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Preferential action of gabapentin and pregabalin at P/Q‐type voltage‐sensitive calcium channels: Inhibition of K + ‐evoked [ 3 H]‐norepinephrine release from rat neocortical slices
Author(s) -
Dooley David J.,
Donovan Cindy M.,
Meder Wolfgang P.,
Whetzel Steven Z.
Publication year - 2002
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.10094
Subject(s) - neurotransmitter , pregabalin , chemistry , gabapentin , pharmacology , voltage dependent calcium channel , neurotransmission , norepinephrine , depolarization , neuroscience , biophysics , calcium , receptor , anesthesia , biochemistry , biology , medicine , dopamine , alternative medicine , organic chemistry , pathology
Gabapentin (GBP; Neurontin®) and pregabalin (PGB; CI‐1008), efficacious drugs in several neurological and psychiatric disorders, inhibit neurotransmitter release from mammalian brain slices at therapeutically relevant concentrations. A detailed investigation, exploring the basis for this in vitro phenomenon, focused on norepinephrine (NE) and rat neocortical tissue in complementary assays of neurotransmitter release and radioligand binding. The results are consistent with the hypothesis that GBP, PGB, and related substances decrease neocortical NE release by acting at the α 2 δ subunit of presynaptic P/Q‐type voltage‐sensitive Ca 2+ channels (VSCC) subserving Ca 2+ influx in noradrenergic terminals. The inhibitory action appears competitive with [Ca 2+ ] o and preferential to those neurons undergoing prolonged depolarization. Other results indicate that the reduction of exocytotic NE release is independent of L‐ and N‐type VSCC, classical drug/peptide binding sites on VSCC, Na + channels, α 2 ‐adrenoceptors, NE transporter, and system L amino acid transporter. These findings suggest a selective modulation of P/Q‐type VSCC that are implicated in neurotransmission and several GBP‐responsive pathologies. Synapse 45:171–190, 2002. © 2002 Wiley‐Liss, Inc.