The basal ganglia cholinergic neurochemistry of progressive supranuclear palsy and other neurodegenerative diseases.

BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder involving motor and cognitive dysfunction. Currently, there is no effective treatment either for symptomatic relief or disease modification. This relates, in part, to a lack of knowledge of the underlying neurochemical abnormalities, including cholinergic receptor status in the basal ganglia. AIM: To measure muscarinic M2 and M4 receptors in the basal ganglia in PSP. METHODS: The muscarinic M2 (presynaptic) and M4 (postsynaptic) receptors in the striatum, pallidum and adjacent insular cortex were autoradiographically measured in pathologically confirmed cases of PSP (n = 18), and compared with cases of Lewy body dementias (LBDs; n = 45), Alzheimer's disease (AD; n = 39) and controls (n = 50). RESULTS: In cases of PSP, there was a reduction in M2 and M4 receptors in the posterior caudate and putamen compared to controls, but no significant changes in the pallidum. Cases with AD showed lower M2 receptors in the posterior striatum. Groups with LBD and AD showed higher M2 binding in the insular cortex compared with controls. CONCLUSIONS: The results suggest loss of posterior striatal cholinergic interneurones in PSP, and reduction in medium spiny projection neurones bearing M4 receptors. These results should be taken in the context of more widespread pathology in PSP, but may have implications for future trials of cholinergic treatments.

Cholinergic nicotinic receptor involvement in movement disorders associated with Lewy body diseases. An autoradiography study using [(125)I]alpha-conotoxinMII in the striatum and thalamus.

The presence of alpha6 subunit containing nicotinic acetylcholine receptors on nigrostriatal dopaminergic neurons has been demonstrated in rodents and monkeys. [(125)I]alpha-conotoxinMII is a radioligand that binds to alpha6, and also alpha3 subunits of nicotinic acetylcholine receptors (nAChRs). In the present study, we have compared the distribution of [(125)I]alpha-conotoxinMII binding in post mortem human tissue from four groups of patients: individuals with dementia with Lewy bodies displaying extra-pyramidal features (DLB + EPF), DLB without extra-pyramidal features (DLB - EPF) Parkinson's disease without dementia (PD) and age-matched controls. Reduced binding was observed in the putamen and caudate in PD and both DLB groups. In DLB patients, the decline was greater in DLB + EPF compared to DLB - EPF group. The declines in nicotinic receptor binding in the striatum were in part paralleled by reductions in the striatal dopamine transporter. In the thalamus, [(125)I]alpha-conotoxinMII binding was significantly reduced in the centromedian nucleus in both DLB groups, and also in the parafascicular nucleus in the DLB - EPF group. In DLB + EPF and PD patients, there was decreased binding in the ventral lateral nucleus. This study demonstrates alterations of alpha6 and/or alpha3 nAChRs binding in DLB and PD, which are likely to relate to extra-pyramidal symptoms.

Cholinergic systems in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease characterized by akinetic-rigid features, falls, a supranuclear gaze palsy and subcortical dementia. Pathologically, there is abnormal accumulation of tau protein. Cholinergic deficits are thought to underlie the postural instability and cognitive impairment of PSP, but trials of cholinergic agonists and cholinesterase inhibitors have failed to show improvement in motor function, quality of life and cognitive impairment. The five cortico-basal ganglia loops, linking functionally related areas of the brain, are damaged in PSP, leading to specific clinical deficits. Cholinergic dysfunction is related to loss of cholinergic interneurons in the striatum, compounded by reduced inputs into the circuits from other cholinergic nuclei, such as the pedunculopontine nucleus and nucleus basalis of Meynert. Normal cholinergic transmission requires the presence of intact cholinergic neurons capable of releasing sufficient acetylcholine, and functional muscarinic and nicotinic receptors. Whilst there is evidence from autopsy and in vivo studies of loss of cholinergic neurons in PSP, the receptor status is unknown. This may be critical to understanding the basis for the poor therapeutic response to cholinomimetics. Symptomatic treatment using cholinergic drugs may thus be improved by more specific targeting of cholinergic receptors or nuclei. There is also evidence that cholinergic agents may have disease-modifying effects. This article reviews the key clinical features of PSP, along with normal basal ganglia anatomy and cholinergic transmission. Cholinergic deficits based on clinical and neurochemical parameters are then discussed, before concluding with suggested future directions for cholinergic treatments.

Clinical presentations in monozygotic twins with dementia with Lewy bodies.

BACKGROUND: Dementia with Lewy bodies (DLB) is widely recognized as the second most common neurodegenerative cause of dementia in patients over the age of 65. The clinical distinction between DLB and Alzheimers's disease (AD) can be difficult due to the significant clinical overlap between the two disorders. Although the specificity of current consensus criteria is high, the sensitivity of case detection is lower and more variable. In some cases, the diagnosis is only made at postmortem examination. CASE REPORT: Monozygotic twins with the neuropathological diagnosis of Lewy body disease are presented in this report. Despite a very similar presentation and a comparable course of illness, the twins received different clinical diagnoses during life, one DLB and the other AD. This highlights the difficulty of making a clinical diagnosis of DLB, which very much depends on recognizing the features of fluctuation in level of awareness, hallucinations, delusions and the occurrence of falls, and the interpretation of the importance of these signs and symptoms. Pathological examination was virtually identical for the two cases showing the classic neuropathological features of Lewy Body disease.

Visual hallucinations are associated with lower alpha bungarotoxin binding in dementia with Lewy bodies.

Patients with dementia with Lewy bodies (DLB) commonly experience psychotic symptoms, most notably visual hallucinations. Previously, it has been shown that visual hallucinations in DLB are associated with reduced cortical choline acetyltransferase activity, a marker of cholinergic innervation, but not with predominantly postsynaptic muscarinic M1 receptor binding. In the present investigation, nicotinic acetylcholine receptor (nAChR) levels in the temporal cortex (Brodmann's areas [BA] 20 and 36) were measured in a group of 24 prospectively assessed DLB patients; comparisons were made between groups with or without visual and auditory hallucinations and delusional misidentification. Visual hallucinations and delusional misidentification were associated with lower [(125)I]alpha bungarotoxin binding in areas 36 and 20 (P<.05), but not with changes in [(3)H]epibatidine binding. There were no significant associations with auditory hallucinations. [(3)H]epibatidine, but not [(125)I]alpha bungarotoxin, binding for all DLB cases was reduced compared to controls (P<.001). Loss of cortical alpha 7 nicotinic receptors may contribute to hallucinations and delusional misidentification in DLB, with implications for treatment and understanding the mechanisms of psychotic symptoms in dementia.

Nicotine binding in human striatum: elevation in schizophrenia and reductions in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease and in relation to neuroleptic medication.

Striatal nicotinic acetylcholine receptors with high affinity for nicotinic agonists are involved with the release of a number of neurotransmitters, including dopamine. Previous findings as to whether these receptors are changed in Parkinson's disease and Alzheimer's disease are inconsistent and no previous investigations have focused on these receptors in dementia with Lewy bodies and schizophrenia, which are also associated with disorders of movement. The present autoradiographic study of striatal [3H]nicotine binding in Alzheimer's and Parkinson's diseases, dementia with Lewy bodies and schizophrenia was conducted with particular reference to the potentially confounding variables of tobacco use and neuroleptic medication. [3H]Nicotine binding in both dorsal and ventral caudate and putamen was significantly reduced in Parkinson's disease (43-67%, n=13), Alzheimer's disease (29-37%, n=13) and dementia with Lewy bodies (50-61%, n=20) compared to age-matched controls (n=42). Although tobacco use in the control group was associated with increased [3H]nicotine binding (21-38%), and neuroleptic treatment in dementia with Lewy bodies and Alzheimer's disease was associated with reduced [3H]nicotine binding (up to 29%), differences between neurodegenerative disease groups and controls persisted in subgroups of Alzheimer's disease cases (26-33%, n=6, in the ventral striatum) and dementia with Lewy body cases (30-49%, n=7, in both dorsal and ventral striatum) who had received no neuroleptic medication compared to controls who had not smoked (n=10). In contrast, striatal [3H]nicotine binding in a group of elderly (56-85 years) chronically medicated individuals with schizophrenia (n=6) was elevated compared with the entire control group (48-78%, n=42) and with a subgroup that had smoked (24-49%, n=8). The changes observed in [3H]nicotine binding are likely to reflect the presence of these receptors on multiple sites within the striatum, which may be differentially modulated in the different diseases. Further study is warranted to explore which nicotinic receptor subunits and which neuronal compartments are involved in the changes in [3H]nicotine binding reported, to aid development of potential nicotinic receptor therapy.

Striatal dopaminergic markers in dementia with Lewy bodies, Alzheimer's and Parkinson's diseases: rostrocaudal distribution.

Dementia with Lewy bodies (DLB) is a neuropsychiatric disease associated with extrapyramidal features which differ from those of Parkinson's disease, including reduced effectiveness of L-dopa and severe sensitivity reactions to neuroleptic drugs. Distinguishing Alzheimer's disease from DLB is clinically relevant in terms of prognosis and appropriate treatment. Dopaminergic activities have been investigated at coronal levels along the rostrocaudal striatal axis from a post-mortem series of 25 DLB, 14 Parkinson's disease and 17 Alzheimer's disease patients and 20 elderly controls. [(3)H]Mazindol binding to the dopamine uptake site was significantly reduced in the caudal putamen in DLB compared with controls (57%), but not as extensively as in Parkinson's disease (75%), and was unchanged in Alzheimer's disease. Among three dopamine receptors measured (D1, D2 and D3), the most striking changes were apparent in relation to D2. In DLB, [(3)H]raclopride binding to D2 receptors was significantly reduced in the caudal putamen (17%) compared with controls, and was significantly lower than in Parkinson's disease at all levels. D2 binding was significantly elevated at all coronal levels in Parkinson's disease compared with controls, most extensively in the rostral putamen (71%). There was no change from the normal pattern of D2 binding in Alzheimer's disease. The only significant alteration in D1 binding ([(3)H]SCH23390) in the groups examined was an elevation (30%) in the caudal striatum in Parkinson's disease. There were no differences in D3 binding, measured using [(3)H]7-OH-DPAT, in DLB compared with controls. A slight, significant decrease in D3 binding in the caudal striatum of Parkinson's disease (13%) patients and an increase in Alzheimer's disease (20%) in the dorsal striatum at the level of the nucleus accumbens were found. The concentration and distribution of dopamine were disrupted in both DLB and Parkinson's disease, although in the caudate nucleus the loss of dopamine in DLB was uniform whereas in Parkinson's disease the loss was greater caudally. In the caudal putamen, dopamine was reduced by 72% in DLB and by 90% in Parkinson's disease. The homovanillic acid : dopamine ratio, a metabolic index, indicated compensatory increased turnover in Parkinson's disease, which was absent in DLB despite the loss of substantia nigra neurons (49%), dopamine and uptake sites. These differences between DLB, Parkinson's disease and Alzheimer's disease may explain some characteristics of the extrapyramidal features of DLB and its limited response to L-dopa and severe neuroleptic sensitivity. The distinct changes in the rostrocaudal pattern of expression of dopaminergic parameters are relevant to the interpretation of the in vivo imaging and diagnosis of DLB.

Dopaminergic activities in the human striatum: rostrocaudal gradients of uptake sites and of D1 and D2 but not of D3 receptor binding or dopamine.

The human striatum, which receives dopaminergic innervation from the substantia nigra and ventral tegmental area (cell groups A8, A9 and A10), has structural and functional subdivisions both rostrocaudally and dorsoventrally. These relate to motor and non-motor origins of cortical projections and the specific areas of the substantia nigra and ventral tegmental area providing dopaminergic innervation. In the present study, we have evaluated the distribution of a number of dopaminergic parameters in the caudate, putamen and nucleus accumbens at separate coronal levels in a post mortem study in a series of elderly normal individuals aged 55-94 years, with analysis of the effect of post mortem variables. Dopamine D1 receptor density displayed a rostrocaudally declining gradient in the putamen but not in the caudate, such that at levels posterior to the anterior commissure, there was significantly lower D1 binding in the putamen compared to the caudate. The density of dopamine D2 receptors was similar in the putamen and caudate, increasing rostrocaudally. The density of dopamine uptake sites exhibited an increasing rostrocaudal gradient in the caudate, especially ventrally, but not in the putamen, where binding was more constant. The dopamine D3 receptor was concentrated in the ventral striatum, particularly the nucleus accumbens, although there was no evidence of a rostrocaudal gradient. With respect to striosome-matrix compartmentalization, there was no complete segregation, although D1 and D3 receptors were concentrated in striosomes, whereas D2 receptors and uptake sites showed higher density in the matrix. Levels of dopamine were similar in the caudate and putamen, and were significantly elevated at levels including the nucleus accumbens and the anterior commissure. Homovanillic acid and the metabolic index (homovanillic acid/dopamine ratio) were significantly higher in the putamen compared to the caudate, especially at levels from and caudal to the anterior commissure. These distributions of dopamine receptors and metabolic indicators, reflecting the different functional domains of the striatum, are relevant to the interpretation of current in vivo imaging of the dopamine transporter and receptors in neurological and psychiatric disorders. They provide information to assist in the detection of perturbations in expression, in specific diseases, at particular points on rostrocaudal, lateromedial and dorsoventral axes, a level of resolution beyond current neuroimaging capability.

Distribution of histamine H3-receptor binding in the normal human basal ganglia: comparison with Huntington's and Parkinson's disease cases.

It is now widely recognized that histamine acts as a neurotransmitter in the mammalian central nervous system. Three selective histamine receptors have been described, all of which are present in the basal ganglia. This study is a detailed, quantitative, autoradiographical examination of the densities of histamine H3-receptors in coronal sections of human basal ganglia, using the selective ligand [3H]-(R)-alpha-methylhistamine. [3H]-(R)-alpha-methylhistamine binding was highest within the external and internal segments of the globus pallidus together with the substantia nigra. High levels were also found in the striatum, where density was significantly higher (P < 0.05) at a pre-, as opposed to post-, anterior commissure coronal level. Within the striatum, binding was noticeably higher in both the nucleus accumbens and acetylcholinesterase-deficient striosomes, while being undetectable in the subthalamic nucleus and very low in both the ventroanterior and ventrolateral thalamic nuclei. An intermediate level of binding, often with a laminar distribution, was seen in the insular cortex. [3H]-(R)-alpha-methylhistamine binding was also examined in both Parkinson's disease and Huntington's disease. No difference from control receptor density was found in any area examined in Parkinson's disease, while values were significantly lower in caudate (P < 0.001), putamen (P < 0.001), external (P < 0.001) and internal (P < 0.05) globus pallidus, although not the insular cortex, in Huntington's disease cases. These data suggest that H3-receptors are present upon striatonigral projection neurons of the direct and indirect movement pathways thus providing histaminergic control over the activity of both these circuits.

Nigrostriatal dopaminergic activities in dementia with Lewy bodies in relation to neuroleptic sensitivity: comparisons with Parkinson's disease.

BACKGROUND: In dementia with Lewy bodies (DLB) mild extrapyramidal symptoms are associated with moderate reductions in substantia nigra neuron density and concentration of striatal dopamine. Many DLB patients treated with typical neuroleptics suffer severe adverse reactions, which result in decreased survival. METHODS: In a series of DLB cases, with and without neuroleptic sensitivity, substantia nigra neuron densities, striatal dopamine and homovanillic acid concentrations, and autoradiographic [3H]mazindol and [3H]raclopride binding (to the dopamine transporter and D2 receptor, respectively) were analyzed and compared to control and idiopathic Parkinson's disease cases. RESULTS: D2 receptors were up-regulated in neuroleptictolerant DLB and Parkinson's disease compared to DLB without neuroleptic exposure and controls. D2 receptors were not up-regulated in DLB cases with severe neuroleptic reactions. Dopamine uptake sites were reduced concomitantly with substantia nigra neuron density in Parkinson's disease compared to controls, but there was no significant correlation between substantia nigra neuron density and [3H]mazindol binding in DLB groups. There was no significant difference in substantia nigra neuron density, [3H]mazindol binding, and dopamine or homovanillic acid concentration between neuroleptic-tolerant and -sensitive groups. CONCLUSIONS: Failure to up-regulate D2 receptors in response to neuroleptic blockade or reduced dopaminergic innervation may be the critical factor responsible for neuroleptic sensitivity.

Dopamine and nicotinic receptor binding and the levels of dopamine and homovanillic acid in human brain related to tobacco use.

Reports of a reduction in the risk of developing Parkinson's disease and Alzheimer's disease in tobacco smokers, together with the loss of high-affinity nicotine binding in these diseases, suggest that consequences of nicotinic cholinergic transmission may be neuroprotective. Changes in brain dopaminergic parameters and nicotinic receptors in response to tobacco smoking have been assessed in this study of autopsy samples from normal elderly individuals with known smoking histories and apolipoprotein E genotype. The ratio of homovanillic acid to dopamine, an index of dopamine turnover, was reduced in elderly smokers compared with age matched non-smokers (P<0.05) in both the caudate and putamen. Dopamine levels were significantly elevated in the caudate of smokers compared with non-smokers (P<0.05). However there was no significant change in the numbers of dopamine (D1, D2 and D3) receptors or the dopamine transporter in the striatum, or for dopamine D1 and D2 receptors in the hippocampus in smokers compared with non-smokers or ex-smokers. The density of high-affinity nicotine binding was higher in smokers than non-smokers in the hippocampus, entorhinal cortex and cerebellum (elevated by 51-221%) and to a lesser extent in the striatum (25-55%). The density of high-affinity nicotine binding in ex-smokers was similar to that of the non-smokers in all the areas investigated. The differences in high-affinity nicotine binding between smokers and the non- and ex-smokers could not be explained by variation in apolipoprotein E genotype. There were no differences in alpha-bungarotoxin binding, measured in hippocampus and cerebellum, between any of the groups. These findings suggest that chronic cigarette smoking is associated with a reduction of the firing of nigrostriatal dopaminergic neurons in the absence of changes in the numbers of dopamine receptors and the dopamine transporter. Reduced dopamine turnover associated with increased numbers of high-affinity nicotine receptors is consistent with attenuated efficacy of these receptors in smokers. A decrease in striatal dopamine turnover may be a mechanism of neuroprotection in tobacco smokers that could delay basal ganglia pathology. The current findings are also important in the interpretation of measurements of nicotinic receptors and dopaminergic parameters in psychiatric conditions such as schizophrenia, in which there is a high prevalence of cigarette smoking.

Nicotinic and muscarinic cholinergic receptor binding in the human hippocampal formation during development and aging.

High-affinity nicotine, alpha-bungarotoxin (alpha BT) and muscarinic receptor binding was measured in the human hippocampal formation in a series of 57 cases aged between 24 weeks gestation and 100 years. Changes in nicotine receptor binding during development and aging were more striking than differences in alpha BT and muscarinic binding. Nicotine binding was higher at the late foetal stage than at any other subsequent time in all areas investigated. In the hippocampus a fall in binding then occurred within the first six months of life, with little or no subsequent fall during aging, whereas in the entorhinal cortex and the presubiculum the major loss of nicotine binding occurred after the fourth decade. alpha BT binding was significantly elevated in the CA 1 region, but in no other region of the hippocampus, in the late foetus, and there was also a fall in alpha BT binding in the entorhinal cortex during aging from the second decade. The modest changes in total muscarinic binding, which appeared to reflect those in M1 and M3 + 4 rather than M2 binding, were a rise in the entorhinal cortex between the foetal stage and childhood and a tendency for receptors to fall with age in the hippocampus and subicular complex. These findings implicate mechanisms controlling the expression of nicotinic receptors to a greater extent than muscarinic receptors in postnatal development and aging in the human hippocampus.

Striatal dopaminergic loss without parkinsonism in a case of corticobasal degeneration.

Neurochemical analyses of post-mortem brain from cases of corticobasal degeneration are extremely rare although nearly 100 cases have been reported in the literature. We detail findings of neurotransmitter derangement in the basal ganglia of a case of neuropathologically confirmed corticobasal degeneration, who presented with dementia. The implications of severe neuronal loss in the substantia nigra and extremely low levels of dopamine and its metabolites in the striatum are considered in relation to the absence of an intrinsic extrapyramidal syndrome.

Glutamate receptor binding in the human hippocampus and adjacent cortex during development and aging.

Distinct patterns of age-related alterations in NMDA (MK801 binding) and non-NMDA, AMPA (CNQX), and kainate binding have been identified in human hippocampus and parahippocampal gyrus in normal individuals with no evidence of degenerative brain disease ranging in age from 24 gestational weeks to 94 years. Whereas MK801 binding did not alter substantially over this age range, CNQX binding rose from low levels in the fetus to maximum levels between neonate and middle age, and kainate binding declined extensively from the perinatal to adult stage. Following maturity, there were no significant changes in kainate binding, although MK801 binding increased in CA1 and CA3 and CNQX binding declined in several regions, particularly CA2 and subiculum. For each receptor binding the timing of these fluctuations ocurring during development and aging varied within different regions of the dentate gyrus, hippocampus proper, subicular complex, and entorhinal cortex examined. The transient peaks of receptor binding are likely to reflect processes of synaptogenesis and pruning and may provide clues regarding the role of the different glutamate receptor subtypes in various pathologies of the hippocampus and adjacent cortex associated with developmental disorders (of genetic origin or due to perinatal trauma or insult). The absence of substantial changes in any subtype examined from middle to old age suggests alterations in transmitter binding to these glutamate receptors are not involved in senescent neurodegeneration.

Beta-amyloidosis in normal aging and transmitter signaling in human temporal lobe.

Interactions between abnormal amyloid precursor protein metabolism and cholinergic dysfunction are increasingly apparent. Both of these major features of Alzheimer's disease occur in restricted loci in normal aging--a potential model for early Alzheimer type pathology. Entorhinal cortex is particularly vulnerable to beta-amyloidosis and compared with other cortical areas is remarkable for the relatively high density of nicotinic (3H-nicotine) but not other cholinergic or glutamate receptor binding. With increasing age, post-maturity, there is a persistent decline in nicotinic receptor binding in entorhinal cortex whereas muscarinic M1 and non-M1, glutamate NMDA and non-NMDA receptors are spared. Normal elderly individuals, distinguished by the absence of beta A4 immunoreactive plaques in this area, are differentiated from those with plaques by higher nicotine binding. Amongst individuals with an established history of smoking tobacco, nicotinic receptor binding and hippocampal choline acetyltransferase were elevated compared with non-smokers and preliminary evidence indicates a reduced density of cortical plaques. These findings are consistent with the hypothesis that down regulation of the nicotinic cholinergic receptor--a ligand gated calcium channel known to control the expression of neurotrophins--plays a role in the evolution of Alzheimer-type pathology.

Transmitters in the developing and senescent human brain.

During development and throughout adult life, modeling of CNS structure and function occurs as a result of experience. Transmitters play a central role in this mechanism both directly and indirectly (through control of neurotrophin expression) by governing synapse formation, elimination or consolidation. Cholinergic and excitatory amino acid transmitter system activities have been examined in postmortem human brain obtained from normal individuals varying from the prenatal period to old age. Whereas glutamate NMDA receptor binding (measured using MK801) was not substantially altered across the postnatal period, dramatic and differing patterns of choline acetyltransferase (ChAT) activity were evident. Thus, in the cerebellum, ChAT activity was 10-fold higher in fetal compared to adult individuals whereas in the hippocampus there was little or no activity in the fetus and activity rose postnatally to reach a maximum in middle age and then declined to half that level by the tenth decade. Acetylcholinesterase (AChE) histochemical reactivity paralleled the developmental pattern for ChAT in the hippocampus and adjacent cortex with respect to fiber reactivity. These findings indicate that cholinergic synaptic plasticity may be restricted to the prenatal period in cerebellum but occur in both the postnatal period and throughout adult life in the hippocampus and cortex, a concept consistent with the temporal and regional expression of cholinoneurotrophins (NGF and related peptides). Vulnerability of the hippocampus and cortex to age-related pathology such as beta-amyloidosis and neuritic plaque formation may relate to the extended period of cholinergic synaptic sculpting in these areas.

Regional patterns of cholinergic and glutamate activity in the developing and aging human brain.

The levels of choline acetyltransferase (ChAT) and the binding activity of N-methyl-D-aspartate (NMDA) and non-NMDA receptors have been measured in the hippocampus, entorhinal cortex, frontal cortex and cerebellum, in a series of human brains from 24 weeks gestation to 100 years. The patterns of ChAT and glutamate receptor activity during aging and development were strikingly different in the different brain areas. In the hippocampus and associated cortex, ChAT activity did not reach a peak until middle age, when it almost immediately started to decline by 50-60% to the 10th decade, whereas in the frontal cortex ChAT peaked transiently in the infant and then stayed constant during aging. In the cerebellum ChAT activity was very high in the foetus and fell in the neonate to maintain a constant level more in line with the concentrations found in the other brain areas through the rest of life. The high levels of ChAT in the foetal cerebellum were not associated with high acetylcholinesterase (AChE) content, which tended to increase during development, and was present initially in Purkinje cells (foetus and neonate) and the molecular layer in the adult. In the hippocampus and entorhinal cortex, autoradiographic [3H]MK-801 binding was relatively constant throughout life, however, [3H]CNQX binding rose from the perinatal period up to a peak in the 1st or 2nd decade and then tended to fall with age. In the cerebellum, autoradiographic binding of both ligands rose from the foetal period to reach a plateau by the age of 10 years and there was no apparent further change during aging. These data on cholinergic and glutamatergic phenotypic changes during development and senescence reflect marked variations in regional plasticity and aging within and between the two transmitter systems and are likely to contribute to our understanding of their role in the different brain areas investigated.

Autoradiographic comparison of cholinergic and other transmitter receptors in the normal human hippocampus.

The vulnerability of the human hippocampal complex to disease, trauma, and aging indicates the necessity to target this area therapeutically. The distribution and density of transmitter receptors provide a rational basis for this approach, and in this study the topography of 11 different pharmacological sites is compared with the cholinergic innervation, which is particularly vulnerable in dementia. The regional distribution of cholinergic innervation to the normal adult human hippocampus and adjacent cortex, marked by acetylcholinesterase (AChE) fiber and terminal reactivity, is notable for its concentration in CA2/3 of Ammon's horn and the dentate fascia. Neither nicotinic (high-affinity nicotine binding) nor muscarinic ("M1" or "M2") cholinergic receptor binding paralleled this distribution. In Ammon's horn, 5-HT2 and kainate receptor binding more closely resembled the pattern of AChE, being concentrated in CA2-4 compared with CA1. By contrast, muscarinic M1 and M2, 5-HT1A, benzodiazepine (including zolpidem-insensitive binding), NMDA (MK801), and AMPA/QUIS receptors were higher in CA1 and/or subiculum. Kainate binding, like AChE, was high in CA4. 5-HT2 and nicotinic binding partially mimicked the pattern of AChE around the granule layer. In the subicular complex and parahippocampal gyrus, where cholinergic activity is relatively lower, muscarinic, 5-HT1A, and benzodiazepine binding were relatively high and the nicotinic receptor was remarkable for its highest density compared to other areas examined. In stratum lacunosum-moleculare of CA1, which was relatively low in AChE activity, there was a dense band of nicotinic, M2, and benzodiazepine receptor binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoradiographic distribution of [3H]nicotine binding in human cortex: relative abundance in subicular complex.

Distinct patterns of [3H]nicotine (3 nM) binding were apparent in various regions of adult human neo- and archicortex. Receptor binding was greatest in the subicular complex--particularly presubiculum--and entorhinal cortex, where it was prominent in the characteristic parvo- and magnocellular islands of these regions and in middle layers of entorhinal cortex. In somatosensory cortex (Brodmann areas 3, 1 and 2) and occipital (area 17) cortex binding was highest in the upper and lower layers, and relatively sparse in the sensory input, layer IV. In primary motor (area 4) and temporal (area 21) cortex, binding in the outer half of the cortical ribbon was denser than that in the inner half and a distinct band was apparent in temporal and cingulate (area 32) in the lower portion of layer III. In prefrontal association cortex the pattern of binding was less distinct although slightly higher in the lower architectonic layers. There was generally little binding in the hippocampus (areas CA1-4) and dentate gyrus with the exception of the stratum lacunosum moleculare in CA2-3 and, to a lesser extent, supra- and subgranule zones of the dentate. These patterns of reactivity, which are distinct from that of the major cortical cholinergic innervation, suggest that the nicotinic receptor, detected using nanomolar concentrations of [3H]nicotine, may primarily be associated with intracortical circuitry in the neocortex. The relatively high density in entorhinal and subicular regions may be related to the extensive phylogenetic development of these regions which has occurred in conjunction with the development of multimodal association circuitry in the human cortex.