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Is Attenuation of Extracellular Dopamine Increase in the Nucleus Accumbens the Major Mechanism by which Dexmedetomidine Increases the Cocaine Seizure Threshold in Rats?: In Reply

Whittington, Robert A. M.D.*; Virag, Laszlo M.S.; Morishima, Hisayo O. M.D., Ph.D.

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In Reply:—
We would like to thank the editor for allowing us the opportunity to reply to Dr. Nakao's interesting correspondence.
We do realize that other mechanisms may play a role in mediating cocaine-induced seizure activity. Indeed, the existence of different mechanisms may be the reason that these seizures are often clinically refractory to anticonvulsant monotherapy. 1 In our study, we focused on the dopaminergic system, because the plasmalemmal dopamine transporter is still thought to be the classic mechanism through which many of the psychomotor effects of cocaine are produced. 2 Moreover, we also concentrated on the role of mesolimbic dopamine, because our previous work suggested that dexmedetomidine effectively decreases dopamine in the nucleus accumbens. 3 Although our findings support the hypothesis that accumbal dopamine has a significant effect on cocaine-induced seizure activity, in no way do they suggest that this is the sole mechanism by which these seizures are mediated.
We agree with Dr. Nakao's relevant comments that ς receptors are also mechanistically involved in cocaine-induced seizures; however, as for the involvement of ς receptors in mediating the anticonvulsant effects of dexmedetomidine, we are currently unaware of any evidence in the literature demonstrating that dexmedetomidine has a significant effect at ς receptors. Given this, it is unlikely that the demonstrated anticonvulsant effects of dexmedetomidine involve these receptors.
Robert A. Whittington, M.D.*
Laszlo Virag, M.S.
Hisayo O. Morishima, M.D., Ph.D.
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1. Gasior M, Ungard JT, Witkin JM: Preclinical evaluation of newly approved and potential antiepileptic drugs against cocaine-induced seizures. J Pharmacol Exp Ther 1999; 290: 1148–56

2. Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ: Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 1987; 237: 1219–23

3. Whittington RA, Virag L, Morishima HO, Vulliemoz Y: Dexmedetomidine decreases extracellular dopamine concentrations in the rat nucleus accumbens. Brain Res 2001; 919: 132–8

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