EFFECTS OF VOLATILE ANESTHETICS, THIOPENTAL, AND KETAMINE ON SPONTANEOUS AND DEPOLARIZATION-EVOKED DOPAMINE RELEASE FROM STRIATAL SYNAPTOSOMES IN THE RAT

Background: Recent experimental data indicate that anesthesia is often associated with significant changes in brain concentrations of dopami ne (DA), an inhibitory neurotransmitter located in restricted, but fun ctionally important, areas such as the striatum. Whether the presynapt ic DA nerve endings represent potential targets for anesthetics remain s unknown. Therefore, the current study was designed to investigate th e effects of volatile anesthetics, thiopental, and ketamine on both sp ontaneous and depolarization-evoked DA release from striatal synaptoso mes in the rat. Methods: Purified striatal synaptosomes preloaded with H-3-DA were superfused with artificial cerebrospinal fluid (1 ml/ min ). Radioactivity obtained from 1-ml fractions was measured over 15 min ; first, in the absence of any treatment (spontaneous release), then i n either the absence (time-dependent control) or presence (evoked-rele ase) of anesthetic and pharmacologic agents, and finally, again, witho ut any pharmacologic stimulation. The compounds tested were: potassium chloride (15 and 50 mM), glutamate, N-methyl-D-aspartate (NMDA) and k ainate (10(-4) hr and 10(-3) M), MK-801 (10(-4) M, an antagonist of NM DA receptors) and 6-cyano-7-nitroquinoxaline-2,3-dione (10(-4) M, an a ntagonist of D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate [AMPA] receptors), halothane, enflurane, isoflurane (1, 1.5, and 2 mi nimum alveolar concentrations), ketamine (10(-5) and 10(-4) M), and th iopental (10(-5) and 10(-4) M). Results: Volatile anesthetics induced a significant, concentration-related increase in spontaneous H-3-DA re lease, but thiopental and ketamine were ineffective. The effect of 2 m inimum alveolar concentration enflurane (but not halothane or isoflura ne) was significantly enhanced when a Mg2+-free cerebrospinal fluid wa s used, and was reduced by MK-801 application. Nomifensine (10(-5) nr, a blocker of monoamine transporter) did not affect the H-3-DA release evoked by volatile anesthetics. Glutamate, kainate, NMDA, and potassi um chloride induced a significant, dose-related, Ca2+-dependent H-3-DA release. Halothane and isoflurane produced a significant and concentr ation-related decrease in the H-3-DA peaks evoked by glutamine, kainat e, and NMDA; however, enflurane significantly attenuated the glutamate - and kainate-mediated release, but enhanced that evoked by NMDA. Thio pental and ketamine (10(-4), but not 10(-5) M) significantly reduced t he glutamate- and NMDA-stimulated release, but only thiopental decreas ed the kainate-induced effect. Furthermore, the effect of potassium ch loride (15 nM) was significantly reduced by all anesthetics examined, whereas that of potassium chloride (50 mM) was unaffected. Conclusion: The authors conclude that: (1) volatile anesthetics, thiopental, and ketamine exert significant changes in both spontaneous and depolarizat ion-evoked 3H-DA release in the rat striatum; (2) enflurane uniquely e nhances NMDA-receptor mediated dopamine release; and (3) the results o btained from these receptor-mediated effects (AMPA and NMDA) may apply to postsynaptic, as well as presynaptic, glutamate receptors.