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Critical Reviews™ in Neurobiology

ISSN for PRINT: 0892-0915

Institutional price:	$649.00
Issues per year:	4

Best Paper Award Selection - Editorial Board Site

2006, Volume18

209 pages

Issue price - $338.00

Cocaine Inhibition of GABA_A Current: Role of Dephosphorylation

Jiang-Hong Ye
Department of Anesthesiology, Pharmacology and Physiology, New Jersey Medical School; The Graduate School of Biomedical Sciences, New Jersey Medical School (UMDNJ), Newark, New Jersey, U.S.A.

Jun Ren
Department of Anesthesiology, New Jersey Medical School, Newark, New Jersey, U.S.A.

ABSTRACT

Acute cocaine toxicity is frequently associated with seizures. The mechanisms underlying the convulsant effect of cocaine are not well understood. Previously, we have shown that cocaine depresses whole-cell current evoked by γ-aminobutyric acid (GABA) in hippocampal neurons freshly isolated from rats. Cocaine's effect was voltage-independent and concentration-dependent. In the present study, using whole-cell patch-clamp recording on rat neurons freshly isolated from hippocampus, we examined the intracellular mechanisms involved in cocaine's action. Increasing intracellular Ca²⁺ concentration ([Ca]i) from 0.01 to 5 μM strongly increased the depressant effect of cocaine. By contrast, 1-[N, O-bis (5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62), a specific antagonist of Ca/calmodulin-depen-dent protein kinase (CaMKII), attenuated or enhanced cocaine's action in different neurons: in three out of nine neurons dialysed with 5 μM KN-62,1 mM cocaine depressed GABA current by only 33%, but in another three out of nine neurons, cocaine depressed GABA current by as much as 83%. Chelerythrine (a specific CaCa²⁺/phospholipid-dependent protein kinase C [PKC] antagonist) had minimal effect on cocaine's action. We suggest that cocaine induces an increase in [Ca]i, which stimulates phosphatase activity and thus leads to dephosphorylation of GABA receptors. This dephosphorylation-mediated disinhibitory action may play a role in cocaine-induced convulsant states.