MERCADO BURSÁTIL O DE CAPITALES

Most types of central mammalian neurones can be depolarised by glutamate, and EAAs mediate neurotransmission at some 50% of central synapses (Curtis and Watkins, 1965; Johnston, 1976) and given the wide distribution of EAA-containing neurons throughout the CNS, it is not surprising that EAA transmitters have been, and continue to be, implicated in the control of a widening range of neural systems affecting almost every aspect of CNS function. From processing of sensory information, through learning and memory based on that information, to motor control of the response, EAA-mediated synaptic transmission is almost certainly involved at every stage.

1.8.1. Long term potentiation

Long-term potentiation (LTP) is the sustained facilitation of a neural pathway induced by tetanic stimulation of the afferent fibres (Bliss and Gardner-Medwin, 1973). In anesthetised rabbits, this amplification of synaptic events could be seen for up to 10 hours following induction and in chronically implanted animals, synaptic activity could remain enhanced for weeks. Additionally, LTP is specific to the synapses activated during tetany and there is a threshold of stimulus intensity which must be reached for

activating a sufficient number of afferent fibres, before potentiation can occur (Andersen et al., 1980). The cooperative and associative properties of LTP have been suggested to represent an underlying mechanism for learning and memory (Collingridge and Bliss, 1987). Induction of LTP in most hippocampal pathways is dependent upon

NMDA receptor activation and this is demonstrated by the ability of AP5 to reversibly block LTP induction in the major excitatory pathways (Harris et al, 1984; Harris and Cotman, 1986; Errington et al., 1987). This feature was also displayed by the non­ competitive NMDA antagonists PCP, ketamine, dizocilpine and 7-chlorokynurenic acid (Stringer et al., 1983; Coan and Collingridge, 1987b), whereas glycine has been reported to synergistically potentiate LTP in the hippocampus (Tauck and Ashbeck, 1990). For NMDA receptor channels to be opened, postsynaptic cells must be sufficiently depolarised to alleviate the voltage-dependent blockade by Mg++. This explains the dependence of LTP induction on high-fi*equency stimulation (Collingridge, 1985). Maintenance of LTP, however, does not require perpetual activation of NMDA receptors since neither unpotentiated nor potentiated EPSPs are significantly affected by APS (Collingridge et al., 1983). Following the demonstration that LTP in CAl neurons displays a delayed increase in sensitivity to AMPA agonists, it appears that full development of LTP is a slow postsynaptic process requiring activation of NMDA receptors (and kinase activity), possibly to produce some functional modification of AMPA receptors (Davies et al, 1989). It has also been demonstrated that, in LTP,

postsynaptic induction leads to enhanced presynaptic glutamate release (Malgaroli and Tsien, 1992).

1.8.2. Production of nitric oxide

Receptor activation by kainate or NMDA can lead to the production and release of nitric oxide (NO), which stimulates soluble guanylate cyclase to produce cGMP (Bredt

and Snyder, 1990; Garthwaite et al., 1989; Kiedrowski et al, 1992). NO was previously known as endothelium-derived relaxing factor which mediates the relaxation of blood vessels and the cytotoxic actions of macrophages (Moncada et al, 1989; Bredt et al,

1990). At low concentrations, nitric oxide appears to act as a diffusible transmitter substance and may also behave as a retrogade messenger released by and acting on the same cell (Dawson et al, 1991). However, since NO and has a high rate of diffusion across the cell membrane, it is uncertain whether the stimulation of guanylate cyclase by NO occurs in the same cells where it is produced, or in a different cellular target. In cerebellar and hippocampal slices, as well as in cortical cultures, NMDA stimulates the activity of NO synthase, since the physiological stimulus for NO synthesis is a rise in cytosolic Ca+^ levels (Bredt and Snyder, 1990; East and Garthwaite, 1991). This enzyme, which converts arginine to citrulline plus NO, depends on calmodulin and Ca"*^ and is expressed particularly in the cerebellum, olfactory bulb and dentate gyrus (Bredt et al, 1990). The NMDA receptor signal causes a protein kinase cascade initiated by cGMP, which could also be a mechanism for alterations to the phenotype of neurones, as occurs in cell maturation. L-N-monomethyl arginine blocks the synthesis of nitric oxide from arginine and inhibits the elevation of cGMP

produced in response to NMDA activation (Gartwaite et al, 1989). Inhibitors of NO synthase inhibit LTP whereas sodium nitroprusside releases NO and facilitates synaptic activity (Bo^Kme et al, 1991). A short-life local NO signal may also be involved in co­

ordinating changes to cerebral blood flow, synapses and transmitter release (Edelman and Gaily, 1992). Studies using NO synthase (NOS) inhibitors have provided initial evidence that NO is involved in the regulation of CBF. While there is agreement on the

participation of NO in the maintenance of resting CBF, there are still disagreements on

the role of NO in other vascular responses of the cerebral circulation (ladecola et al., 1994). Evidence has been presented favouring both a beneficial and a detrimental effect of NO in focal ischaemia (Schmidt et al., 1992). A redox-based mechanism for the

neuroprotective and neurodestructive effects of NO and related nitroso compounds has been suggested (Lipton et al., 1993).

1.8.3. Alteration of cell proteins

EAA agonists rapidly and specifically increase levels of mRNA for neurotrophic factors and nerve growth factor (NGF) in rat hippocampus in vivo and in vitro, possibly linked to physical neuronal changes during LTP (Zafra et al, 1991). NMDA receptor activation in cultured cerebellar granule cells is followed by increased expression of mRNA for the proto-oncogene c-fos (Szekely et al, 1989). Several other examples where EAA receptors are activated also showed induction of c-fos expression in brain tissue: seizures, cerebral ischaemia and administration of kainate, NMDA or glutamate (Dragunow and Robertson, 1987; Popovici et al, 1988; Szekely et al, 1989). Altered transcription of functional or structural genes follows c-fos induction, in such a way that transitory second messenger signals are converted to long-term cellular changes (Morgan and Curran, 1991).

In additon to cellular maturation, communication between neurones and glia, LTP and

learning, EAA receptors seem to be involved in the perception of pain, sight, smell, hearing and in the tonic and reflex control of the cardiovascular system. Although EAA

receptors participate widely in the normal function of the mammalian CNS, they also contribute to various pathological states.

1.9. RELEVANCE OF EAA RECEPTORS IN PATHOLOGICAL