Preferential action of gabapentin and pregabalin at P/Q‐type voltage‐sensitive calcium channels: Inhibition of K⁺‐evoked [³H]‐norepinephrine release from rat neocortical slices

Abstract

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.

In vivo imaging reveals that pregabalin inhibits cortical spreading depression and propagation to subcortical brain structures

“…Pregabalin has a direct inhibitory effect on calcium-mediated glutamate release in brain slices from neocortex (41) and entorhinal cortex (42). In addition, pregabalin displays two-to threefold enhanced efficacy in the depression of noradrenaline release upon sustained depolarization as compared with brief stimulation (26,43). The long-lasting depolarization that occurs during SD may further increase the efficacy of pregabalin on neurotransmitter release when attenuating the synaptic gain of function resulting from R192Q and S218L mutations.…”

“…Although pregabalin's exact mechanism of action has not been deciphered, it has been shown to inhibit calcium currents acutely (24) and to suppress calcium channel trafficking chronically (25). Furthermore, pregabalin displays greater efficacy for P/Q-type (Ca V 2.1) channels than for L-type (Ca V 1.1-Ca V 1.4) and N-type (Ca V 2.2) channels (26). Although there is some controversy about the putative acute versus chronic molecular mechanisms, pregabalin has been associated convincingly with a reduction in excitatory neurotransmitter release, further implicating Ca V 2.1 calcium channels (27).…”

Choosing the Correct Antiepileptic Drugs: From Animal Studies to the Clinic

“…Topiramate has been shown to attenuate non-NMDA (AMPA) and kainate currents [7]. Gabapentin and pregabalin bind to the α2γ subunit of the voltage-gated Ca 2+ channel and modulate Ca 2+ currents [8]. Recently, another target of AEDs, the H-channel, has been characterized.…”

Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence

“…Gabapentin increases (1) the concentration and probably the synthesis of GABA in the brain (Taylor et al, 1998), (2) GABA release from rat striatal brain slices in vitro (Gotz et al, 1993), and (3) the nonvesicular release of GABA in rat optic nerves (Kocsis and Honmou, 1994) and rat hippocampal slices (Honmou et al, 1995). Gabapentin also decreases monoaminergic synaptic transmission in rat hippocampus and neocortex by selectively inhibiting Ca 2ϩ influx through voltage-operated Ca 2ϩ channels (VOCCs) (Fink et al, 2000;Dooley et al, 2002;van Hooft et al, 2002). In addition, gabapentin is an agonist for the endogenously expressed GABA B gb1a-gb2 heteromers coupled to inhibition of VOCCs in intermediate pituitary melanotrope cell lines and in hippocampal neurons Ng et al, 2001;van Hooft et al, 2002).…”