title: Hippocampal noradrenaline release is modulated by gamma- and delta-hexachlorocyclohexane isomers: which mechanisms are involved?
abstract: The differential effects of gamma- and delta-hexachlorocyclohexane isomers on 25 mM K(+)-evoked release of [3H]noradrenaline were studied in hippocampal slices treated with selected agents to activate or block L- and N-type Ca2+ and Na+ voltage-sensitive ion channels, Cl- transport and Ca(2+)-dependent protein activity. At maximally effective concentrations, the L- and N-type Ca2+ channel blockers nifedipine and omega-conotoxin, respectively, and the Na+ channel antagonist tetrodotoxin did not modify the enhancement of K(+)-evoked [3H]noradrenaline release induced by gamma-hexachlorocyclohexane. Likewise, under activation of protein kinase C by phorbol 12,13-dibutyrate (PDB) or inhibition of calmodulin by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), the stimulatory effect of gamma-hexachlorocyclohexane remained almost unchanged. The Cl- transport blocker 4,4-diisothiocyanato-stilbene-2,2'-disulfonic acid (DIDS) significantly reduced the effect of gamma-hexachlorocyclohexane on [3H]noradrenaline release. The enhanced release in the presence of Bay K 8644, the L-type Ca2+ channel activator, was significantly inhibited by nifedipine but not by delta-hexachlorocyclohexane. The combination of omega-conotoxin and tetrodotoxin with delta-hexachlorocyclohexane did not alter the [3H]noradrenaline release effects of each agent alone. Activation of protein kinase C in the presence of delta-hexachlorocyclohexane resulted in a reduction of the delta isomer effect and in a potentiation of the PDB effect. W-7 did not further facilitate the inhibition induced by delta-hexachlorocyclohexane alone. These data suggest that hexachlorocyclohexane isomers may modify K(+)-evoked [3H]noradrenaline release by interacting with presynaptic molecular processes involving changes in Cl- membrane permeability and intracellular Ca2+ homeostasis.
authors.affiliation: Department of Pharmacology and Toxicology, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.
authors.forename: R M
authors.initials: RM
authors.lastname: Cristòfol
authors.forename: E
authors.initials: E
authors.lastname: Rodríguez-Farré
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D002712:Chlorides / Q000378:metabolism; D001556:Hexachlorocyclohexane / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007536:Isomerism; D009638:Norepinephrine / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D020866:omega-Conotoxin GVIA
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002712:Chlorides; D010455:Peptides; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013449:Sulfonamides; D013779:Tetrodotoxin; D001556:Hexachlorocyclohexane; C017967:W 7; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D020866:omega-Conotoxin GVIA; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D011188:Potassium; D009638:Norepinephrine