.

Neuroscience

J. Biol. Chem.

Brain Res.