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Neurotransmitter receptor plasticity in aging
Life Sciences, Vol. 55, No.s 25/26, pp. 1985-1991, 1994 Copyright © 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0024-3205/94 $6.00 + .00
Pergamon 0024-3205(94)00378-5
NEUROTRANSMITrER RECEPTOR PLASTICITY IN AGING
Norman W. Pedigo, Jr.
Departments of Pharmacology and Anesthesiology, University of Kentucky A. B. Chandler Medical Center, Lexington, KY 40536-0216, USA
Summary. Neurotransmitter receptor plasticity is an important part of the compensatory processes by which the central nervous system adapts to pathological insult, long-term exposure to drugs or neuronal loss with advanced age. Receptor plasticity can be manifest as changes in the number of receptors (i.e., up- or down-regulation), changes in expression of mRNA for discrete receptor proteins, or alterations in receptor coupling to signal transduction systems. Evidence exists for impaired plasticity of neurons in the aged brain, which results in decreased ability to adjust to changes in their environment. However, such data are highly dependent on the neurotransmitter examined, the stimulus for receptor regulation and the animal model chosen for study. For example, senescent rats show an age-related impairment of muscarinic receptor up- or down-regulation after long-term exposure to cholinergic drugs. Thus, young rats exposed to chronic (three weeks) intracerebroventricular infusions of methylatropine or oxotremorine exhibit compensatory changes in the density of muscarinic receptors in frontal cortex and hypothalamus. In contrast, 3H-QNB binding is unaltered in the same brain regions of identically treated senescent rats. Similar observations of impaired muscarinic receptor plasticity in senescent animals have been confirmed by other investigators. Age-related differences in coupling of brain muscarinic receptors to Gproteins and in muscarinic receptor-stimulated phosphoinositide hydrolysis have also been reported. Interestingly, neuropeptides such as neurotensin, cholecystokinin and VIP can potentiate carbachol-stimulated phosphoinositide hydrolysis in frontal cortex of both young and aged rats. This adds another level at which cholinergic neurotransmission may be modulated in senescent animals. Potential age-related differences in the effects of chronic drug treatments or experimental brain lesions on muscarinic receptor coupling to second messenger systems or on expression of mRNA for particular muscarinic receptors are currently unknown. Hence, it is possible that senescent animals may show additional deficiencies in plasticity of muscarinic receptor mediated signal transduction or expression of muscarinic receptors subtypes. Key Words: aging, A l z h e i m e r ' s disease, m e m o r y , nootropics, P a r k i n s o n ' s disease, m u s c a r i n i c receptors,
nicotine, dopamine, receptor regulation,signal transduction
1986
Receptor Plasticityin Aging
Vol. 55, No.s 25/26, 1994
Neuronal damage resulting from age-related brain disorders, such as Parkinson's disease, ischemia or stroke, multiinfarct dementia, and Alzheimer's disease, can precipitate compensatory, adaptive processes, including changes in neurotransmitter receptors and signal transduction systems. Receptor plasticity in the aged brain depends on the neurotransmitter examined, the stimulus for receptor regulation and the animal model or human disease state chosen for study (l). Loss of afferent neurons may induce an increase in the number, or less often the affinity, of postsynaptic receptors. This receptor up-regulation is also seen after chronic exposure of the central nervous system (CNS) to antagonist drugs. Conversely, down-regulation of receptors may occur after chronic overstimulation of afferent pathways or after long-term administration of agonists. Mechanisms of such receptor plasticity are poorly understood, but could include changes in the expression or translation of mRNA for receptor proteins, in the interaction of receptors with other proteins within the microenvironment of lipid membranes, or in the rates of receptor desensitization or degradation. Dopaminergic receptor plasticity in Parkinson's disease
The definition of Parkinson's disease as a dopamine deficiency and its successful, symptomatic treatment with levodopa has served as a model for the past three decades of neurological research (2). Many current basic and clinical investigations are founded on the assumption that a thorough understanding of the neurochemical deficits of brain disorders can lead to rational therapeutic interventions. Although replacement therapy, such as levodopa, does not deter the neurodegenerative process in substantia nigral neurons, this approach has dramatically improved the quality of life for Parkinsonian patients. One reason for the therapeutic efficacy of dopamine precursors and agonists in Parkinson's disease is the apparent up-regulation of postsynaptic dopamine receptors in the striatum (3,4). This compensatory process provides an optimized, "supersensitive" target for dopaminergic neurotransmission. Indeed, the first demonstration of denervation supersensitivity in the CNS was from the classic work by Ungersted (5) on an animal model of Parkinson's disease. Unfortunately, continued use of direct or indirect dopaminergic agonists may lead to severe side-effects (dyskinesias, on-off phenomena, psychoses) which may be related to further dopamine receptor adaptations (3). A more complete knowledge of dopamine receptor subtypes, interactions and plasticity in Parkinson's disease is required to optimize symptomatic treatment of this disorder (6,7). Cholinergic receptor adaptations in Alzheimer's disease While many neurotransmitter receptors have been evaluated in AIzheimer's disease (reviewed in 8), much of this work has focused on forebrain cholinergic receptors. Most researchers note a significant decrease in nicotinic receptors in hippocampus and frontal cortex from Alzheimer's disease brains, consistent with a presynaptic localization of these receptors and the degeneration of forebrain cholinergic neurons in Alzheimer's disease. However, there is considerable disagreement over changes in forebrain muscarinic receptors. The majority of studies indicate no change or a decrease (see 8-10), but some investigators report an increase in total muscarinic receptors (11,12). Several factors undoubtedly contribute to these disparities, including the extent of Alzheimer's disease pathology, choice of age-matched controls, postmortem delays, and differences in receptor binding methodologies. Further studies must define the functionality of remaining receptors in Alzheimer's disease and especially the plasticity of muscarinic receptor subtypes.
Vol. 55, No.s 25/26, 1994
Receptor Plasticityin Aging
1987
Novel cholinergic treatments for Alzheimer's disease
Attempts to provide symptomatic relief of Alzheimer's type dementia via cholinergic precursors, cholinesterase inhibitors or nonselective muscarinic agonists have been met with very limited success (see review in 13). The rationale for such therapies is analogous to the design of effective drug regimens for Parkinson's disease, as described above. However, it should be noted that the postsynaptic muscarinic receptors may not be up-regulated in Alzheimer's disease. This lack of denervation supersensitivity could limit the effectiveness of cholinergic drugs. The debilitating side-effects associated with parasympathetic stimulation are especially problematic in elderly patients, further narrowing their therapeutic window. Finally, there are profound difficulties in designing clinical trials to evaluate the therapeutic potential of drugs in this progressive neurodegenerative disorder. Initial disappointment in the clinical efficacy of cholinergic drugs has led some to question the usefulness of the cholinergic theory of Alzheimer's disease (14), although this position has been met with vigorous debate (15-19). There is considerable evidence that other neurotransmitter systems are altered in Alzheimer's disease (20,21). However, the most consistent and pronounced neurochemical deficits can be ascribed to a loss of forebrain cholinergic neurons innervating cortex and hippocampus. There is also excellent agreement between the magnitude of cognitive deficits in patients with Alzheimer's disease and their depletion of choline acetyltransferase, the synthetic enzyme for acetylcholine and a postmortem marker for cholinergic neurons (22). Since the etiology of Alzheimer's disease is currently unknown, novel treatments will be directed towards symptomatic relief of cognitive dysfunction through the enhancement of cholinergic neurotransmission. Potential strategies may include use of presynaptic M2 (autoreceptor) antagonists in combination with selective cholinesterase inhibitors (23), combined administration of cholinergic and 5HT~A agonists (15), or use of subtype-selective muscarinic agonists (see Ehlert, Roeske and Yamamura, this volume). Other approaches may involve restoration of muscarinic receptor plasticity, facilitation of second messenger functions or potentiation of signal transduction pathways. Brain muscarinic receptors in animal models of aging Numerous investigators have reported an age-related loss of brain muscarinic receptors in various animal models (reviewed in 24). Experimental approaches have included assessing subtype selective mRNA expression (25), quantitative receptor autoradiography (26) and radioligand binding techniques (27-30). Limitations of these studies include, in some cases, the number of brain regions examined, use of nonselective muscarinic receptor ligands, and the absence of functional or biochemical correlates to receptor binding. Research in my laboratory has focused on muscarinic receptor plasticity in a rat model of aging. Our working hypothesis is that muscarinic receptors fail to up-regulate in Alzheimer's disease because of an age-related impairment in receptor plasticity. Since Alzheimer's disease is a dementia that occurs late in life, deterioration of compensatory adaptive processes would exacerbate the progressive nature of this disorder. A similar theoretical construct relating neural plasticity and aging has been proposed by Agnati and colleagues (31), dubbed the "red queen theory" after the character in Lewis Carroll's book Through the Looking Glass who was always running faster and faster just to keep up .
1988
Receptor Plasticity in Aging
Frontal Cortex
3000 ! ~_ 2500
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Hypothalamus
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Vol. 55, No.s 25/26, 1994
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9-12
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Age ( m o n t h s ) Fig. 1 Density of muscarinic receptors in frontal cortex and hypothalamus of young, adult and senescent rats treated with intracerebroventricular (ivt) methylatropine (MeATR) or oxotremorine (OXO), determined from saturation studies of 3H-QNB binding. Male, Fischer 344 rats were infused with MeATR or OXO (3/zg/2 pl/h, ivt) for three weeks. Muscarinic receptor affinity was the same for all ages and treatment groups (K~ = 40-80 pM). *p<.05 compared to age-matched controls (adapted from 32,33) Our experimental design has been to compare adaptive muscarinic receptor changes following chronic (three weeks) intracerebroventricular infusions of cholinergic drugs to young (3-6 months), adult (9-12 months) and senescent (24-27 months) Fischer 344 rats. While young and adult animals administered methylatropine or oxotremorine exhibit compensatory changes in the density of muscarinic receptors in frontal cortex and hypothalamus, identically treated senescent rats show no changes in 3H-QNB binding (32,33). These data are summarized in Fig. 1. Interestingly, the muscarinic receptor upor down-regulation observed in the hypothalamus of young rats was paralleled by alterations in their hypothermic response to a muscarinic agonist (33). In contrast, senescent rats showed no such compensatory pharmacologic adaptations after long-term exposure to cholinergic drugs. Similar observations of reduced muscarinic receptor plasticity in senescent animals have been reported by other investigators (34-37). Long-term (4 weeks) treatment with piracetam increases muscarinic receptor density and function in frontal cortex of senescent, but not young, mice (38,39). However, treatment with this nootropic drug does not restore muscarinic receptor plasticity (39). Pintor and colleagues (36,37) have also noted an agerelated impairment in the rate of recovery of brain muscarinic receptors that down-regulate in rats exposed to organophosphate cholinesterase inhibitors. Finally, the potential role of presynaptic terminals in facilitating muscarinic receptor plasticity must be considered in light of the observations by Vige and Briley (40). These investigators found that lesions of cholinergic cell bodies in the nucleus basalis prevent scopolamine-induced up-regulation of muscarinic receptors in young rats. Perhaps the loss of eholinergic projection neurons with aging could relate to the age-related impairments in muscarinic receptor plasticity.
Vol. 55, No.s 25/26, 1994
Receptor Plasticityin Aging
1989
Age-related changes in muscarinic receptor coupling and signal transduction Aging also affects the coupling of brain muscarinic receptors to crucial membranebound proteins, such as G-proteins mediating second messenger systems. Roth and colleagues have shown that age-related reductions in muscarinic-stimulated, dopamine release from striatal slices are due, in part, to impaired muscarinic receptor coupling to Gproteins (41). Similar results were seen in hippocampal slices from senescent rats (42). Potential age-related differences in the effects of chronic drug treatments or experimental brain lesions on muscarinic receptor coupling or on expression of mRNA for particular muscarinic receptors remain to be defined experimentally. Hence, it is possible that senescent animals may show additional deficiencies in plasticity of muscarinic receptor mediated signal transduction or adaptive expression of muscarinic receptor subtypes. It may also be possible to modify muscarinic-stimulated signal transduction through the actions of neuromodulatory peptides. Recent experiments from my laboratory have examined the possible influence of several neuropeptides on muscarinic receptor binding and function in fronto-parietal cortex of young and senescent Fischer 344 rats (43). Low concentrations (100 nM) of cholecystokinin, neurotensin and vasoactive intestinal polypeptide (VIP), added in vitro, enhance carbachol-stimulated phosphoinositide metabolism in cortical miniprisms from both young and senescent rats, while somatostatin is ineffective. Interestingly, the VIP receptor antagonist d-parachloro-Phe 6, Leu~7-VIP significantly inhibits phosphoinositide hydrolysis by increasing the ECs0 for carbachol. These neuropeptide actions are not due to changes in the number or affinity of 3H-QNB binding sites nor on agonist conformation states of the muscarinic receptor. Furthermore, the neuropeptide modulation of phosphoinositide metabolism is not due to presynaptic release of acetylcholine and is selective for muscarinic systems, as norepinephrine-stimulated phosphoinositide hydrolysis is not affected. Neuropeptide-induced increases in carbacholmediated phosphoinositide metabolism are likely due to a selective enhancement of muscarinic receptor-effector coupling within postsynaptic membranes. Hence, it is possible that pharmacologic manipulation of peptidergic processes could improve cholinergic neurotransmission in brains of senescent animals.
Conclusions Effectively treating age-related brain disorders remains a crucial challenge for today's clinicians and researchers. One of the numerous issues affecting the design and implementation of novel treatment strategies for Parkinson's disease and Alzheimer's-type dementia is that of receptor plasticity. In the case of Parkinson's disease, dopaminergic receptor supersensitivity may potentiate the actions of levodopa and other dopamine agonists, but continued receptor adaptations may limit the long-term efficacy of such drugs. For Alzheimer's disease patients there appears to be an age-related impairment in muscarinic receptor plasticity. This makes it more difficult for cholinergic drugs to improve the cognitive deficits associated with this disorder, but may predict fewer problems with continuous receptor stimulation. Further research may provide additional opportunities for manipulating receptor-mediated signal transduction or expression of receptor subtypes, thereby enhancing neuronal communication and function in age-related brain disorders.
1990
Receptor Plasticityin Aging
Vol. 55, No.s 25/26, 1994
Acknowledgements The dedicated and expert technical assistance of M. Andrea Rice, Darrell Polk, Winston Powell, Joan Whiteman, George Brown and David McCracken is gratefully acknowledged. Portions of the author's work cited in this paper were supported by the American Federation for Aging Research, the Alzheimer's Disease and Related Disorders Association and the National Institute on Aging.
References 1. 2. 3. 4.
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G. RACAGNI, A.C. ROVESCALLI, R. GALIMBERTI and N. BRUNELLO, Mod. Probl. Pharmacopsych. 2__3321-27 (1989). I.J. KOPIN, Neuropsychopharmacol. 9 1-12 (1993). M. GUTTMAN, Neurologic Clinics I__Q0377-386 (1992). G.A. DONNAN, D.G. WOODHOUSE, S.J. KACZMARCZYK, J.E. HOLDER, G. PAXINOS, P.J. CHILCO, A.J. CHURCHYARD, R.M. KALNINS, G.C.A. FABINYI and F.A.O. MENDELSOHN, Mol. Neurobiol. 5 421-433 (1991). U. UNGERSTEDT, Acta Physiol. Stand. Suppl. 367 69-93 (1971). I.J. KOPIN, Ann. Rev. Pharmacol. Toxicol. 32 467-495 (1993). H.A. ROBERTSON, Trends Neurosci. 15 201-206 (1992). J.T. GREENAMYRE and W.F. MARAGOS, Cerebrovascular Brain Metab. Rev. 5 61-94 (1993). P.J. WHITEHOUSE, Alzheimer Dis. Assoc. Disorders 1_9-18 (1987). E.K. PERRY, R.H. PERRY, C.J. SMITH, D. PUROHIT, J. BONHAM, D.J. DICK, J.M. CANDY, J.A. EDWARDSON and A. FAIRBAIRN, Can. J. Neurol. Sei. 13 521-527 (1986). A. NORDBERG, Acta. Neurol. Stand. Suppl 139 54-58 (1992). A. NORDBERG, I. ALAFUZOFF and B. WINBLAD, J. Neurosci. Res. 31 103-111 (1992). M. DAVIDSON, R.G. STERN, L.M. BIERER, T.B. HORVATH, Z. ZEMISHLANI, R. MARKOFSKY and R.C. MOHS, Acta. Psychiatr. Scand. Suppl 366 47-51 (1991). H.C. FIBIGER, Trends Neurosci. 14 220-223 (1991). D.M. BOWEN, P.T. FRANCIS, M.N. PANGALOS, P.H. STEPHENS, A.W. PROCTER and I.P. CHESSELL, Trends Neurosci. 15 84-85 (1992). R.M. RIDLEY, H.F. BAKER and A. FINE, Trends Neurosci. 14 482-483 (1991). E.K. PERRY, D. IRVING and R.H. PERRY, Trends Neurosci. 1__44483-484 (1991). M. SARTER, J.P. BRUNO and P. DUDCHENKO, Trends Neurosci. 14 484 (1991). H.C. FIBIGER, Trends Neurosci. 14 485-486 (1991). J.A. COURT AND E.K. PERRY, Pharmac. Ther. 52 423-443 (1991). C.G. GOTFRIES, Dementia 1 56-64 (1990). N.R. SIMS and D.M. BOWEN, Alzheimer's Disease, ed. B. Reisberg, 88-92, Free Press, New York (1983). M. McKINNEY, Mayo Clin. Proc. 66 1225-1237 (1991). N.W. PEDIGO, JR., Liver and aging - 1986, Liver and Brain, K. Kitani (ed), 195-208, Elsevier Science Publishers B.V. (Biomedical Division), (1986). M.J. BLAKE, N.M. APPEL, J.A. JOSEPH. C.A. STAGG, M.ANSON, E.B. DeSOUZA and G.S. ROTH, Neurobio. Aging 12 193-199 (1991).
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A. BIEGON, R. DUVDEVANI, V. GREENBERGER and M. SEGAL, J. Neurochem. 51 1381-1385 (1988). R.D. SCHWARZ, A.A. BERNABEI, C.J. SPENCER and T.A. PUGSLEY, Pharmacol. Biochem. Behav. 35 589-593 (1990). K.A. SHERMAN and E. FRIEDMAN, Int. J. Devl. Neuroscience 8 689-708 (1990). S.B. WALLER and E.D. LONDON, Neurochem. Int. 14 483-490 (1989). N.W. PEDIGO, JR., L.D. MINOR and T.N. KRUMREI, Neurobiol. of Aging 5 227233 (1984). L.F. AGNATI, M. ZOLL, G. BIAGINI and K. FUXE, Acta Physiol. Scand. 145 301309 (1992). N.W. PEDIGO and D.M. POLK, Life Sci. 37 1443-1449 (1985). N.W. PEDIGO, Psychopharmacology 95 497-501 (1988). H. PILCH and W.E. MULLER, J. Neural. Transm. 71 39-43 (1988). E.R. PIETRZAK, P.A. WILCE and B.C. SHANLEY, Neurosci. Lett. 104 331-335 (1989). A. PINTOR, S. FORTUNA, S. D'ANGELIS and H. MICHALEK, Life Sci. 46 10271036 (1990). A. PINTOR, S. FORTUNA, M.T. VOLPE and H. MICHALEK, Life Sci. 42 21132121 (1988). L. STOLL, T. SCHUBERT and W.E. MULLER, Neurobiol. Aging 13 39-44 (1992). H. PILCH and W.E. MULLER, Psychopharmacol. 94 74-78 (1988). X. VIGE and M. BRILEY, Neuropharmacology 28 727-732 (1989). R.M. ANSON, R. CUTLER, J.A. JOSEPH, K. YAMAGAMI and G.S. ROTH, Brain Res. 598 302-306 (1992). K. YAMAGAMI, J.A. JOSEPH and G.S. ROTH, Brain Res. 576 327-331 (1992). N.W. PEDIGO, JR. and M.A. RICE, Eur. J. Pharmacol. - Mol. Pharmacol. Section 225 151-159 (1992).
Pergamon 0024-3205(94)00378-5
NEUROTRANSMITrER RECEPTOR PLASTICITY IN AGING
Norman W. Pedigo, Jr.
Departments of Pharmacology and Anesthesiology, University of Kentucky A. B. Chandler Medical Center, Lexington, KY 40536-0216, USA
Summary. Neurotransmitter receptor plasticity is an important part of the compensatory processes by which the central nervous system adapts to pathological insult, long-term exposure to drugs or neuronal loss with advanced age. Receptor plasticity can be manifest as changes in the number of receptors (i.e., up- or down-regulation), changes in expression of mRNA for discrete receptor proteins, or alterations in receptor coupling to signal transduction systems. Evidence exists for impaired plasticity of neurons in the aged brain, which results in decreased ability to adjust to changes in their environment. However, such data are highly dependent on the neurotransmitter examined, the stimulus for receptor regulation and the animal model chosen for study. For example, senescent rats show an age-related impairment of muscarinic receptor up- or down-regulation after long-term exposure to cholinergic drugs. Thus, young rats exposed to chronic (three weeks) intracerebroventricular infusions of methylatropine or oxotremorine exhibit compensatory changes in the density of muscarinic receptors in frontal cortex and hypothalamus. In contrast, 3H-QNB binding is unaltered in the same brain regions of identically treated senescent rats. Similar observations of impaired muscarinic receptor plasticity in senescent animals have been confirmed by other investigators. Age-related differences in coupling of brain muscarinic receptors to Gproteins and in muscarinic receptor-stimulated phosphoinositide hydrolysis have also been reported. Interestingly, neuropeptides such as neurotensin, cholecystokinin and VIP can potentiate carbachol-stimulated phosphoinositide hydrolysis in frontal cortex of both young and aged rats. This adds another level at which cholinergic neurotransmission may be modulated in senescent animals. Potential age-related differences in the effects of chronic drug treatments or experimental brain lesions on muscarinic receptor coupling to second messenger systems or on expression of mRNA for particular muscarinic receptors are currently unknown. Hence, it is possible that senescent animals may show additional deficiencies in plasticity of muscarinic receptor mediated signal transduction or expression of muscarinic receptors subtypes. Key Words: aging, A l z h e i m e r ' s disease, m e m o r y , nootropics, P a r k i n s o n ' s disease, m u s c a r i n i c receptors,
nicotine, dopamine, receptor regulation,signal transduction
1986
Receptor Plasticityin Aging
Vol. 55, No.s 25/26, 1994
Neuronal damage resulting from age-related brain disorders, such as Parkinson's disease, ischemia or stroke, multiinfarct dementia, and Alzheimer's disease, can precipitate compensatory, adaptive processes, including changes in neurotransmitter receptors and signal transduction systems. Receptor plasticity in the aged brain depends on the neurotransmitter examined, the stimulus for receptor regulation and the animal model or human disease state chosen for study (l). Loss of afferent neurons may induce an increase in the number, or less often the affinity, of postsynaptic receptors. This receptor up-regulation is also seen after chronic exposure of the central nervous system (CNS) to antagonist drugs. Conversely, down-regulation of receptors may occur after chronic overstimulation of afferent pathways or after long-term administration of agonists. Mechanisms of such receptor plasticity are poorly understood, but could include changes in the expression or translation of mRNA for receptor proteins, in the interaction of receptors with other proteins within the microenvironment of lipid membranes, or in the rates of receptor desensitization or degradation. Dopaminergic receptor plasticity in Parkinson's disease
The definition of Parkinson's disease as a dopamine deficiency and its successful, symptomatic treatment with levodopa has served as a model for the past three decades of neurological research (2). Many current basic and clinical investigations are founded on the assumption that a thorough understanding of the neurochemical deficits of brain disorders can lead to rational therapeutic interventions. Although replacement therapy, such as levodopa, does not deter the neurodegenerative process in substantia nigral neurons, this approach has dramatically improved the quality of life for Parkinsonian patients. One reason for the therapeutic efficacy of dopamine precursors and agonists in Parkinson's disease is the apparent up-regulation of postsynaptic dopamine receptors in the striatum (3,4). This compensatory process provides an optimized, "supersensitive" target for dopaminergic neurotransmission. Indeed, the first demonstration of denervation supersensitivity in the CNS was from the classic work by Ungersted (5) on an animal model of Parkinson's disease. Unfortunately, continued use of direct or indirect dopaminergic agonists may lead to severe side-effects (dyskinesias, on-off phenomena, psychoses) which may be related to further dopamine receptor adaptations (3). A more complete knowledge of dopamine receptor subtypes, interactions and plasticity in Parkinson's disease is required to optimize symptomatic treatment of this disorder (6,7). Cholinergic receptor adaptations in Alzheimer's disease While many neurotransmitter receptors have been evaluated in AIzheimer's disease (reviewed in 8), much of this work has focused on forebrain cholinergic receptors. Most researchers note a significant decrease in nicotinic receptors in hippocampus and frontal cortex from Alzheimer's disease brains, consistent with a presynaptic localization of these receptors and the degeneration of forebrain cholinergic neurons in Alzheimer's disease. However, there is considerable disagreement over changes in forebrain muscarinic receptors. The majority of studies indicate no change or a decrease (see 8-10), but some investigators report an increase in total muscarinic receptors (11,12). Several factors undoubtedly contribute to these disparities, including the extent of Alzheimer's disease pathology, choice of age-matched controls, postmortem delays, and differences in receptor binding methodologies. Further studies must define the functionality of remaining receptors in Alzheimer's disease and especially the plasticity of muscarinic receptor subtypes.
Vol. 55, No.s 25/26, 1994
Receptor Plasticityin Aging
1987
Novel cholinergic treatments for Alzheimer's disease
Attempts to provide symptomatic relief of Alzheimer's type dementia via cholinergic precursors, cholinesterase inhibitors or nonselective muscarinic agonists have been met with very limited success (see review in 13). The rationale for such therapies is analogous to the design of effective drug regimens for Parkinson's disease, as described above. However, it should be noted that the postsynaptic muscarinic receptors may not be up-regulated in Alzheimer's disease. This lack of denervation supersensitivity could limit the effectiveness of cholinergic drugs. The debilitating side-effects associated with parasympathetic stimulation are especially problematic in elderly patients, further narrowing their therapeutic window. Finally, there are profound difficulties in designing clinical trials to evaluate the therapeutic potential of drugs in this progressive neurodegenerative disorder. Initial disappointment in the clinical efficacy of cholinergic drugs has led some to question the usefulness of the cholinergic theory of Alzheimer's disease (14), although this position has been met with vigorous debate (15-19). There is considerable evidence that other neurotransmitter systems are altered in Alzheimer's disease (20,21). However, the most consistent and pronounced neurochemical deficits can be ascribed to a loss of forebrain cholinergic neurons innervating cortex and hippocampus. There is also excellent agreement between the magnitude of cognitive deficits in patients with Alzheimer's disease and their depletion of choline acetyltransferase, the synthetic enzyme for acetylcholine and a postmortem marker for cholinergic neurons (22). Since the etiology of Alzheimer's disease is currently unknown, novel treatments will be directed towards symptomatic relief of cognitive dysfunction through the enhancement of cholinergic neurotransmission. Potential strategies may include use of presynaptic M2 (autoreceptor) antagonists in combination with selective cholinesterase inhibitors (23), combined administration of cholinergic and 5HT~A agonists (15), or use of subtype-selective muscarinic agonists (see Ehlert, Roeske and Yamamura, this volume). Other approaches may involve restoration of muscarinic receptor plasticity, facilitation of second messenger functions or potentiation of signal transduction pathways. Brain muscarinic receptors in animal models of aging Numerous investigators have reported an age-related loss of brain muscarinic receptors in various animal models (reviewed in 24). Experimental approaches have included assessing subtype selective mRNA expression (25), quantitative receptor autoradiography (26) and radioligand binding techniques (27-30). Limitations of these studies include, in some cases, the number of brain regions examined, use of nonselective muscarinic receptor ligands, and the absence of functional or biochemical correlates to receptor binding. Research in my laboratory has focused on muscarinic receptor plasticity in a rat model of aging. Our working hypothesis is that muscarinic receptors fail to up-regulate in Alzheimer's disease because of an age-related impairment in receptor plasticity. Since Alzheimer's disease is a dementia that occurs late in life, deterioration of compensatory adaptive processes would exacerbate the progressive nature of this disorder. A similar theoretical construct relating neural plasticity and aging has been proposed by Agnati and colleagues (31), dubbed the "red queen theory" after the character in Lewis Carroll's book Through the Looking Glass who was always running faster and faster just to keep up .
1988
Receptor Plasticity in Aging
Frontal Cortex
3000 ! ~_ 2500
~ ~i
1
Hypothalamus
,oooi l Control ~MeATR
ooo_ Iii 1500
Vol. 55, No.s 25/26, 1994
/
ooo 500
o 3-6
9-12
24-27
3-6
9-12
24-27
Age ( m o n t h s ) Fig. 1 Density of muscarinic receptors in frontal cortex and hypothalamus of young, adult and senescent rats treated with intracerebroventricular (ivt) methylatropine (MeATR) or oxotremorine (OXO), determined from saturation studies of 3H-QNB binding. Male, Fischer 344 rats were infused with MeATR or OXO (3/zg/2 pl/h, ivt) for three weeks. Muscarinic receptor affinity was the same for all ages and treatment groups (K~ = 40-80 pM). *p<.05 compared to age-matched controls (adapted from 32,33) Our experimental design has been to compare adaptive muscarinic receptor changes following chronic (three weeks) intracerebroventricular infusions of cholinergic drugs to young (3-6 months), adult (9-12 months) and senescent (24-27 months) Fischer 344 rats. While young and adult animals administered methylatropine or oxotremorine exhibit compensatory changes in the density of muscarinic receptors in frontal cortex and hypothalamus, identically treated senescent rats show no changes in 3H-QNB binding (32,33). These data are summarized in Fig. 1. Interestingly, the muscarinic receptor upor down-regulation observed in the hypothalamus of young rats was paralleled by alterations in their hypothermic response to a muscarinic agonist (33). In contrast, senescent rats showed no such compensatory pharmacologic adaptations after long-term exposure to cholinergic drugs. Similar observations of reduced muscarinic receptor plasticity in senescent animals have been reported by other investigators (34-37). Long-term (4 weeks) treatment with piracetam increases muscarinic receptor density and function in frontal cortex of senescent, but not young, mice (38,39). However, treatment with this nootropic drug does not restore muscarinic receptor plasticity (39). Pintor and colleagues (36,37) have also noted an agerelated impairment in the rate of recovery of brain muscarinic receptors that down-regulate in rats exposed to organophosphate cholinesterase inhibitors. Finally, the potential role of presynaptic terminals in facilitating muscarinic receptor plasticity must be considered in light of the observations by Vige and Briley (40). These investigators found that lesions of cholinergic cell bodies in the nucleus basalis prevent scopolamine-induced up-regulation of muscarinic receptors in young rats. Perhaps the loss of eholinergic projection neurons with aging could relate to the age-related impairments in muscarinic receptor plasticity.
Vol. 55, No.s 25/26, 1994
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1989
Age-related changes in muscarinic receptor coupling and signal transduction Aging also affects the coupling of brain muscarinic receptors to crucial membranebound proteins, such as G-proteins mediating second messenger systems. Roth and colleagues have shown that age-related reductions in muscarinic-stimulated, dopamine release from striatal slices are due, in part, to impaired muscarinic receptor coupling to Gproteins (41). Similar results were seen in hippocampal slices from senescent rats (42). Potential age-related differences in the effects of chronic drug treatments or experimental brain lesions on muscarinic receptor coupling or on expression of mRNA for particular muscarinic receptors remain to be defined experimentally. Hence, it is possible that senescent animals may show additional deficiencies in plasticity of muscarinic receptor mediated signal transduction or adaptive expression of muscarinic receptor subtypes. It may also be possible to modify muscarinic-stimulated signal transduction through the actions of neuromodulatory peptides. Recent experiments from my laboratory have examined the possible influence of several neuropeptides on muscarinic receptor binding and function in fronto-parietal cortex of young and senescent Fischer 344 rats (43). Low concentrations (100 nM) of cholecystokinin, neurotensin and vasoactive intestinal polypeptide (VIP), added in vitro, enhance carbachol-stimulated phosphoinositide metabolism in cortical miniprisms from both young and senescent rats, while somatostatin is ineffective. Interestingly, the VIP receptor antagonist d-parachloro-Phe 6, Leu~7-VIP significantly inhibits phosphoinositide hydrolysis by increasing the ECs0 for carbachol. These neuropeptide actions are not due to changes in the number or affinity of 3H-QNB binding sites nor on agonist conformation states of the muscarinic receptor. Furthermore, the neuropeptide modulation of phosphoinositide metabolism is not due to presynaptic release of acetylcholine and is selective for muscarinic systems, as norepinephrine-stimulated phosphoinositide hydrolysis is not affected. Neuropeptide-induced increases in carbacholmediated phosphoinositide metabolism are likely due to a selective enhancement of muscarinic receptor-effector coupling within postsynaptic membranes. Hence, it is possible that pharmacologic manipulation of peptidergic processes could improve cholinergic neurotransmission in brains of senescent animals.
Conclusions Effectively treating age-related brain disorders remains a crucial challenge for today's clinicians and researchers. One of the numerous issues affecting the design and implementation of novel treatment strategies for Parkinson's disease and Alzheimer's-type dementia is that of receptor plasticity. In the case of Parkinson's disease, dopaminergic receptor supersensitivity may potentiate the actions of levodopa and other dopamine agonists, but continued receptor adaptations may limit the long-term efficacy of such drugs. For Alzheimer's disease patients there appears to be an age-related impairment in muscarinic receptor plasticity. This makes it more difficult for cholinergic drugs to improve the cognitive deficits associated with this disorder, but may predict fewer problems with continuous receptor stimulation. Further research may provide additional opportunities for manipulating receptor-mediated signal transduction or expression of receptor subtypes, thereby enhancing neuronal communication and function in age-related brain disorders.
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Acknowledgements The dedicated and expert technical assistance of M. Andrea Rice, Darrell Polk, Winston Powell, Joan Whiteman, George Brown and David McCracken is gratefully acknowledged. Portions of the author's work cited in this paper were supported by the American Federation for Aging Research, the Alzheimer's Disease and Related Disorders Association and the National Institute on Aging.
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