Abstract
In this quantitative neurochemical study, we investigated age-related changes in the GABAergic, glutamatergic, and cholinergic neurotransmitter systems in rats and rhesus monkeys. Sixteen young (5 months) and 20 aged (24 months) rats and seven “young” (4–9 years), six “adult” (20–25 years), and five “aged” (29–34 years) monkeys were studied. NMDA-displaceable L-[3H]glutamate binding was significantly decreased in many neocortical and subcortical regions examined in aged rats and monkeys. The levels of choline acetyltransferase (CHAT) activity and [3H]muscimol binding were unchanged in aged animals.
Keywords: Acetylcholine, Glutamate, NMDA, GABA, Receptors, Aging, Rats, Monkeys
INTRODUCTION
Glutamate and gamma-aminobutyric acid (GABA) are major excitatory and inhibitory neurotransmitters, respectively, in the central nervous system, L-Glutamate is the principal neurotransmitter of the corticocortical associational pathways, and several hippocampal pathways, including the entorhinal, intrahippocampal, and hippocampal efferent pathways (16,35). N-methyl-D-aspartate (NMDA) selectively stimulates one class of glutamate receptors that mediates excitatory synaptic transmission within these pathways (61). NMDA receptors may play a critical role in many neurophysiological processes that underlie neuronal plasticity, long-term potentiation, and learning and memory (15, 29, 39, 42).
GABA is a neurotransmitter in neurons of many regions of brain, including a population of intrinsic neocortical interneurons (31). Most neocortical GABA is located within intrinsic interneurons where it is frequently colocalized with specific neuropeptides (36), although a small amount of GABA may arise from subcortical neurons (23, 24, 58, 60). GABAergic neurons regulate the activity of central noradrenergic, serotonergic, dopaminergic and acetylcholinergic neurons (37, 38, 56, 62, 68) and therefore may influence many different cognitive processes and behaviors. The GABA-A receptor subtype is a major site for the inhibitory activities of GABA; this receptor is present on the majority of cerebral neurons in mammals (3) and is the site of action for the benzodiazepines and barbiturates (3,12).
In aged rats, as compared to young controls, the concentration of glutamate in the brain (30,57), high affinity glutamate uptake in the striatum (52) and cortex (66), and the conversion of radioactively labeled glucose into glutamate (57) were decreased. In contrast, the total number of [3H]glutamate binding sites was increased in the brains of aged rats (7) and monkeys (65). The present study was designed to further investigate the nature of these changes by examination of the specific NMDA-sensitive glutamate binding site.
Evidence for age-related changes in GABAergic systems is contradictory. In aging rats, the concentration of GABA was either slightly increased (30) or unchanged, the number of GABA-A receptors was unchanged (12, 26, 40, 45), and the activity of glutamic acid decarboxylase (GAD), the synthetic enzyme for GABA, was either unchanged (32) or decreased (33). In aging humans, the number of GABA receptors increased, the density of GABAergic terminals decreased, the clinical response to benzodiazepines was enhanced (2,21), and GAD activity was either decreased in selected regions (43,44) or unchanged (10).
The level of choline acetyltransferase (CHAT) activity, a specific biochemical marker for cholinergic neurons, was unchanged throughout the neocortex and hippocampus in aged rats (19,22) and decreased only in the frontal pole and motor cortex of aged monkeys (65). The cholinergic cells in the basal forebrain that project to these cortical regions may decrease in size and number with aging in rats (22); measures of neuronal size have not been reported in aged humans, but the number of cells in the nucleus basalis of Meynert was not changed (14). The level of ChAT activity is usually unchanged in the brains of healthy elderly humans (5). Experimental destruction of basal forebrain cholinergic cells in rats and monkeys produces memory deficits similar to those associated with normal aging and Alzheimer’s disease (AD) (1, 34, 53, 54, 64).
In AD, the amount of glutamate and GABA, the number of glutamate terminals (17,28), and various biochemical markers of cholinergic function (18) are decreased in many cortical and subcortical brain regions. The decline in cholinergic function in AD correlates somewhat with the degeneration of acetylcholine-containing cells in the basal forebrain, the density of neuropathological changes in the cortex and hippocampus, and the degree of dementia (9,64).
An investigation of age-associated changes in glutamatergic and GABAergic systems in nonhuman primates would provide valuable information that cannot be reliably obtained from aged humans. In humans, extensive postmortem delays and antemortem treatments with various pharmacotherapies can significantly alter many neurochemical markers. The present study investigated ChAT activity, as a measure of the integrity of cholinergic presynaptic terminals, and NMDA-type glutamate and bicuculline-sensitive GABA-A binding in the brains of young and aged rats and monkeys. If neurons giving rise to long corticocortical pathways are most vulnerable to aging, then there should be a decline in glutamatergic, but not GABAergic, markers in the neocortex of aged animals.
METHOD
Subjects.
The subjects were 16 young (5 months) and 20 aged (24 months) male F344 rats. Each rat was housed in a metal hanging cage and maintained on a 16:8 h light/dark cycle with lights on at 07:00 h.
Eighteen rhesus monkeys (Macaca mulatta) were studied, including seven “young” (4–9 years), six “adult” (20–25 years), and five “aged” monkeys (29–34 years). All of the young and adult monkeys, and two of the aged monkeys, had known birthdates. The ages of the other two aged monkeys were minimum estimates based on their years in captivity and their sexual maturity when captured. Because rhesus monkeys reach sexual maturity between 3–4 years of age (3–4 kg body weight), animals weighing more than 3–4 kg, or which were sexually mature at capture, were assumed to be at least 3 years of age.
Tissue Preparation.
Each rat was sacrificed by decapitation (between 09:00 and 11:00 h) and the brain was quickly removed and dissected on ice. Five areas were sampled from each rat brain, including the anterior (sensory-motor) and posterior (parietal-occipital) cerebral cortex, the entire hippocampus, caudate nucleus and cerebellum.
Each monkey was restrained with ketamine, euthanized with a lethal dose of sodium pentobarbital, and then perfused transcardially for 3–5 minutes with cold (4°C) isotonic saline. The brain was quickly blocked stereotaxically in a cold room (4°C) and removed; the blocks were frozen on dry ice and stored at −80°C. Samples of specific regions were later taken from the frozen blocks at −20°C and then returned to −80°C until assayed. Each monkey had a complete autopsy after tissues were taken for analysis. No significant pathological changes, e.g., brain tumors, cerebrovascular or metabolic diseases, were found that might affect the interpretation of the neurochemical data.
Tissues from all rats and monkeys were processed identically. Each sample was homogenized in 0.32 M sucrose and stored at −80°C until assayed. Repeated freeze-thawing of the tissues does not inactivate, and may improve, the NMDA-sensitive L-[3H]glutamate (50) and [3H]muscimol (49) binding. For these binding assays, the membranes were extensively washed in order to remove any endogenous ligands present in the tissue. In order to perform all three biochemical analyses on each small tissue sample, only single-point determinations were made for the two receptor sites. Therefore, changes in binding could reflect either a change in the number and/or affinity of the receptors. Proteins were measured by standard methods (41).
GABA Receptor Binding Studies.
[3H]Muscimol binding to the bicuculline-sensitive GABA-A binding site was performed according to the method of Williams and Risley (67). The incubation was conducted in a sodium-free medium in order to inactivate high-affinity GABA uptake sites. Membrane preparations were incubated in 50 mM Tris-citrate buffer (pH 7.1) with [3H]muscimol (2 nM) in the presence or absence of GABA (10 μM) to define nonspecific binding.
NMDA Receptor Binding Studies.
NMDA-displaceable L-[3H]glutamate binding sites were defined according to a modified method of Monahan and Michel (46). These sites are probably associated with postsynaptic, Na+-independent, NMDA-type glutamate binding sites (8,46). The tissue preparation has been described previously (63). Membrane preparations were incubated in 50 mM Tris-acetate buffer (pH 7.4) with L-[3H]-glutamate (10 nM) in the presence or absence of NMDA (0.5 mM) to define nonspecific binding.
ChAT Activity.
A 40-μl sucrose aliquot was combined with 10 μl of a solution containing 2% Triton X-100 and 50 mM EDTA (pH 7.4). ChAT activity was determined (25) using [14C]acetyl Coenzyme-A.
RESULTS
NMDA-displaceable L-[3H]glutamate binding was decreased in many brain regions in aged rats, and particularly in the frontal and temporal lobes of the aged monkeys (see Fig. 1 and Table 1). NMDA binding tended to increase, but not significantly, between ages 4–25 years; in the middle frontal gyrus and superior temporal gyrus the decline in NMDA binding sites was only significant as compared to these elevated levels. [3H]Muscimol binding and the level of ChAT activity in rats and monkeys did not change with age (see Fig. 1 and Tables 2 and 3).
Figure 1.
The number of NMDA-displaceable L-[3H]glutamate and [3H]muscimol binding sites, and the level of ChAT activity in five brain regions of rats. Each value represents the mean ± S.E.M. of 16 young (5 months) or 20 aged (24 months) Fisher 344 rats. *Indicates a significant difference, p<0.05, as compared to levels in young rats. (x10) indicates that the unit of measurement for this region should be multiplied by 10.
Ant.C, sensory-motor cortex; Post.Ct, parietal-occipital cortex; Hippo, hippocampus; Cerebel, cerebellum; Caud, caudate nucleus.
TABLE 1.
NMDA-DISPLACEABLE L-[3H]GLUTAMATE BINDING SITES§ IN MONKEY BRAIN
| Brain Region | 4–9 Years | 20–25 Years | 29–34 Years |
|---|---|---|---|
| Gyrus Rectus | 211.5 ± 26.9 | 269.2 ± 33.9 | 131.4 ± 8.5* |
| Dorsal Fr. Pole | 180.1 ± 37.6 | 306.2 ± 57.4 | 153.8 ± 35.8 |
| Ant. Sup. Cing. Gyr. | 206.5 ± 56.8 | 260.2 ± 63.2 | 122.3 ±22.7 |
| Superior Fr. Gyr. | 162.4 ± 19.9 | 257.9 ± 33.8 | 138.9 ± 33.7* |
| Middle Ft. Gyr. | 168.1 ± 12.0 | 205.9 ± 51.1 | 61.1 ± 15.5++ |
| Inf. Fr. Gyr. | 139.1 ± 22.9 | 324.3 ± 39.1 | 80.6 ± 9.1* |
| Medial Orbital Gyr. | 121.1 ± 21.8 | 368.4 ± 63.1 | 51.6 ± 6.6+ |
| Ant. Inf. Cing. Gyr. | 189.1 ± 58.0 | 150.6 ± 59.0 | 48.3 ± 21.3 |
| Precentral Gyr. | 155.4 ± 22.3 | 187.9 ± 37.6 | 128.9 ± 41.6 |
| Postcentral Gyr. | 124.8 ± 26.7 | 230.9 ± 15.4 | 90.3 ± 18.8+ |
| Inf. Parietal Lobule | 126.1 ± 38.6 | 183.4 ± 31.0 | 93.2 ± 26.8 |
| Sup. Temporal Gyr. | 206.0 ± 48.2 | 325.6 ± 67.0 | 112.1 ± 17.7++ |
| Middle Temporal Gyr. | 221.5 ± 31.2 | 276.5 ± 31.8 | 146.1 ± 32.5* |
| Parahippocampal Gyr. | 212.7 ± 74.7 | 284.6 ± 44.0 | 68.7 ± 8.6* |
| Hippocampus | 146.7 ± 32.2 | 436.9 ± 39.7 | 70.3 ± 20.8+ |
| Dorsal Occipital Pole | 175.4 ± 30.1 | 338.5 ± 47.7 | 167.7 ± 30.2+ |
p<0.05,
p<0.01 by ANOVA.
p<0.05 vs. “Adult” levels, by t-test. Each value represents the mean ± S.E.M. of seven young (4–9 years), six adult (20–25 years), and five aged (29–34 years) rhesus monkeys.
fmol/mg protein.
TABLE 2.
ChAT ACTIVITY* IN MONKEY BRAIN
| Brain Region | 4–9 Years | 20–25 Years | 29–34 Years |
|---|---|---|---|
| Gyrus Rectus | 8.71 ± 0.84 | 10.7 ± 0.7 | 7.61 ± 0.42 |
| Dorsal Fr. Pole | 8.89 ± 1.10 | 8.08 ± 0.52 | 8.48 ± 1.18 |
| Ant. Sup. Cing. Gyr. | 12.2 ± 2.2 | 17.2 ± 0.6 | 11.0 ± 0.7 |
| Superior Fr. Gyr. | 7.64 ± 1.51 | 10.9 ± 0.4 | 9.13 ± 2.19 |
| Middle Ft. Gyr. | 10.7 ± 1.9 | 11.8 ± 0.7 | 7.73 ± 1.32 |
| Inf. Fr. Gyr. | 9.60 ± 1.50 | 12.9 ± 1.7 | 7.26 ± 0.84 |
| Medial Orbital Gyr. | 11.6 ± 1.8 | 13.6 ± 1.1 | 14.1 ± 2.3 |
| Ant. Inf. Cing. Gyr. | 14.4 ± 2.6 | 14.9 ± 2.8 | 13.9 ± 1.4 |
| Caudate Nuc., Head | 112.8 ± 11.5 | 140.1 ± 43.1 | 76.2 ± 12.2 |
| Rostral Putamen | 141.5 ± 24.5 | 232.9 ± 85.3 | 150.1 ± 26.1 |
| Precentral Gyr. | 11.7 ± 1.4 | 13.5 ± 1.4 | 8.45 ± 0.49 |
| Postcentral Gyr. | 8.27 ± 0.86 | 10.8 ± 0.6 | 7.87 ± 0.91 |
| Inf. Parietal Lobule | 9.26 ± 1.42 | 11.5 ± 0.9 | 8.69 ± 0.67 |
| Sup. Temporal Gyr. | 10.3 ± 0.6 | 9.04 ± 0.59 | 9.01 ± 1.35 |
| Middle Temporal Gyr. | 7.98 ± 0.71 | 6.70 ± 0.26 | 6.89 ± 0.52 |
| Parahippocampal Gyr. | 13.9 ± 1.6 | 12.7 ± 2.0 | 12.8 ± 3.4 |
| Hippocampus | 20.9 ± 1.9 | 20.1 ± 1.7 | 20.7 ± 4.2 |
| Dorsal Occipital Pole | 5.26 ± 0.79 | 6.01 ± 0.50 | 3.53 ± 0.77 |
Each value represents the mean ± S.E.M. of seven young (4–9 years), six adult (20–25 years), and five aged (29–34 years) rhesus monkeys.
nmol acetylcholine/mg protein/h.
TABLE 3.
[3H]MUSCIMOL BINDING SITES* IN MONKEY BRAIN
| Brain region | 4–6 years | 31–34 years |
|---|---|---|
| Frontal Pole | 171.1 ± 17.4 | 145.1 ± 17.7 |
| Middle Temporal Gyrus | 103.1 ± 27.7 | 125.1 ± 23.7 |
| Occipital Pole | 147.6 ± 23.5 | 147.5 ± 20.7 |
| Cerebellum | 278.5 ± 39.9 | 250.2 ± 57.8 |
Each value represents the mean ± S.E.M. of 4 young (4–6 years) or 4 aged (31–34 years) rhesus monkeys.
fmol/mg protein.
DISCUSSION
The primary finding of this investigation was a widespread decline in NMDA-displaceable L-[3H]glutamate binding in the brains of aged rats and rhesus monkeys. The decline in NMDA binding in the aged rat and monkey brain is similar to that reported in aged humans with AD (17,28) and may be due to the loss of neurons that give rise to corticocortical associational pathways (11,35), the entorhinal pathways into the hippocampus (16), cortical afferents (20), and/or the cortical projections to the caudate nucleus (55).
Two recent reports determined that the total number of [3H]glutamate binding sites, including both NMDA and non-NMDA sites, was increased in the brains of aged rats (7) and monkeys (65). In the present study, a general widespread increase in NMDA-displaceable L-[3H]glutamate binding was observed between ages 4 and 25 years in monkeys, although the increase was not statistically significant. Taken together, these results suggest that future investigations should examine this age group more closely, with particular emphasis on the number and distribution of non-NMDA type glutamate binding sites.
NMDA-displaceable L-[3H]glutamate binding in hippocampus and neocortex of young rats correlated significantly with performance in tasks that require learning and memory (63), and pharmacological antagonism of NMDA receptors, using AP5, impaired the performance of rats in tasks that require learning and memory (47). Similar to the effects of AP5, the loss of NMDA binding sites, coupled with a decrease of glutamate synthesis (57), could contribute to the cognitive decline observed in aged rats (32,33), aged monkeys (6, 48, 51, 59) and humans with AD.
The overall stability of the levels of ChAT activity with age confirms previous reports on aged rats (19), monkeys (65), and humans (10). We had previously shown that there is considerable variability in the individual levels of ChAT activity in monkey brain, and that the selection of cases might influence whether an age-related statistical decline in ChAT activity is observed (65). Fischer et al. (22) report a degeneration of cholinergic basal forebrain neurons without the loss of cortical or hippocampal levels of ChAT activity, suggesting that cholinergic cells that survive the age-associated neurodegenerative processes may augment ChAT activity to compensate for the loss of cholinergic terminals within the cortex. The elevated levels of cholinergic synthetic enzyme may underlie the finding that selected cholinergic agents can facilitate performance in aged, memory-impaired monkeys (4). Increased levels of neuronal ChAT would allow the cholinergic cell to respond to increased levels of precursors, provided by choline or lecithin in the diet, and thereby produce more acetylcholine for release.
GABA may provide postsynaptic inhibition of interneurons via GABA-A receptors (37). GABA may also inhibit transmitter release presynaptically via GABA-A or GABA-B receptors on the terminals of glutamatergic, noradrenergic or serotonergic cortical afferent pathways (37,38). In the present study, [3H]muscimol binding to GABA-A sites was unchanged in aged rats and rhesus monkeys. In rats, aging was associated with a decreased number of [3H]GABA receptors in the substantia nigra, but not in the cerebral cortex (26,27). In humans, aging was associated with an increased number of [3H]muscimol receptors in the temporal lobe, decreased GAD activity in the temporal cortex, and decreased [3H]GABA uptake in the frontal neocortex (2). These results are consistent with the loss of a selected population of GABAergic terminals with normal aging in humans. In patients with AD, the number of GABA-A receptors was unchanged, while the density of GABA-B receptors was decreased by 68% (13). The apparent sparing of GABA-A sites, the loss of GABAergic terminals, and the significant loss of NMDA sites are all consistent with the hypothesis that smaller intracortical interneurons are spared with normal aging in rats, monkeys, and aged humans with or without AD, and that corticocortical associational and selected cortical afferent pathways, many of which may be glutamatergic (36), are lost (11, 13, 20).
ACKNOWLEDGMENTS
We thank Anu Durr for typing the manuscript and Irene Malak for excellent technical assistance. This work was supported by PHS grants (NIH P50 NS020471 and AG 07735).
REFERENCES
- 1.Aigner TG; Mitchell SJ; Aggleton JP; DeLong MR; Struble RG; Price DL; Wenk GL; Mishkin M Effects of scopolamine and physostigmine on recognition memory in monkeys with ibotenic acid lesions of the nucleus basalis of Meynert. Psychopharmacology (Berlin) 92:292–300; 1987. [DOI] [PubMed] [Google Scholar]
- 2.Allen SJ; Benton JS; Goodhardt MJ; Haan EA; Sims NR; Smith CCT; Spillane JA; Bowen DM; Davison AN Biochemical evidence of selective nerve cell changes in the normal ageing human and rat brain. J. Neurochem 41:256–265; 1983. [DOI] [PubMed] [Google Scholar]
- 3.Barnard EA; Darlison MG; Seeburg P Molecular biology of the GABA-A receptor: the receptor/channel superfamily. Trends Neurosci. 10:502–509; 1987. [Google Scholar]
- 4.Bartus RT; Dean RL; Beer B Memory deficits in aged Cebus monkeys and facilitation with central cholinomimetics. Neurobiol. Aging 1:145–152; 1980. [DOI] [PubMed] [Google Scholar]
- 5.Bartus RT; Dean RL; Beer B; Lippa AS The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–417; 1982. [DOI] [PubMed] [Google Scholar]
- 6.Bartus RT; Fleming D; Johnson HR Aging in the rhesus monkey: debilitating effects on short-term memory. J. Gerontol 33: 858–871; 1978. [DOI] [PubMed] [Google Scholar]
- 7.Baudry M; Arst DS; Lynch G Increased [3H]glutamate receptor binding in aged rats. Brain Res. 223:195–198; 1981. [DOI] [PubMed] [Google Scholar]
- 8.Baudry M; Lynch G Characterization of two [3H]-glutamate binding sites in rat hippocampal membranes. J. Neurochem 36:811–820; 1981. [DOI] [PubMed] [Google Scholar]
- 9.Blessed G; Tomlinson BE; Roth M The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br. J. Psychiatry 14:797–811; 1968. [DOI] [PubMed] [Google Scholar]
- 10.Bowen DM; Smith CB, White P; Davison AN Neurotransmitter-related indices of hypoxia in senile dementia and other abiotrophies. Brain 99:459–496; 1976. [DOI] [PubMed] [Google Scholar]
- 11.Brizzee KR; Ordy JM; Bartus RT Localization of cellular changes within multimodal sensory regions in aged monkey brain: Possible implications for age-related cognitive loss. Neurobiol. Aging 1:45–52; 1980. [DOI] [PubMed] [Google Scholar]
- 12.Calderini G; Bonetti AC; Aldinio A; Savoini G; DiPerri B; Biggio G; Toffano G Functional interaction between benzodiazepine and GABA recognition sites in aged rats. Neurobiol. Aging 2: 309–323; 1981. [DOI] [PubMed] [Google Scholar]
- 13.Chu DCM; Penney JB; Young AB Cortical GABA-B and GABA-A receptors in Alzheimer’s disease: A quantitative autoradiographic study. Neurology 37:1454–1459; 1987. [DOI] [PubMed] [Google Scholar]
- 14.Chui HC; Bondareff W; Zarow C; Slager U Stability of neuronal number in the human nucleus basalis of Meynert with age. Neurobiol. Aging 5:83–88; 1984. [DOI] [PubMed] [Google Scholar]
- 15.Collingridge GL The role of NMDA receptors in learning and memory. Nature 330:604–605; 1987. [DOI] [PubMed] [Google Scholar]
- 16.Collingridge GL; Kehl SJ; McLennan H Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus. J. Physiol 334:33–46; 1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Cowburn R; Hardy J; Roberts P; Briggs R Presynaptic and postsynaptic glutamatergic function in Alzheimer’s disease. Neurosci. Lett 86:109–113; 1988. [DOI] [PubMed] [Google Scholar]
- 18.Coyle JT; Price DL; DeLong MR Alzheimer’s disease: A disorder of cortical cholinergic innervation. Science 219:1184–1190; 1983. [DOI] [PubMed] [Google Scholar]
- 19.Decker MW The effects of aging on hippocampal and cortical projections of the forebrain cholinergic system. Brain Res. Rev 12: 423–438; 1987. [DOI] [PubMed] [Google Scholar]
- 20.DeKosky ST; Bass NH Aging, senile dementia, and the intralaminar microchemistry of cerebral cortex. Neurology 32:1227–1233; 1982. [DOI] [PubMed] [Google Scholar]
- 21.Epstein JL Anxiolytics, antidepressants, and neuroleptics in the treatment of geriatric patients. In: Lipton MA; DiMascio A; Killam KF, eds. Psychopharmacology: A generation of progress. New York: Raven Press; 1978:1517–1523. [Google Scholar]
- 22.Fischer W; Gage FH; Bjorklund A Degenerative changes in forebrain nuclei correlate with cognitive impairments in aged rats. Eur. J. Neurosci 1:34–45; 1989. [DOI] [PubMed] [Google Scholar]
- 23.Fisher RS; Levine MS Transmitter cosynthesis by corticopetal basal forebrain neurons. Brain Res. 491:163–168; 1989. [DOI] [PubMed] [Google Scholar]
- 24.Fisher RS; Buchwald NA; Hull CD; Levine MS GABAergic basal forebrain neurons project to the neocortex: The localization of glutamic acid decarboxylase and choline acetyltransferase in feline corticopetal neurons. J. Comp. Neurol 272:489–502; 1988. [DOI] [PubMed] [Google Scholar]
- 25.Fonnum F Radiochemical micro assays for the determination of choline acetyltransferase and acetylcholinesterase activities. Biochem. J 115:465–472; 1969. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Govoni S; Memo M; Saiani L; Spano PF; Trabucchi M Impairment of brain neurotransmitter receptors in aged rats. Mech. Ageing Dev 12:39–46; 1980. [DOI] [PubMed] [Google Scholar]
- 27.Govoni S; Trabucchi M; Bosio A; Spano PF Functional changes of neurotransmitter receptors in the brains of aged rats. In: Cervos-Navarro J; Sarkander H-I, eds. Brain aging: Neuropathology and neuropharmacology. New York: Raven Press; 1983:363–371. (Aging, vol. 21.) [Google Scholar]
- 28.Gramsbergen JBP; Mountjoy CQ; Rossor MN; Reynolds GP; Roth M; Korf J A correlative study on hippocampal cation shifts and amino acids and clinico-pathological data in Alzheimer’s disease. Neurobiol. Aging 8:487–494; 1987. [DOI] [PubMed] [Google Scholar]
- 29.Harris EW; Ganong AH; Cotman CW Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors. Brain Res. 323:132–137; 1984. [DOI] [PubMed] [Google Scholar]
- 30.Himwich WA Neurobiological aspects of maturation and ageing. In: Ford DH, ed. Progress in brain research. New York: Elsevier; 1973:13–25. [Google Scholar]
- 31.Houser CR; Vaughn JE; Hendry SHC; Jones EG; Peters A GABA neurons in the cerebral cortex. In: Jones EG; Peters A, eds. Cerebral cortex, vol. 2, Functional properties of cortical cells New York: Plenum; 1984:63–89. [Google Scholar]
- 32.Ingram DK; London ED; Goodrick CL Age and neurochemical correlates of radial maze performance in rats. Neurobiol. Aging 2:41–47; 1981. [DOI] [PubMed] [Google Scholar]
- 33.Ingram DK; London ED; Waller SB; Reynolds MA Age-dependent correlation of motor performance with neurotransmitter synthetic enzyme activities in mice. Behav. Neural Biol 39:284–298; 1983. [DOI] [PubMed] [Google Scholar]
- 34.Irle E; Markowitsch HJ Basal forebrain-lesioned monkeys are severely impaired in tasks of association and recognition memory. Ann. Neurol 22:735–743; 1987. [DOI] [PubMed] [Google Scholar]
- 35.Jones EG Neurotransmitters in the cerebral cortex. J. Neurosurg 65:135–153; 1986. [DOI] [PubMed] [Google Scholar]
- 36.Jones EG; Hendry SHC Co-localization of GABA and neuropeptides in neocortical neurons. Trends Neurosci. 9:71–81; 1986. [Google Scholar]
- 37.Karbon EW; Duman R; Enna SJ Biochemical identification of multiple GABA-B binding sites: Association with noradrenergic terminals in rat forebrain. Brain Res. 274:393–396; 1983. [DOI] [PubMed] [Google Scholar]
- 38.Kilpatrick GJ; Muhyaddin MS; Roberts PJ; Woodruff GN GABA-B binding sites on rat striatal synaptic membranes. Br. J. Pharmacol 78:(Suppl.)6P; 1983. [Google Scholar]
- 39.Kleinschmidt A; Bear MF; Singer W Blockade of “NMDA” receptors disrupts experience-dependent plasticity of kitten striate cortex. Science 238:355–357; 1987. [DOI] [PubMed] [Google Scholar]
- 40.Lippa AS; Critchett DJ; Ehlert F; Yamamura HI; Enna SJ; Bartus RT Age-related alterations in neurotransmitter receptors: An electrophysiological and biochemical analysis. Neurobiol. Aging 2:3–8; 1981. [DOI] [PubMed] [Google Scholar]
- 41.Lowry OH; Rosenbrough NJ; Farr AL; Randall RJ Protein measurement with folin phenol reagent. J. Biol. Chem 193: 265–275; 1951. [PubMed] [Google Scholar]
- 42.McCabe BJ; Horn G Learning and memory: Regional changes in N-methyl-D-aspartate receptors in the chick brain after imprinting. Proc. Natl. Acad. Sci. USA 85:2849–2853; 1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.McGeer PL; McGeer DG Enzymes associated with the metabolism of catecholamines, acetylcholine and GABA in human controls and patients with Parkinson’s disease and Huntington’s chorea. J. Neurochem 26:65–79; 1976. [PubMed] [Google Scholar]
- 44.McGeer PL; McGeer DG; Suzuki JS Aging and extrapyramidal function. Arch. Neurol 34:33–35; 1977. [DOI] [PubMed] [Google Scholar]
- 45.Maggi A; Schmidt MJ; Ghetti B; Enna SJ Effect of aging on neurotransmitter receptor binding in rat and human brain. Life Sci. 24:367–374; 1979. [DOI] [PubMed] [Google Scholar]
- 46.Monahan JB; Michel J Identification and characterization of an N-methyl-D-aspartate-specific L-[3H]glutamate recognition site in synaptic plasma membranes. J. Neurochem 48:1699–1708; 1987. [DOI] [PubMed] [Google Scholar]
- 47.Morris RGM; Anderson E; Lynch GS; Baudry M Selective impairment of learning and blockade of long-term potentiation of a N-methyl-D-aspartate receptor antagonist, AP5. Nature 319:774–776; 1986. [DOI] [PubMed] [Google Scholar]
- 48.Moss M; Rosene DL; Peters A Effects of aging on visual recognition memory in the rhesus monkey. Primate Rep. 14:133; 1986. [DOI] [PubMed] [Google Scholar]
- 49.Olsen RW The gamma-aminobutyric acid/benzodiazepine/barbiturate receptor-chloride ion channel complex of mammalian brain. In: Edelman GM; Gall WE; Cowan MW, eds. Synaptic function. New York: John Wiley & Sons; 1987:257–271. [Google Scholar]
- 50.Periyasamy S; Masatoshi I; Chiu TH Binding of L-[3H]glutamate to repeatedly frozen-thawed rat brain membranes. Neurochem. Int 11:69–75; 1987. [DOI] [PubMed] [Google Scholar]
- 51.Presty SK; Bachevalier J; Walker LC; Struble RG; Price DL; Mishkin M; Cork LC Age differences in recognition memory of the rhesus monkey (Macaca mulatta). Neurobiol. Aging 8:435-4-440; 1987. [DOI] [PubMed] [Google Scholar]
- 52.Price MT; Olney JW; Haft R Age-related changes in glutamate concentration and synaptosomal glutamate uptake in adult rat striatum. Life Sci. 28:1365–1370; 1981. [DOI] [PubMed] [Google Scholar]
- 53.Ridley RM; Baker HF; Drewett B; Johnson JA Effects of ibotenic acid lesions of the basal forebrain on serial reversal learning in marmosets. Psychopharmacology (Berlin) 86:438–443; 1985. [DOI] [PubMed] [Google Scholar]
- 54.Ridley RM; Murray TK; Johnson JA; Baker HF Learning impairment following lesion of the basal nucleus of Meynert in the marmoset: modification by cholinergic drugs. Brain Res. 376: 108–116; 1986. [DOI] [PubMed] [Google Scholar]
- 55.Roberts PJ; McBean GJ; Sharif NJ; Thomas EM Striatal glutamatergic function: Modifications following specific lesions. Brain Res. 235:83–91; 1982. [DOI] [PubMed] [Google Scholar]
- 56.Scatton B; Bartholini G Gamma-aminobutyric acid (GABA) receptor stimulation. IV. Effect of progabide (SL 76002) and other GABAergic agents on acetylcholine turnover in rat brain areas. J. Pharmacol. Exp. Ther 220:689–695; 1982. [PubMed] [Google Scholar]
- 57.Tyce GM; Wong K-L Conversion of glucose to neurotransmitter amino acids in the brains of young and aging rats. Exp. Gerontol 15:527–532; 1980. [DOI] [PubMed] [Google Scholar]
- 58.Vincent SR; Hokfelt T; Skirboll LR; Wu J-Y Hypothalamic gamma-aminobutyric acid neurons project to the neocortex. Science 220:1309–1310; 1983. [DOI] [PubMed] [Google Scholar]
- 59.Walker LC; Kitt CA; Struble RG; Wagster MV; Price DL; Cork LC The neural basis of memory decline in aged monkeys. Neurobiol. Aging 9:657–666; 1988. [DOI] [PubMed] [Google Scholar]
- 60.Walker LC; Price DL; Young WS GABAergic neurons in the primate basal forebrain magnocellular complex. Brain Res. 499: 188–192; 1989. [DOI] [PubMed] [Google Scholar]
- 61.Watkins JC; Evans RH Excitatory amino acid transmitters. Annu. Rev. Pharmacol 21:165–204; 1981. [DOI] [PubMed] [Google Scholar]
- 62.Wenk GL Pharmacological manipulations of the substantia innominata-cortical cholinergic pathway. Neurosci. Lett 51:99–103;1984. [DOI] [PubMed] [Google Scholar]
- 63.Wenk GL; Grey CM; Ingram DK; Spangler EL; Olton DS Retention of maze performance inversely correlates with NMDA receptor number in hippocampus and frontal neocortex in rat. Behav. Neurosci 103:688–690; 1989. [DOI] [PubMed] [Google Scholar]
- 64.Wenk GL; Olton DS Basal forebrain cholinergic neurons and Alzheimer’s disease. In: Coyle JT, ed. Animal models of dementia: A synaptic neurochemical perspective, Neurology and Neurobiology, vol. 33. New York: Alan R. Liss; 1987:81–101. [Google Scholar]
- 65.Wenk GL; Pierce DJ; Struble RG; Price DL; Cork LC Age-related changes in multiple neurotransmitter systems in the monkey brain. Neurobiol. Aging 10:11–19; 1989. [DOI] [PubMed] [Google Scholar]
- 66.Wheeler DD Aging of membrane transport mechanisms in the central nervous system - high affinity glutamic acid transport in rat cortical synaptosomes. Exp. Gerontol 15:269–284. [DOI] [PubMed] [Google Scholar]
- 67.Williams M; Risley EA Characterization of the binding of [3H]muscimol, a potent gamma-aminobutyric acid agonist, to rat brain synaptosomal membranes using a filtration assay. J. Neurochem 32: 713–718; 1979. [DOI] [PubMed] [Google Scholar]
- 68.Wood PL; Richard J GABAergic regulation of the substantia innominata-cortical cholinergic pathway. Neuropharmacology 21:969–972; 1982. [DOI] [PubMed] [Google Scholar]