Stereospecific effects of ketamine on dopamine efflux and uptake in the rat nucleus accumbens.
In addition to being a general anaesthetic, ketamine is a recognized drug of abuse. Many, if not all, drugs of abuse have been shown to increase dopamine efflux in the nucleus accumbens (NAc). As ketamine is optically active, we examined if its actions on dopamine efflux in the NAc were stereoselective. Slices of rat NAc were superfused with artificial CSF at 32 degrees C. Dopamine efflux was evoked by electrical stimulation (1 or 20 pulses, 100 Hz) and measured using fast cyclic voltammetry. (+/-)-Ketamine 100 mumol litre-1 increased dopamine efflux (to mean 174 (SEM 17)% of control, P < 0.05) and slowed dopamine uptake half-time (T1/2) to 164 (17)% of control, as did (+)-ketamine 100 mumol litre-1 (efflux 236 (16)% (P < 0.001); uptake T1/2 177 (25)% (P < 0.05)). The (-)-isomer was inactive. The effect of (+)-ketamine on dopamine efflux did not correlate with its action on dopamine uptake. (+)-Ketamine increased dopamine efflux on single pulse stimulation but to a lesser extent than on 20 pulse trains (P < 0.05). (+)-Ketamine was unable to block the inhibitory effect of quinpirole on single pulse dopamine efflux. Neither MK 801 10 mumol litre-1 nor metoclopramide 1 mumol litre-1 had any effect on dopamine release after short train stimuli (20 pulses, 100 Hz). We conclude that the (+)-isomer is the active form of ketamine and increases NAc dopamine efflux not by block of dopamine uptake; autoreceptors or NMDA receptors, but by mobilization of the dopamine storage pool to releasable sites.
Hancock
P J
PJ
Academic Department of Anaesthesia and Intensive Care, St Bartholomew's and the Royal London School of Medicine and Dentistry, Whitechapel, UK.
Stamford
J A
JA
D000778:Anesthetics, Dissociative / Q000494:pharmacology*; D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D066298:In Vitro Techniques; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D000778:Anesthetics, Dissociative; D007649:Ketamine; D004298:Dopamine