Stereoselective effects of ketamine on dopamine, serotonin and noradrenaline release and uptake in rat brain slices

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Ketamine (2-(2-chlorophenyl)-(1-methylamino)-cyclohexanone) is a rapid-acting dissociative general anaesthetic whose hallucinogenic properties have made it a popular drug of abuse. Ketamine comprises two optical isomers, with differing pharmacology. In the present study, the effects of (+)- and (−)-ketamine on stimulated efflux and reuptake of dopamine (DA), noradrenaline (NA) and serotonin (5-HT) were compared in isolated superfused slices of the rat caudatoputamen (CPu), ventral bed nucleus of the stria terminalis (BSTV) or dorsal raphe nucleus (DRN), respectively. Monoamine efflux was elicited by local electrical stimulation (20 pulses, 100 Hz trains) at tungsten microelectrodes and measured at adjacent carbon fibre microelectrodes using fast cyclic voltammetry (FCV). In CPu (+)-ketamine increased stimulated DA efflux and slowed DA reuptake in a concentration-dependent manner (25–200 μM). At 100 μM (+)-ketamine increased DA efflux by 109±20% (mean±S.E.M., n=13) of control values after 30 min (P<0.001 versus control) and prolonged uptake half-time (t1/2) by 76±38% (n=9, P<0.001) of control. In contrast (−)-ketamine (100 μM) had no effect on DA efflux or uptake. In DRN, both isomers (100 μM) increased stimulated 5-HT efflux. (−)-Ketamine had a larger effect (P<0.001), an 88±15% increase in 5-HT efflux (n=9) versus 46±10% (n=8) for the (+)-isomer. The isomers had similar effects on 5-HT uptake, increasing t1/2 by approximately 200%. No evidence of stereospecificity was seen in BSTV: both isomers had small effects (+)- and (−)-ketamine (100 μM) increasing NA efflux by 43±10% (n=7, P<0.001) and 29±8% (n=7, P<0.001), respectively. The isomers also had identical effects on NA uptake, each increasing uptake t1/2 by approximately 100%. In summary, our data show that the optical isomers of ketamine have strikingly different stereospecificity for the monoamine systems and one might predict, therefore, a different psychotomimetic potential.

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