Dopamine D-1 regulation of caudate neurotensin mRNA in the presence or absence of the nigrostriatal dopamine pathway.

Changes in extrapyramidal dopamine (DA) function significantly alter the activity of striatal neurotensin (NT) systems. Specifically, stimulation of DA D-1 or D-2 receptors increases or decreases striatal NT tissue levels, respectively. In contrast, removal of D-2 receptor basal activity with either an antagonist or lesion of the nigrostriatal DA projection increases striatal NT content. To understand better the significance of these changes in the levels of NT peptide, we determined the effects of treatment with the selective D-1 agonist, SKF 82958, alone or in combination with a lesion of the nigrostriatal DA pathway, on the levels of NT mRNA in various regions of the caudate nucleus. Removal of at least 90% of this DA pathway significantly increased NT mRNA in most, but not all, regions throughout the caudate nucleus. In contrast, four, but not one, administrations of SKF 82958 (2 mg kg-1 dose-1) increased NT mRNA levels in principally middle, but not rostral, caudate regions. Lesioning the nigrostriatal DA pathway enhanced the effects of SKF 82958 so that a lower, single dose (1 mg/kg) of this D-1 agonist also increased NT mRNA levels predominantly in the middle caudate sections. These findings demonstrate that DA D-1 receptors profoundly regulate the striatal expression of NT mRNA in a regionally selective fashion, which appears to be unique from that principally influenced by DA D-2 regulation.

Comparison of the patterns of altered cerebral glucose utilisation produced by competitive and non-competitive NMDA receptor antagonists.

Recent studies indicate that competitive and non-competitive NMDA receptor antagonists can be readily distinguished by their effects on local cerebral glucose utilisation (1CGU). In the present study we compare the effects of the novel NMDA antagonist, (+)-1-methyl-1phenyl-1,2,3,4-tetrahydroisoquinoline (FR115427) on 1CGU, comparing its metabolic profile with that of the non-competitive NMDA receptor antagonist, dizocilpine (MK801) and of the competitive NMDA receptor antagonist CGS19755, using the 2-deoxyglucose metabolic mapping approach. Local cerebral glucose utilisation was measured in 80 anatomically discrete regions of the conscious rat brain using [14C]2-deoxyglucose quantitative autoradiography. Studies were initiated 10 min after the administration of FR115427 (0.1-3 mg/kg i.v.; n = 20), dizocilpine (0.03-0.3 mg/kg; n = 15), CGS19755 (1-30 mg/kg; n = 15) or saline (2 ml/kg; n = 5). Dizocilpine produced characteristic alterations in 1CGU with widespread increases in 1CGU in primary olfactory and limbic areas while reducing 1CGU in somatosensory and motor cortex. FR115427 produced a pattern of altered 1CGU which was broadly similar to that elicited by dizocilpine with increases in 1CGU in the pontine nuclei, presubiculum and hippocampus and reductions in somatosensory and motor cortex and within components of the auditory system. However, FR115427 was approximately 30-fold less potent than dizocilpine in this regard. In limbic structures, the effects of FR115427 were less pronounced than those produced by dizocilpine. Increases in 1CGU of 62-98% were found in retrosplenial, piriform and entorhinal cortex of dizocilpine-treated rats whereas these areas appeared relatively unaffected following FR115427 administration. A comparison of the pattern of metabolic response produced by each of these agents was performed by constructing a hierarchy of regional responsiveness using the f statistic: while focal differences in the metabolic profiles of dizocilpine and FR115427 were evident, a plot of the regional f values for dizocilpine and FR115427 revealed a strong overall relationship between the metabolic responses with a Pearson's product moment correlation of 0.78. In contrast, the correlation between the patterns produced by CGS19755 and that for dizocilpine or FR115427 was poor (r = 0.28 and 0.5 respectively).

Differential distribution of N-acetylaspartylglutamate and N-acetylaspartate immunoreactivities in rat forebrain.

Contradictory immunohistochemical data have been reported on the localization of N-acetylaspartylglutamate in the rat forebrain, using different carbodiimide fixation protocols and antibody purification methods. In one case, N-acetylaspartylglutamate immunoreactivity was observed in apparent interneurons throughout all allocortical and isocortical regions, suggesting possible colocalization with GABA. In another case, strong immunoreactivity was observed in numerous pyramidal cells in neocortex and hippocampus, suggesting colocalization with glutamate or aspartate. Reconciling these disparate findings is crucial to understanding the role of N-acetylaspartylglutamate in nervous system function. Antibodies to N-acetylaspartylglutamate and a structurally related molecule, N-acetylaspartate, were purified in stages, and their cross-reactivities with protein conjugates of N-acetylaspartylglutamate and N-acetylaspartate were monitored at each stage by solid-phase immunoassay. Reduction of the cross-reactivity of the anti-N-acetylaspartylglutamate antibodies of N-acetylaspartate-protein conjugates to about 1% eliminated significant staining of most pyramidal neurons in the rat forebrain. Utilizing highly purified antibodies, the distributions of N-acetylaspartylglutamate and N-acetylaspartate were examined in several major telencephalic and diencephalic regions of the rat, and were found to be distinct. N-acetylaspartylglutamate-immunoreactivity was observed in specific neuronal populations, including many groups thought to use GABA as a neurotransmitter. Among these were the globus pallidus, ventral pallidum, entopeducular nucleus, thalamic reticular nucleus, and scattered non-pyramidal neurons in all layers of isocortex and allocortex. N-acetylaspartate-immunoreactivity was more broadly distributed than N-acetylaspartylglutamate-immunoreactivity in the rat forebrain, appearing strongest in many pyramidal neurons. Although N-acetylaspartate-immunoreactivity was found in most neurons, it exhibited a great range of intensities between different neuronal types.