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Block of voltage-gated calcium channels stimulates dopamine efflux in rat mesocorticolimbic system.
Neuropharmacology. 2009 May-Jun; 56(6-7):984-93.N

Abstract

Dopamine (DA) efflux from terminals of the mesocorticolimbic system is linked to incentive motivation, drug dependency and schizophrenia. Strategies for modulating dopaminergic activity have focused on transmitter receptors or the DA transporter, not on DA release, largely due to lack of systemically available drugs acting at this level. Central synapses use two main calcium channels for excitation-secretion coupling, either P/Q-type, N-type, or both. Here we investigate changes in mesocorticolimbic DA efflux following administration of NP078585, a novel orally available calcium channel blocker exhibiting high affinity block of N- and T-types versus P/Q- and L-types. NP078585 was applied either intra peritoneally (i.p.; 2.5-10 mg/kg) or by reverse-dialysis (10-25 microM) into either the Ventral Tegmental Area (VTA) or the Nucleus Accumbens (NAc), and the changes in DA levels in both the VTA and NAc were monitored using microdialysis. We found that both systemic and central administration of NP078585, but not vehicle, enhanced DA efflux in the NAc but not the VTA. The enhancement of DA levels was replicated by local applications of omega-conotoxin GVIA (2.5 microM), a selective peptide N-type channel blocker, to either VTA or NAc, suggesting N-type mediation. Furthermore, application of the GABA(A)-selective antagonist bicuculline (50 microM) to the VTA enhanced DA efflux in both VTA and NAc, and occluded the NP078585-induced enhancement in the latter structure. We propose that the actions of NP078585 and omega-conotoxin largely reflect block of N-type channels in terminals of GABAergic interneurons, leading to reduced GABA release, disinhibition of DA neurons and enhanced DA release in the NAc.

Authors+Show Affiliations

Neuromed Pharmaceuticals Inc., Suite 301-2389 Health Sciences Mall, Vancouver, BC V6T1Z3, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19371580

Citation

Belardetti, Francesco, et al. "Block of Voltage-gated Calcium Channels Stimulates Dopamine Efflux in Rat Mesocorticolimbic System." Neuropharmacology, vol. 56, no. 6-7, 2009, pp. 984-93.
Belardetti F, Ahn S, So K, et al. Block of voltage-gated calcium channels stimulates dopamine efflux in rat mesocorticolimbic system. Neuropharmacology. 2009;56(6-7):984-93.
Belardetti, F., Ahn, S., So, K., Snutch, T. P., & Phillips, A. G. (2009). Block of voltage-gated calcium channels stimulates dopamine efflux in rat mesocorticolimbic system. Neuropharmacology, 56(6-7), 984-93. https://doi.org/10.1016/j.neuropharm.2009.02.001
Belardetti F, et al. Block of Voltage-gated Calcium Channels Stimulates Dopamine Efflux in Rat Mesocorticolimbic System. Neuropharmacology. 2009 May-Jun;56(6-7):984-93. PubMed PMID: 19371580.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Block of voltage-gated calcium channels stimulates dopamine efflux in rat mesocorticolimbic system. AU - Belardetti,Francesco, AU - Ahn,Soyon, AU - So,Kitty, AU - Snutch,Terrance P, AU - Phillips,Anthony G, Y1 - 2009/02/11/ PY - 2008/11/08/received PY - 2009/01/31/revised PY - 2009/02/02/accepted PY - 2009/4/18/entrez PY - 2009/4/18/pubmed PY - 2009/7/8/medline SP - 984 EP - 93 JF - Neuropharmacology JO - Neuropharmacology VL - 56 IS - 6-7 N2 - Dopamine (DA) efflux from terminals of the mesocorticolimbic system is linked to incentive motivation, drug dependency and schizophrenia. Strategies for modulating dopaminergic activity have focused on transmitter receptors or the DA transporter, not on DA release, largely due to lack of systemically available drugs acting at this level. Central synapses use two main calcium channels for excitation-secretion coupling, either P/Q-type, N-type, or both. Here we investigate changes in mesocorticolimbic DA efflux following administration of NP078585, a novel orally available calcium channel blocker exhibiting high affinity block of N- and T-types versus P/Q- and L-types. NP078585 was applied either intra peritoneally (i.p.; 2.5-10 mg/kg) or by reverse-dialysis (10-25 microM) into either the Ventral Tegmental Area (VTA) or the Nucleus Accumbens (NAc), and the changes in DA levels in both the VTA and NAc were monitored using microdialysis. We found that both systemic and central administration of NP078585, but not vehicle, enhanced DA efflux in the NAc but not the VTA. The enhancement of DA levels was replicated by local applications of omega-conotoxin GVIA (2.5 microM), a selective peptide N-type channel blocker, to either VTA or NAc, suggesting N-type mediation. Furthermore, application of the GABA(A)-selective antagonist bicuculline (50 microM) to the VTA enhanced DA efflux in both VTA and NAc, and occluded the NP078585-induced enhancement in the latter structure. We propose that the actions of NP078585 and omega-conotoxin largely reflect block of N-type channels in terminals of GABAergic interneurons, leading to reduced GABA release, disinhibition of DA neurons and enhanced DA release in the NAc. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/19371580/Block_of_voltage_gated_calcium_channels_stimulates_dopamine_efflux_in_rat_mesocorticolimbic_system_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(09)00046-X DB - PRIME DP - Unbound Medicine ER -