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.

[1]  G. Chiara,et al.  Amphetamine, cocaine, phencyclidine and nomifensine increase extracellular dopamine concentrations preferentially in the nucleus accumbens of freely moving rats , 1989, Neuroscience.

[2]  O. Paulsen,et al.  The chiral forms of ketamine as probes for NMDA receptor functions in humans , 1991 .

[3]  Activity of two primary human metabolites of nomifensine on stimulated efflux and uptake of dopamine in the striatum: In vitro voltammetric data in slices of rat brain , 1992, Neuropharmacology.

[4]  J. Millar,et al.  Presynaptic regulation of dopamine release in corpus striatum monitored in vitro in real time by fast cyclic voltammetry , 1990, Brain Research.

[5]  J. Stamford,et al.  Characteristics of the NMDA receptor modulating hypoxia/hypoglycaemia-induced rat striatal dopamine release in vitro. , 1997, European journal of pharmacology.

[6]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[7]  W. L. Way,et al.  Comparative pharmacology of the optical isomers of ketamine in mice. , 1978, European journal of pharmacology.

[8]  B. Urban,et al.  Molecular actions of racemic ketamine on human CNS sodium channels. , 1992, British journal of anaesthesia.

[9]  Takao Shimizu,et al.  Ketamine-induced hyperlocomotion associated with alteration of presynaptic components of dopamine neurons in the nucleus accumbens of mice , 1991, Pharmacology Biochemistry and Behavior.

[10]  R. Karler,et al.  A dopaminergic-glutamatergic basis for the action of amphetamine and cocaine , 1994, Brain Research.

[11]  J. Mantz,et al.  Effects of Volatile Anesthetics, Thiopental, and Ketamine on Spontaneous and Depolarizationevoked Dopamine Release from Striatal Synaptosomes in the Rat , 1994, Anesthesiology.

[12]  M. Armstrong‐James,et al.  Carbon fibre microelectrodes , 1979, Journal of Neuroscience Methods.

[13]  K. Sugiyama,et al.  Effects of ketamine on dopamine metabolism during anesthesia in discrete brain regions in mice: comparison with the effects during the recovery and subanesthetic phases , 1997, Brain Research.

[14]  L. Arendt-Nielsen,et al.  Sensory Changes and Pain After Abdominal Hysterectomy: A Comparison of Anesthetic Supplementation with Fentanyl Versus Magnesium or Ketamine , 1998, Anesthesia and analgesia.

[15]  J. Mantz,et al.  Is inhibition of dopamine uptake relevant to the hypnotic action of i.v. anaesthetics? , 1996, British journal of anaesthesia.

[16]  E. Domino,et al.  Neural mechanisms of ketamine-induced anesthesia. , 1968, International journal of neuropharmacology.

[17]  C. Werner,et al.  [From the racemate to the eutomer: (S)-ketamine. Renaissance of a substance?]. , 1997, Der Anaesthesist.

[18]  M. Cohen,et al.  Distribution in the Brain and Metabolism of Ketamine in the Rat after Intravenous Administration , 1973, Anesthesiology.

[19]  N. Koshikawa,et al.  Ketamine anaesthesia has no effect on striatal dopamine metabolism in rats , 1988, Brain Research.

[20]  M. Tohyama,et al.  Ketamine Inhibits Monoamine Transporters Expressed in Human Embryonic Kidney 293 Cells , 1998, Anesthesiology.

[21]  P. Upton,et al.  Key Topics In Anaesthesia , 1995 .

[22]  Keith A. Jones,et al.  Stereospecific effects of ketamine enantiomers on canine tracheal smooth muscle , 1997, British journal of pharmacology.

[23]  N. Lindefors,et al.  Differential effects of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in rat medial prefrontal cortex , 1997, Brain Research.

[24]  Jonathan A. Stamford,et al.  Fast cyclic voltammetry: Measuring transmitter release in ‘real time’ , 1990, Journal of Neuroscience Methods.

[25]  P. A. Shore Actions of amfonelic acid and other non‐amphetamine stimulants on the dopamine neuron * , 1976, The Journal of pharmacy and pharmacology.

[26]  R. Kuczenski,et al.  Amphetamine, cocaine, and fencamfamine: relationship between locomotor and stereotypy response profiles and caudate and accumbens dopamine dynamics , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[27]  A. Bowdle,et al.  Psychedelic Effects of Ketamine in Healthy Volunteers: Relationship to Steady‐state Plasma Concentrations , 1998, Anesthesiology.

[28]  E. Kharasch,et al.  Metabolism of ketamine stereoisomers by human liver microsomes. , 1992, Anesthesiology.

[29]  Carol A. Tamminga,et al.  Subanesthetic Doses of Ketamine Stimulate Psychosis in Schizophrenia , 1995, Neuropsychopharmacology.

[30]  N. Hirsch,et al.  Anaesthesia A-Z : an encyclopaedia of principles and practice , 1993 .

[31]  K. Jansen Non-medical use of ketamine. , 1993, BMJ.

[32]  P. White,et al.  Ketamine--its pharmacology and therapeutic uses. , 1982, Anesthesiology.

[33]  D. Reich,et al.  Ketamine: an update on the first twenty-five years of clinical experience , 1989, Canadian journal of anaesthesia = Journal canadien d'anesthesie.

[34]  G. S. Morato,et al.  Lack of the effect of ketamine on some dopaminergic behaviors in rats. , 1986, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[35]  G. Collingridge,et al.  Ketamine blocks an NMDA receptor-mediated component of synaptic transmission in rat hippocampus in a voltage-dependent manner , 1988, Neuroscience Letters.

[36]  D. Lodge,et al.  Ketamine acts as a non-competitive N-methyl-d-aspartate antagonist on frog spinal cord in vitro , 1985, Neuropharmacology.

[37]  W. D. Winters,et al.  Comparison of isomers of ketamine on catalepsy in the rat and electrical activity of the brain and behavior in the cat , 1989, Neuropharmacology.

[38]  A. Waterman,et al.  THE DEVELOPMENT OF TOLERANCE TO KETAMINE IN RATS AND THE SIGNIFICANCE OF HEPATIC METABOLISM , 1978, British journal of pharmacology.