The developmental pattern of L-3Hglutamate binding to rat brain in the presence of saturating concentrations of unlabeled N-methyl-D-aspartate (NMDA), kainate (KA) and quisqualate (QQA) was examined ...in an autoradiographic assay. The unique glutamate binding site defined by this assay displayed four distinct, regionally specific patterns of development. (1) In reticular nucleus of thalamus there was an initial very high level of binding at postnatal day 1 (PND1) followed by a progressive 80% decline in binding during maturation. (2) In entorhinal cortex, a progressive 500-1100% increase in binding was seen during development. (3) In ventral posterior medial nucleus of thalamus, there was an initial transient 200-300% increase in binding, peaking at PND10, followed by a steady decline in binding. (4) In frontal cortex, binding remained relatively stable throughout development. At all stages of development, the distribution of these recognition sites was different from NMDA, KA or QQA receptors. The function of this glutamate binding site remains to be determined, but the distinct regional and temporal patterns of binding suggest that it may be important in normal development of the central nervous system.
The binding of D-3Haspartate to sections of rat brain was examined in an autoradiographic assay. Binding was entirely dependent on the presence of sodium ions, but not chloride ions, and was optimal ...at 2 degrees C. D-Aspartate bound rapidly, reached equilibrium within 20 min and remained stable for 45 min. The rate of dissociation was relatively rapid with a t1/2 of 56 s, but was not as fast as anticipated, perhaps because of some sequestration of ligand. Binding had a Kd of 6.8 +/- 1.2 microM and a Bmax of 49.4 +/- 8.6 pmol/mg protein. The high Bmax value may further indicate some sequestration of D-aspartate. L-Glutamate, unlabeled D-aspartate, and D,L-threo-hydroxyaspartate, a potent inhibitor of synaptosomal uptake, each competed for D-3Haspartate binding with IC50s of 7.0 +/- 4.3 microM, 5.4 +/- 1.5 microM, and 2.5 +/- 1.0 microM, respectively. N-methyl-D-aspartate (NMDA), quisqualate, and kainate had no affinity for this site. The regional distribution of D-aspartate binding sites was unique and did not conform to the distribution of neuronal uptake sites described by others. Striatal D-aspartate binding was unaffected by unilateral decortication or striatal quinolinic acid lesions. In contrast, binding to NMDA, quisqualate, and kainate receptors was reduced by 80-90% by quinolinate lesions of the striatum. The results of D-aspartate binding after lesions strongly suggest that this site is not associated with either lesioned glutamatergic afferents or intrinsic neurons of the striatum; it may be associated with glia.
This chapter provides general information about rotenone and reviews the body of work in which rotenone has been used to model Parkinson's disease (PD). Rotenone occurs naturally in roots and stems ...of several tropical and subtropical plant species especially those belonging to the genus Lonchocarpus or Derris. Rotenone is highly lipophilic and thus readily gains access to all organs including the brain. After a single intravenous injection, rotenone reaches maximal concentration in the CNS within 15 min and decays to about half of this level in approximately 100 min. Its brain distribution is heterogeneous paralleling regional differences in oxidative metabolism. Rotenone also freely crosses all cellular membranes and can accumulate in subcellular organelles such as mitochondria. The rotenone model is crucial for studying the underlying mechanisms involved in the progression and evolution of PD pathogenesis that appears to be a multisystems disorder affecting the gastrointestinal tract and various brain regions including higherorder cognitive areas. However, this model also bears some specific technical challenges and also has some interesting shortcomings. The chapter discusses in detail different aspects of the rotenone model.
Human immunodeficiency virus infection is frequently complicated by a syndrome of central nervous system dysfunction known as the acquired immunodeficiency syndrome dementia complex (ADC). The ADC is ...characterized by abnormalities in cognition, motor performance, and behavior, and it produces serious morbidity in a significant number of patients with acquired immunodeficiency syndrome. The pathogenesis of ADC is unclear, but appears to be caused by the human immunodeficiency virus itself, rather than by a secondary opportunistic process. Herein, we review the data regarding the pathogenesis of ADC and hypothesize a mechanism involving excitotoxicity and dopaminergic dysfunction. N-methyl-D-aspartate receptor antagonists may be of therapeutic benefit, as these agents may both limit glutamate-mediated neuronal dysfunction and improve dopaminergic neuronal function.
This chapter discusses various aspects of excitotoxicity and neurodegenerative diseases. Metabolic impairment and excitotoxicity are involved in the pathogenesis of neurodegenerative diseases. These ...two distinct mechanisms may be related by the unique properties of the N-methyl-D-aspartate (NMDA) receptor. At the normal resting potential of a neuron, the NMDA receptor calcium channel is blocked by extracellular magnesium. It is found that the gating is voltage-dependent, and if the neuron becomes depolarized for any reason, the magnesium blockade is lifted, the receptor is activated, and calcium ions can flow through the channel. The ability to maintain the membrane potential is dependent on adequate functioning of membrane ion pumps, particularly Na+/K+ ATPase. These pumps are highly dependent on neuronal production of ATP to maintain their consistent high level of activity. The proposed link between bioenergetics and NMDA receptor-mediated excitotoxicity permits several modifications of the excitotoxic hypothesis of neurodegenerative diseases. The first in vivo evidence supporting the “weak” excitotoxic hypothesis was generated from experiments involving amino-oxyacetic acid (AOAA), a nonspecific inhibitor of transaminases. The findings implicate weak excitotoxicity not only in the MPTP model of Parkinsonism but also in the pathogenesis of idiopathic Parkinson's disease (PD).
There is no known glutamatergic innervation of globus pallidus (GP) in adult mammals, but we report that during postnatal development of the GP there are large, transient increases in both ...presynaptic high-affinity glutamate uptake and postsynaptic Na+-independent glutamate receptor binding. These glutamatergic markers increase rapidly in rat GP after birth and then decrease to adult levels over a period of weeks. A similar developmental pattern of pallidal glutamate binding was found in human brains. In contrast, binding in rat caudate-putamen (CPu) increases after birth, reaches a peak, and remains constant into adulthood. The results suggest that a glutamatergic pathway transiently innervates the globus pallidus during the perinatal period. Because glutamate is an excitotoxin, this pathway may account, in part, for the basal ganglia damage seen in some forms of cerebral palsy after perinatal hypoxia/ischemia.
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