Regulation by glutamate- and adenosine-receptors of dopamine and acetylcholine release from rat striatal slices

The striatum, which is critically involved in sensory motor integration, receives an excitatory glutamatergic input from the cerebral cortex and the thalamus. The effects of the glutamatergic stimulation are modulated by dopamine (DA) released from a prominent dopaminergic input, acetylcholine (ACh) released from cholinergic interneurons and by the ubiquitous neuromodulator adenosine. The aim of present study was to investigate the roles of glutamate- and adenosine-receptors in regulating release of DA and ACh in the striatum. Agonists at ionotropic glutamate receptors, of both NMDA and non-NMDA types, induced DA and ACh release. The largest release was caused by NMDA receptors sensitive to Mg2+ and MK-801. Of the non-NMDA receptors, kainate receptors may be more important in causing release of ACh, and AMPA receptors in releasing DA.

Three different NMDA receptor antagonists (kynureinate, AP-5 and MK-801) all caused, in the absence but not presence of Mg2+, a concentration-dependent decrease in electrically evoked release of DA and ACh. By contrast, CNQX (an antagonist at non-NMDA receptors) significantly decreased the evoked release of these two transmitters in the presence, but not in the absence of Mg2+. In addition, transmitter release evoked by the potassium channel blocker 4-AP is at least partly dependent on endogenous glutamate acting on both NMDA (for DA) and non-NMDA receptors (for DA and ACh). Thus, both NMDA and non-NMDA receptors regulating transmitter release are activated also by endogenous glutamate.

Activation of adenosine Al receptors produced a concentration-dependent inhibition of electrically evoked DA and ACh release. The adenosine A2A receptor-selective agonist CGS 21680 never caused any stimulation of DA and ACh release from the striatum. On the other hand, ACh release from the hippocampus was stimulated by agonists at adenosine A2A receptors and this was especially obvious after blockade of adenosine Al receptors. These results show that only inhibitory Al are receptors present on dopaminergic terminals and cholinergic neurons m the striatum. Whereas CGS 21680 left the reduction of DA release by quinpirole unaffected, it did reduce the ability of this D2 receptor agonist to decrease ACh release. Since CGS 21680 modulated ACh release both in the absence and in the presence of DPCPX, the receptor involved is probably an A2A receptor. This provides evidence that A2A and D2 receptors interact at the level of neurotransmitter release.

Mild hypoxia caused a significant increase of the evoked release of endogenous adenosine, hypoxanthine and inosine, and a significant decrease of the evoked release of DA and ACh. The addition of DPCPX antagonized the hypoxia-induced inhibition of transmitter release. Thus, reduction of the oxygen supply to striatal slices results in an increased release of endogenous adenosine that, acting on adenosine A1 receptors, decreases the evoked release of DA and ACh. Hypoglycemia, on the other hand, increased the basal and evoked release of DA and ACh as well endogenous adenosine. This stimulation of transmitter release was slightly enhanced in the presence of DPCPX and markedly inhibited in the presence of MK-801. The results suggest that substrate lack induces release both of glutamate, which by actions on presynaptic NMDA receptors causes release of DA, and of adenosine, which via A1 receptors reduces the electrically evoked release of both DA and ACh. Thus adenosine may be able to limit the alterations in transmitter release induced by minor alterations in energy metabolism, but not those induced by major insults.

In summary, the present results confirm that in the striatum there are stimulatory glutamate receptors of both the NMDA and non-NMDA type and inhibitory adenosine Al receptors that regulate DA and ACh release in an antagonistic manner. The results also indicate that these receptors are important under both physiological and pathophysiological conditions.