Glutamate Neurotransmission And The Limbic System

Excitatory amino acids represent the main excitatory neurotransmitters within the mammalian central nervous system and exert their effects through the interaction with ionotropic receptors of the N-methyl-d-aspartate (NMDA) and non-NMDA type and metabotropic receptors. In addition, glutamate also stimulates the synthesis of the diffusible messenger nitric oxide (NO). Through activation of NMDA receptors, glutamate promotes the influx of calcium into the postsynaptic neuron. In turn, binding to calmodulin stimulates the activity of nitric oxide synthase (18). Nitric oxide is a gaseous neurotransmitter that acts as a retrograde messenger and affects the release of various neurotransmit-ters through increases in cyclic GMP (18). Therefore, NO acts as an important intracellular effector of excitatory amino acid neurotransmission through NMDA receptors.

The nucleus accumbens is functionally linked to a number of structures within the limbic system and is part of a ventrotegmental-accumbens-pallidal circuit that seems to be critically involved in drug-seeking behavior (19). In addition to the dopamine-containing projections originating from the ventral tegmental area, the nucleus accumbens also receives primary neuronal afferents from allocorti-cal areas such as the amygdaloid complex and the hippocampal formation as well as from the frontal and prelimbic cortexes (20). These fibers use excitatory amino acids as neurotransmitters (21). Ultrustructural studies revealed that, within the nucleus accumbens, these fibers form both presynaptic contact with tyrosine hydroxylase-containing terminals of the axons of A10 neurons and postsynaptic contacts onto medium spiny output neurons of the nucleus accumbens. The latter also receive convergent input from the A10 region (22). In addition, electrophysiological studies suggest that nucleus accumbens neurons are mostly quiescent under normal conditions, and allocortical afferents are thought to play a major role in driving their activity (23,24). Glutamate inputs from the hippocampus appear to be responsible for the induction of a depolarized state of nucleus accumbens neurons from which an action potential is thought to be generated when these neurons are excited by convergent glutamate inputs from the prefrontal cortex (25). Thus, there is substantial anatomical and electrophysio-logical evidence to suggest that excitatory amino acid neurotransmission may modulate the integrated function of the nucleus accumbens, possibly through an interaction with dopamine.

Excitatory amino acid-containing fibers also interconnect other areas of the mesolimbic system. The prefrontal cortex, for example, in addition to sending glutamate fibers to the nucleus accumbens, also provides dense innervation of the ventral tegmental area (26). In contrast, the ventral subiculum of the hippocampus sends a vast contingent of fibers to the nucleus accumbens, but not to the ventral tegmental area (20,22). Finally, the excitatory efferent fibers of the amygdala to the nucleus accumbens originate mainly within the basolateral nucleus, whereas the central nucleus projects to the ventrotegmental area (27,28).

In vitro studies have provided much evidence regarding the modulation of the dopamine system by excitatory amino acids. Electrophysiological evidence indicates that glutamate induces a current-dependent increase of firing of quiescent nucleus accumbens neurons (24). Activation of non-NMDA receptors appear particularly important in this respect and activation of NMDA receptors seem to come into play after neurons have been primed with activation of other receptors (24). This observation has prompted speculation that the stimulation of NMDA receptor function in the nucleus accumbens might gain particular significance during periods of behaviorally relevant neural inputs, probably of limbic origin. Activation of metabotropic receptors within the nucleus accumbens, in contrast, does not appear to modify the activity of nucleus accumbens neurons, but it reduced the excitation induced by glutamate acting at the level of ionotropic receptors (24). Anatomical distribution of metabotropic receptors and the pharmacological profile of ACPD (29,30) suggests that group I/group II metabotropic receptors might be more relevant for these effects playing a potential role of feedback mechanism (24).

The dopamine-releasing activity of excitatory amino acids has been confirmed in freely moving animals with microdialysis, and it has been shown that both NMDA and non-NMDA receptors may play a role (31,32). However, a reduction of extracellular dopamine in the nucleus accumbens following local application of glutamate agonists has also been reported (33). The hippocampus appears to play a major role in the modulation of dopamine function within the ventral striatum. For example, chemical and electrical stimulation of the ventral subiculum of the hippocampus increased dopamine levels in the nucleus accumbens, an effect that appears to be mediated by glutamate receptors within the ventral striatum (34) or, indirectly, via a subiculum-accumbens-ventral tegmental area indirect pathway (35,36). These observations are also in agreement with the findings that activation of both NMDA and non-NMDA receptors within the ventral tegmental area appears to stimulate the firing rate of midbrain dopamine neurons (37,38). Much evidence from various research lines suggests that this phenomenon may be relevant for psychostimulant sensitization (for a review, see ref. 39).

Finally, the increase of extracellular dopamine content in the nucleus accumbens produced by systemic administration of cocaine has been shown to be reduced by local infusion of both the NMDA receptors antagonist AP-5 and the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (40). However, the interaction between dopamine and excitatory amino acids appear to be complex because, in untreated animals, local infusion of NMDA antagonists has been shown to increase dopamine release (41). It is also noteworthy that increasing endogenous extracellular glutamate concentrations through local microinfusion of the selective glutamate reuptake inhibitor transpyrrolidine-2,4-dicarboxylic acid (PDC) produced an increase of dopamine release in the rat striatum (42) and an increase in locomotor activity has been reported after microinfusion of PDC within the core of the nucleus accumbens (43). Investigation using in vivo microdialysis has also shown that activation of dopamine receptors with amphetamine or the direct dopamine agonists SKF 38393 and quinpirole increased the amount of extracellular glutamate within the nucleus accumbens (44) and cocaine and amphetamine appear to preferentially stimulate glutamate release in the nucleus accumbens (45). However, the functional relevance of the increase of extracellular glutamate concentration after administration of psychostimulant drugs awaits further investigation.

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