Age-dependent decrease in the affinity of muscarinic M1 receptors in neocortex of rhesus monkeys.

Abstract

In vitro autoradiography on tissue sections and receptor assay in cortical membrane homogenates revealed that pirenuzepine h-affinity muscarink sites (Ml) decrease in affinity in the prefrontal cortex and in other cortical areas of aged rhesus monkey (Macaca miudta). Carbachol competition experiments detected only a single, low-affinity da of sites in old monkeys, while two classes of sites (low and hh affity) were observed in young adults. The change in affinity in the aged monkeys is not accomaed by a decrease in the density ofthese sites and, further, the age-related decline in the affinity ofthe Ml site is reversible. In the presence of Mg2e, the Ml muarnic receptors in the aged monkeys were capable of forming carbachol high-affinity sites. These results provide evidence for agedependent funtional changes in receptor activity in cerebral cortex and indicate that these receptors maintain a degree of plasticity that could be a strategc target for research aimed at treatment of memory disorders in aged humans.Memory decline during aging has been extensively documented in rodents (1, 2), nonhuman primates (3, 4), and humans (5). Although the aging process seems to impinge on several neurotransmitter systems, special emphasis has been placed on the role of the cortical cholinergic innervation in geriatric memory dysfunction (6). Studies in rodents have shown a consistent decline in cortical acetylcholine (ACh) synthesis and release during aging (7-9), although little or no change occurs in cortical choline acetyltransferase activity (1,8,6,10). Further, the cholinergic basal forebrain neurons that project to the cortex undergo an age-related decrease in size though their number is apparently not diminished (11).In the present study we have examined the status of the Ml muscarinic cholinergic receptor in aged rhesus monkey, a species that exhibits behavioral impairment and cortical pathological changes remarkably similar to those observed in elderly humans (4,6,12). Ml sites are present in high concentration in the primate neocortex (13,14) and are involved in cortical cholinergic excitation (15). However, little is known about changes in these cortical receptors with age. In aged rats, there have been conflicting reports of decrease (16) or no change (17) in binding-site density. Only two recent studies have examined the status of ACh receptors in monkey cortex during aging, and both found a decrease of nicotinic and muscarinic receptors, mainly in temporal (18,19) and parahippocampal (18) cortex. Neither study found any significant decreases in the affinity of binding sites in aged monkey cortex.In the present study we confirm that the number of Ml sites does not change with age but we provide evidence for changes in the molecular structure of the cortical receptor or of the coupled effector systems able to alter the affinity of these sites. To obtain this evidence, we studied the binding of the highly selective compound pirenzepine (PZ) (20) to the Ml sites in nine distinct areas of monkey cortex both i...

Effects of normal aging on prefrontal area 46 in the rhesus monkey

“…For example, one study reported a modest reduction in ChAT levels in the frontal pole of aged rhesus monkeys (Wenk et al, 1989), but a subsequent study reported that the levels of this synthetic enzyme were not changed in the frontal cortex in a different cohort of aged monkeys (Wenk et al, 1991). Further, another study reported that neither M1 nor nicotinic ACh receptors are reduced with age in monkey prefrontal cortex (Wenk et al, 1989) while a subsequent study reported a significant decrease in M1 receptor binding in area 46 (Vannucchi and Goldman-Rakic, 1991). Clearly further work is required to unequivocally demonstrate whether cholinergic systems are substantially changed with age in the primate area 46.…”

Long-Term Dietary Strawberry, Spinach, or Vitamin E Supplementation Retards the Onset of Age-Related Neuronal Signal-Transduction and Cognitive Behavioral Deficits

“…Key words: antioxidants; aging; diet; dopamine; GABA; norepinephrine; striatum; cerebellum; cognitive behavior It is well known that there are numerous declines in central neuronal f unctioning that can occur in aging in the absence of neurodegenerative disease. These alterations may be manifested as a loss of neurotransmitter receptor sensitivity such as: (1) muscarinic (Amenta et al, 1989;Araujo et al, 1990;Joseph et al, 1990;Sherman and Friedman, 1990;Vannucchi, 1991;Viana et al, 1992;Yuf u et al, 1994;Egashira et al, 1996), (2) adrenergic (Burnett et al, 1990;Gelbmann and Muller, 1990;Gould and Bickford, 1997), (3) dopaminergic (Joseph et al, 1978;Roth and Joseph, 1994;Gould et al, 1996;Volkow et al, 1996;Araki et al, 1997;Z hang et al, 1997;Levine and C epeda, 1998), and (4) opioid (Dondi et al, 1992;Kornhuber et al, 1996;Nagahara et al, 1996).…”

Hippocampal M1 receptor function associated with spatial learning and memory in aged female rhesus macaques

“…The potential discrepancy in these studies is the age range used in each study. Previous studies used animals that were only 20 years old (Wagster et al 1990) or did not include middle-aged animals (Vannucchi and Goldman-Rakic 1991). In contrast, in the current study, we used adult, middle-aged, and aged animals, and our aged animals were 22-30 years.…”