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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 alpha2delta subunit of presynaptic P/Q-type voltage-sensitive Ca2+ channels (VSCC) subserving Ca2+ influx in noradrenergic terminals. The inhibitory action appears competitive with [Ca2+]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, alpha2-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.

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