Kristen A. Keefe

Extracellular dopamine in striatum: influence of nerve impulse activity in medial forebrain bundle and local glutamatergic input.

Microdialysis probes were used to measure dopamine in, and to administer glutamate receptor antagonists and agonists to, the striatum of unanesthetized rats. Antagonists used were: kynurenate, 2-amino-5-phosphonovalerate and 6-cyano-7-nitroquinoxaline-2,3-dione. Agonists used were: N-methyl-D-aspartate and kainate. In some rats an additional dialysis probe was implanted in medial forebrain bundle for infusion of tetrodotoxin (10 microM) to block action potential propagation along dopaminergic axons in this pathway. The latter treatment reduced dopamine in striatal dialysate to below detectable levels (less than 0.5 pg). The quantity of dopamine in striatal dialysate was not reduced by the local application of glutamate receptor antagonists. At lower concentrations, the receptor antagonists failed to alter significantly the quantity of dopamine, whereas the highest concentration of each antagonist increased the amount of dopamine in the dialysate. At the highest concentration tested (0.75 mM or 1.0 mM), as well as at a lower concentration (0.1 mM), 2-amino-5-phosphonovalerate and 6-cyano-7-nitroquinoxaline-2,3-dione blocked the dopamine-releasing effects of exogenously applied N-methyl-D-aspartate (1.0 mM) or kainate (0.1 mM), respectively. Thus, concentrations of glutamate receptor antagonists that produced effective pharmacological blockade of the respective receptors had no effect on the basal amount of dopamine in striatal extracellular fluid. Finally, N-methyl-D-aspartate and kainate produced a significant elevation in extracellular dopamine during the infusion of tetrodotoxin into the medial forebrain bundle, indicating that impulse activity in this pathway is not necessary for dopamine release produced by glutamate receptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Stress-induced dopamine release in the neostriatum : evaluation of the role of action potentials in nigrostriatal dopamine neurons or local initiation by endogenous excitatory amino acids

Abstract: It has been hypothesized that excitatory amino acids can initiate dopamine release in neostriatum. We examined whether the increase in extracellular dopamine in neostriatum produced by acute stress reflects presynaptic initiation of dopamine release by endogenous excitatory amino acids. Thirty minutes of intermittent tail‐shock stress significantly elevated extracellular concentrations of dopamine, glutamate, aspartate, and γ‐aminobutyric acid in neostriatum of freely moving rats as measured with in vivo microdialysis. Local infusion of the N‐methyl‐d‐aspartate receptor antagonist 2‐amino‐5‐phosphonovaler‐ate or the non‐N‐methyl‐d‐aspartate receptor antagonist 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione via the dialysis probe did not attenuate the stress‐induced increase in extra cellular dopamine. In fact, the increase was prolonged in rats treated with specific excitatory amino acid receptor antagonists. Infusion of tetrodotoxin into medial forebrain bundle increased extra cellular glutamate and aspartate in neostriatum yet reduced basal dopamine in extra cellular fluid to below the limit of detection of the assay and eliminated the stress‐induced increase in extra cellular dopamine. These findings fail to support the hypothesis that the stress‐induced increase in extra cellular dopamine in neostriatum is initiated locally by excitatory amino acids. Rather, the effects of stress on extra cellular dopamine seem to be determined by impulse propagation in dopamine neurons.

In vivo regulation of extracellular dopamine in the neostriatum: influence of impulse activity and local excitatory amino acids

It has been suggested that dopamine release can be evoked by excitatory amino acids acting on dopaminergic terminals, as well as by the classical process of impulse-evoked exocytosis. We used in vivo microdialysis to examine whether endogenous excitatory amino acids locally evoke dopamine efflux under basal conditions. Infusion of N-methyl-d-aspartate (NMDA) or kainate into the neostriatum increased extracellular dopamine, and this effect was blocked by co-infusion of 2-amino-5-phosphonovalerate (APV) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), respectively. However, neither these antagonists nor kynurenate decreased extracellular dopamine when administered alone. In contrast, infusion of tetrodotoxin into the medial forebrain bundle reduced extracellular dopamine to below the limit of detection of our assay. These and other findings reviewed in this report suggest to us that extracellular dopamine in the neostriatum is not stimulated locally by endogenous excitatory amino acids.

Environmental stress increases extracellular dopamine in striatum of 6-hydroxydopamine-treated rats: in vivo microdialysis studies

Bilateral intraventricular injections of 6-hydroxydopamine depleted dopamine (DA) in striatal tissue of rats by 88%. Tail shock increased DA in striatal extracellular fluid of these rats from 10 to 17 pg/20 microliters as measured by microdialysis, values less than half those seen in normal striatum. The increase was observed even in rats that were akinetic. DA in extracellular fluid after stress was negatively correlated with behavioral performance. Thus, residual nigrostriatal DA neurons are responsive to stress but do not produce normal DA levels in striatal extracellular fluid.