To the Editor:—

I am very impressed with the recent article by Whittington et al. , which demonstrated that dexmedetomidine increased the cocaine-induced seizure threshold via  the attenuation of the cocaine-induced increase in extracellular dopamine concentration in the rat nucleus accumbens. 1It is true that the increase in extracellular dopamine concentration in the nucleus accumbens may be closely related to the cocaine-induced seizure activity because cocaine inhibits dopamine transporters, but recent studies have suggested that ς receptors, which are endoplasmic reticulum protein and directly activated by cocaine, are more likely involved in the cocaine-induced seizure activity than the dopamine transporters. 2On the other hand, we have recently demonstrated that ketamine, which has anticonvulsant and also proconvulsant properties, markedly increases dopamine release in the nucleus accumbens. 3Ketamine affected the ς receptors 4and ketamine-induced c-fos protein expression in the posterior cingulate and retrosplenial cortices, which might be a reliable indicator of ketamine-induced psychotomimetic activity, was mediated at least partly via  the ς receptors. 5Therefore, I wonder whether the cocaine-induced increase in extracellular dopamine concentration in the nucleus accumbens is the major mechanism by which cocaine induces seizures and furthermore the ς receptors may be involved in the inhibitory effects of dexmedetomidine on the cocaine-induced seizures.

Whittington RA, Virag L, Vulliemoz Y, Cooper TB, Morishima HO: Dexmedetomidine increases the cocaine seizure threshold in rats. A nesthesiology 2002; 97: 693–700
Matsumoto RR, Hewett KL, Pouw B, Bowen WD, Husbands SM, Cao JJ, Hauck Newman A: Rimcazole analogs attenuate the convulsive effects of cocaine: Correlation with binding to sigma receptors rather than dopamine transporters. Neuropharmacology 2001; 41: 878–86
Masuzawa M, Nakao S, Miyamoto E, Yamada M, Murao K, Nishi K, Shingu K: Pentobarbital inhibits ketamine-induced dopamine release in the rat nucleus accumbens: A microdialysis study. Anesth Analg 2003; 96: 148–52
Hustveit O, Maurset A, Oye I: Interaction of chiral forms of ketamine with opioids, phencyclidine, sigma and muscarinic receptor. Pharmacol Toxicol 1995; 77: 355–9
Nakao S, Miyamoto E, Masuzawa M, Kambara T, Shingu K: Ketamine-induced c-Fos expression in the mice posterior cingulate and retrosplenial cortices are mediated not only via NMDA receptors but also via sigma receptors. Bain Res 2002; 926: 191–6