Physiopathological aspects of NMDA transmission in the basal ganglia : in vitro and in vivo release studies

Abstract

N-methyl-D-aspartic acid (NMDA) is an excitatory amino acid selectively acting on a subclass of glutamate receptors (the NMDA ionotropic receptor) which has been involved in many of the physiological and pathological effects of glutamate in the CNS. The basal ganglia are particularly enriched in NMDA receptors and NMDA receptor activation in the basal ganglia has been involved in the expression of motor behaviour.

The aim of my thesis was to investigate the neurochemical effects produced by NMDA receptor stimulation in a specific region of the basal ganglia (i.e. the striatum) in order to shed light on the mechanisms by which NMDA is involved in motor control.

The effects of intrastriatal perfusion with NMDA on local DA, GABA and GLU release were first evaluated in the halothane anaesthetized rat by means of microdialysis technique (paper I). In this study both basal and NMDA-stimulated neurotransmitter release was characterized in terms of TTX- and Ca++-sensitivity as well as sensitivity to NMDA antagonists. This paper demonstrated that striatal NMDA receptor activation increases striatal DA, GABA and GLU release via different mechanisms.

A follow up study was then undertaken to test the sensitivity of the NMDA effects to D1 and D2 dopamine receptor antagonists (paper II). The major finding of this study was that D1 and D2 receptor blockade inhibited and potentiated NMDA-evoked GABA release respectively. This finding suggested the possibility of an interaction between DA and NMDA receptors in the modulation of the striatonigral pathways. For this reason, dual probe microdialysis technique was used in the awake freely moving rat to test the effects of intrastriatal NMDA perfusion on nigral GABA and GLU release.

In paper III, the TTX- and Ca++-sensitivity of basal DA, GABA and GLU release from the striatum and GABA release from the substantia nigra pars reticulate (SNr) was analyzed. In addition, the reciprocal modulation between these two areas was studied. A correlation was made between contralateral rotation induced by intranigral perfusion with TTX and changes in striatal and nigral neurotransmitter release.

The effects of intrastriatal perfusion with NMDA on striatal DA, GABA and GLU as well as SNr GABA release were subsequently analyzed (paper IV). This study has led to the important finding that, at variance to that observed in the anaesthetized rat, NMDA receptor activation inhibited striatal DA release, possibly via the activation of the striatonigral- nigrostriatal loop. Striatal NMDA receptor activation was also found to subserve motor activation induced by intranigral TTX.

In a follow up study (paper V), it was shown that nigral GLU release was modulated by changes in striatal neurotransmission and, particularly, that striatal NMDA receptor activation resulted in an increased nigral GLU release, consistent with an activation of the indirect striatonigral pathway.

In paper VI, the effects of NMDA and non-NMDA receptor activation on ACh release from striatal slices and synaptosomes in vitro! were characterized. An important finding of this study was the demonstration of the presence of both NMDA and non-NMDA ionotropic receptors facilitating ACh release on the presynaptic cholinergic terminals.

In paper VII, the response of the cholinergic neurons to NMDA was evaluated in the 60H-dopamine model of Parkinson's disease. An enhanced responsitivity of both pre- and postsynaptic NMDA receptors was observed in the DA-depleted striatum, consistent with an altered glutamatergic regulation of cholinergic transmission in course of Parkinson's disease.

In summary, our data show that NMDA receptor activation in the striatum regulates intrastriatal transmission via multiple mechanisms and also modulates striatal output via the striatonigral direct and indirect pathways. Striatal NMDA receptors may be involved in the expression of motor behaviour and pharmacological properties of NMDA receptors regulating ACh release appear to be altered in course of Parkinson's disease. These data support the general notion that striatal NMDA receptors represent a target for pharmacological management of motor disorders.