Changes In Cholinergic System Research Articles

Cholinergic Basal Forebrain Integrity and Cognition in Parkinson's Disease: A Reappraisal of Magnetic Resonance Imaging Evidence.

Cognitive impairment is a well-recognized and debilitating symptom of Parkinson's disease (PD). Degradation in the cortical cholinergic system is thought to be a key contributor. Both postmortem and in vivo cholinergic positron emission tomography (PET) studies have provided valuable evidence of cholinergic system changes in PD, which are pronounced in PD dementia (PDD). A growing body of literature has employed magnetic resonance imaging (MRI), a noninvasive, more cost-effective alternative to PET, to examine cholinergic system structural changes in PD. This review provides a comprehensive discussion of the methodologies and findings of studies that have focused on the relationship between cholinergic basal forebrain (cBF) integrity, based on T1- and diffusion-weighted MRI, and cognitive function in PD. Nucleus basalis of Meynert (Ch4) volume has been consistently reduced in cognitively impaired PD samples and has shown potential utility as a prognostic indicator for future cognitive decline. However, the extent of structural changes in Ch4, especially in early stages of cognitive decline in PD, remains unclear. In addition, evidence for structural change in anterior cBF regions in PD has not been well established. This review underscores the importance of continued cross-sectional and longitudinal research to elucidate the role of cholinergic dysfunction in the cognitive manifestations of PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dynamic balance and gait impairments in Parkinson's disease: novel cholinergic patterns.

The cholinergic system has been implicated in postural deficits, in particular falls, in Parkinson's disease (PD). Falls and freezing of gait typically occur during dynamic and challenging balance and gait conditions, such as when initiating gait, experiencing postural perturbations, or making turns. However, the precise cholinergic neural substrate underlying dynamic postural and gait changes remains poorly understood. The aim of this study was to investigate whether brain vesicular acetylcholine transporter binding, as measured with [18F]-fluoroethoxybenzovesamicol binding PET, correlates with dynamic gait and balance impairments in 125 patients with PD (mean age 66.89 ± 7.71 years) using the abbreviated balance evaluation systems test total and its four functional domain sub-scores (anticipatory postural control, reactive postural control, dynamic gait, and sensory integration). Whole brain false discovery-corrected (P < 0.05) correlations for total abbreviated balance evaluation systems test scores included the following bilateral or asymmetric hemispheric regions: gyrus rectus, orbitofrontal cortex, anterior part of the dorsomedial prefrontal cortex, dorsolateral prefrontal cortex, cingulum, frontotemporal opercula, insula, fimbria, right temporal pole, mesiotemporal, parietal and visual cortices, caudate nucleus, lateral and medial geniculate bodies, thalamus, lingual gyrus, cerebellar hemisphere lobule VI, left cerebellar crus I, superior cerebellar peduncles, flocculus, and nodulus. No significant correlations were found for the putamen or anteroventral putamen. The four domain-specific sub-scores demonstrated overlapping cholinergic topography in the metathalamus, fimbria, thalamus proper, and prefrontal cortices but also showed distinct topographic variations. For example, reactive postural control functions involved the right flocculus but not the upper brainstem regions. The anterior cingulum associated with reactive postural control whereas the posterior cingulum correlated with anticipatory control. The spatial extent of associated cholinergic system changes were least for dynamic gait and sensory orientation functional domains compared to the anticipatory and reactive postural control functions. We conclude that specific aspects of dynamic balance and gait deficits in PD associate with overlapping but also distinct patterns of cerebral cholinergic system changes in numerous brain regions. Our study also presents novel evidence of cholinergic topography involved in dynamic balance and gait in PD that have not been typically associated with mobility disturbances, such as the right anterior temporal pole, right anterior part of the dorsomedial prefrontal cortex, gyrus rectus, fimbria, lingual gyrus, flocculus, nodulus, and right cerebellar hemisphere lobules VI and left crus I.

Extra-Striatal Cholinergic System Changes in Dopamine Replacement Therapy Responsive versus Non-Responsive Freezing of Gait in Parkinson's Disease: [18F]-FEOBV PET study

Extra-Striatal Cholinergic System Changes in Dopamine Replacement Therapy Responsive versus Non-Responsive Freezing of Gait in Parkinson's Disease: [18F]-FEOBV PET study

Retro-Walking and Cholinergic System Changes in Parkinson's Disease

Retro-Walking and Cholinergic System Changes in Parkinson's Disease

Topography of cholinergic system changes associated with visuomotor-cognitive multitasking simulating real-life mobility in Parkinson’s disease

Topography of cholinergic system changes associated with visuomotor-cognitive multitasking simulating real-life mobility in Parkinson’s disease

The increased effective connectivity from left middle occipital gyrus to right medial septum/diagonal bands in AD patients after donepezil intervention.

Donepezil enhances the function of cholinergic nerves by increasing the concentration of acetylcholine, thereby improving clinical symptoms in patients with Alzheimer's disease (AD). However, the neural mechanisms of how donepezil modulates the effective connectivity (EC) network of cholinergic system in AD patients remain unknown. We speculated that the effective network of the cholinergic system changes in AD patients after donepezil intervention. We employed resting-state functional magnetic resonance imaging and Granger causality analysis approach to explore changes in the effective connectivity network of the basal forebrain in AD patients before and after donepezil intervention. This study included 32 participants, including 16 healthy controls (HCs) and 16 AD patients. In a 3T MRI scanner, the 16 AD patients were scanned before and after the donepezil intervention. To compare EC differences between the three groups of participants, ANOVA and post-hoc t-tests analysis were employed. Compared to baseline status, AD patients after donepezil intervention had an increased EC from left middle occipital gyrus to right medial septum/diagonal bands. Compared to HCs, AD patients after donepezil intervention had an increased EC from right inferior frontal gyrus/orbit part to right medial septum/diagonal bands, AD patients before donepezil intervention had a reduced EC from right precuneus to right medial septum/diagonal bands. A significant positive correlation was found between EC values in right precuneus and Mini-Mental State Examination in pre-intervention AD patients (r = 0.7338, p = 0.0012). Our study showed that effective connectivity of brain regions associated with the default mode network in the cholinergic pathway was enhanced after donepezil intervention. The results of this study will help us to better understand the neural mechanisms of donepezil intervention in AD and to find clinical targets for intervention.

Cholinergic innervation topography in GBA-associated de novo Parkinson's disease patients.

The most common genetic risk factors for Parkinson's disease are GBA1 mutations, encoding the lysosomal enzyme glucocerebrosidase. Patients with GBA1 mutations (GBA-PD) exhibit earlier age of onset and faster disease progression with more severe cognitive impairments, postural instability and gait problems. These GBA-PD features suggest more severe cholinergic system pathologies. PET imaging with the vesicular acetylcholine transporter ligand 18F-F-fluoroethoxybenzovesamicol (18F-FEOBV PET) provides the opportunity to investigate cholinergic changes and their relationship to clinical features in GBA-PD. The study investigated 123 newly diagnosed, treatment-naïve Parkinson's disease subjects-with confirmed presynaptic dopaminergic deficits on PET imaging. Whole-gene GBA1 sequencing of saliva samples was performed to evaluate GBA1 variants. Patients underwent extensive neuropsychological assessment of all cognitive domains, motor evaluation with the Unified Parkinson's Disease Rating Scale, brain MRI, dopaminergic PET to measure striatal-to-occipital ratios of the putamen and 18F-FEOBV PET. We investigated differences in regional cholinergic innervation between GBA-PD carriers and non-GBA1 mutation carriers (non-GBA-PD), using voxel-wise and volume of interest-based approaches. The degree of overlap between t-maps from two-sample t-test models was quantified using the Dice similarity coefficient. Seventeen (13.8%) subjects had a GBA1 mutation. No significant differences were found in clinical features and dopaminergic ratios between GBA-PD and non-GBA-PD at diagnosis. Lower 18F-FEOBV binding was found in both the GBA-PD and non-GBA-PD groups compared to controls. Dice (P < 0.05, cluster size 100) showed good overlap (0.7326) between the GBA-PD and non-GBA-PD maps. GBA-PD patients showed more widespread reduction in 18F-FEOBV binding than non-GBA-PD when compared to controls in occipital, parietal, temporal and frontal cortices (P < 0.05, FDR-corrected). In volume of interest analyses (Bonferroni corrected), the left parahippocampal gyrus was more affected in GBA-PD. De novo GBA-PD show a distinct topography of regional cholinergic terminal ligand binding. Although the Parkinson's disease groups were not distinguishable clinically, in comparison to healthy controls, GBA-PD showed more extensive cholinergic denervation compared to non-GBA-PD. A larger group is needed to validate these findings. Our results suggest that de novo GBA-PD and non-GBA-PD show differential patterns of cholinergic system changes before clinical phenotypic differences between carriers versus non-carrier groups are observable.

Cholinergic system correlates of postural control changes in Parkinson's disease freezers.

Postural instability and freezing of gait are the most debilitating dopamine-refractory motor impairments in advanced stages of Parkinson's disease because of increased risk of falls and poorer quality of life. Recent findings suggest an inability to efficaciously utilize vestibular information during static posturography among people with Parkinson's disease who exhibit freezing of gait, with associated changes in cholinergic system integrity as assessed by vesicular acetylcholine transporter PET. There is a lack of adequate understanding of how postural control varies as a function of available sensory information in patients with Parkinson's disease with freezing of gait. The goal of this cross-sectional study was to examine cerebral cholinergic system changes that associate with inter-sensory postural control processing features as assessed by dynamic computerized posturography and acetylcholinesterase PET. Seventy-five participants with Parkinson's disease, 16 of whom exhibited freezing of gait, underwent computerized posturography on the NeuroCom© Equitest sensory organization test platform, striatal dopamine, and acetylcholinesterase PET scanning. Findings demonstrated that patients with Parkinson's disease with freezing of gait have greater difficulty maintaining balance in the absence of reliable proprioceptive cues as compared to those without freezing of gait [β = 0.28 (0.021, 0.54), P = 0.034], an effect that was independent of disease severity [β = 0.16 (0.062, 0.26), P < 0.01] and age [β = 0.092 (-0.005, 0.19), P = 0.062]. Exploratory voxel-based analysis revealed an association between postural control and right hemispheric cholinergic network related to visual-vestibular integration and self-motion perception. High anti-cholinergic burden predicted postural control impairment in a manner dependent on right hemispheric cortical cholinergic integrity [β = 0.34 (0.065, 0.61), P < 0.01]. Our findings advance the perspective that cortical cholinergic system might play a role in supporting postural control after nigro-striatal dopaminergic losses in Parkinson's disease. Failure of cortex-dependent visual-vestibular integration may impair detection of postural instability in absence of reliable proprioceptive cues. Better understanding of how the cholinergic system plays a role in this process may augur novel treatments and therapeutic interventions to ameliorate debilitating symptoms in patients with advanced Parkinson's disease.

Cholinergic system changes of falls and freezing of gait in Parkinson's disease.

ObjectivePostural instability and gait difficulties (PIGDs) represent debilitating disturbances in Parkinson's disease (PD). Past acetylcholinesterase positron emission tomography (PET) imaging studies implicate cholinergic changes as significant contributors to PIGD features. These studies were limited in quantification of striatal cholinergic synapse integrity. Vesicular acetylcholine transporter (VAChT) PET ligands are better suited for evaluation of high binding areas. We examined associations between regional VAChT expression and freezing of gait (FoG) and falls.MethodsNinety‐four PD subjects underwent clinical assessment and VAChT ([18F]FEOBV) PET.ResultsThirty‐five subjects (37.2%) reported a history of falls, and 15 (16%) had observed FoG. Univariate volume‐of‐interest analyses demonstrated significantly reduced thalamic (p = 0.0016) VAChT expression in fallers compared to nonfallers. VAChT expression was significantly reduced in the striatum (p = 0.0012) and limbic archicortex (p = 0.004) in freezers compared to nonfreezers. Whole‐brain voxel‐based analyses of FEOBV PET complemented these findings and showed more granular changes associated with falling history, including the right visual thalamus (especially the right lateral geniculate nucleus [LGN]), right caudate nucleus, and bilateral prefrontal regions. Freezers had prominent VAChT expression reductions in the bilateral striatum, temporal, and mesiofrontal limbic regions.InterpretationOur findings confirm and extend on previous PET findings of thalamic cholinergic deficits associated with falling history and now emphasize right visual thalamus complex changes, including the right LGN. FoG status is associated with reduced VAChT expression in striatal cholinergic interneurons and the limbic archicortex. These observations suggest different cholinergic systems changes underlying falls and FoG in PD. Ann Neurol 2019;85:538–549

Combined exposure to methylmercury and manganese during L1 larval stage causes motor dysfunction, cholinergic and monoaminergic up-regulation and oxidative stress in L4 Caenorhabditis elegans

Humans are exposed simultaneously to a variety of neurotoxic agents, including manganese (Mn) and methylmercury (MeHg). Therefore, the study of combined exposures to toxicants is timely. This work aimed to study changes in cholinergic system focusing on acetylcholinesterase (ace-2), monoaminergic system focusing on vesicular monoamine transporter (VMAT, cat-1) expression, to address changes in antioxidant enzymatic systems, namely, the expression of superoxide dismutase (sod-3 and sod-4) and catalase (ctl-3), as well as worm reproduction and locomotion. C. elegans in the L1 larval stage were exposed to Mn, MeHg or both. All analyses were done 24 h after the end of exposure, except for behavior and reproduction tests that were assessed in L4 larval stage worms. The values obtained for lethal dose 50% (LD50) were 17.78 mM for Mn and 30.63 μM for MeHg. It was observed that body bends, pharyngeal pumping and brood size decreased in worms exposed to metals when undergoing combined exposures. Relative mRNA content of ace-2, cat-1, sod-3, sod-4 and ctl-3 was increased at the highest concentration of the interaction (50 mM Mn + 50 μM MeHg). Cholinergic degeneration was observed in all groups co-exposed to both metals. Notably, combined exposure to metals was more toxic to the worms than when exposed to a single metal.

Recent advances in cholinergic imaging and cognitive decline-Revisiting the cholinergic hypothesis of dementia.

Although the cholinergic hypothesis of dementia provided a successful paradigm for the development of new drugs for dementia, this hypothesis has waned in popularity. Cholinergic brain imaging may provide novel insights into the viability of this hypothesis. Cholinergic receptor and forebrain volumetric studies suggest an important role of the cholinergic system in maintaining brain network integrity that may deteriorate with cognitive decline in Alzheimer disease (AD) and Lewy body disorders (LBD). Bidirectional changes in regional receptor expression may suggest the presence of compensatory responses to neurodegenerative injury. Cholinergic system changes are more complex in LBD because of additional subcortical degenerations compared to AD. Cholinergic-dopaminergic interactions affect attentional, verbal learning and executive functions, and impairments in these two transmitter systems may jointly increase the risk of dementia in Parkinson disease. The cholinergic hypothesis is evolving from a primary focus on memory toward expanded cognitive functions modulated by regionally more complex and interactive brain networks. Cholinergic network adaptation may serve as a novel research target in neurodegeneration.

Ameliorative Effect of Ginsenoside Rg1 on Lipopolysaccharide-Induced Cognitive Impairment: Role of Cholinergic System.

Bacterial endotoxin lipopolysaccharide (LPS) can induce systemic inflammation, and therefore disrupt learning and memory processes. Ginsenoside Rg1, a major bioactive component of ginseng, is shown to greatly improve cognitive function. The present study was designed to further investigate whether administration of ginsenoside Rg1 can ameliorate LPS-induced cognitive impairment in the Y-maze and Morris water maze (MWM) task, and to explore the underlying mechanisms. Results showed that exposure to LPS (500μg/kg) significantly impaired working and spatial memory and that repeated treatment with ginsenoside Rg1 (200mg/kg/day, for 30days) could effectively alleviate the LPS-induced cognitive decline as indicated by increased working and spatial memory in the Y-maze and MWM tests. Furthermore, ginsenoside Rg1 treatment prevented LPS-induced decrease of acetylcholine (ACh) levels and increase of acetylcholinesterase (AChE) activity. Ginsenoside Rg1 treatment also reverted the decrease of alpha7 nicotinic acetylcholine receptor (α7 nAChR) protein expression in the prefrontal cortex (PFC) and hippocampus of LPS-treated rats. These findings suggest that ginsenoside Rg1 has protective effect against LPS-induced cognitive deficit and that prevention of LPS-induced changes in cholinergic system is crucial to this ameliorating effect.

Alpha-lipoic acid protects oxidative stress, changes in cholinergic system and tissue histopathology during co-exposure to arsenic-dichlorvos in rats

We investigated protective efficacy of α-lipoic acid (LA), an antioxidant against arsenic and DDVP co-exposed rats. Biochemical variables suggestive of oxidative stress, neurological dysfunction, and tissue histopathological alterations were determined. Male rats were exposed either to 50ppm sodium arsenite in drinking water or in combination with DDVP (4mg/kg, subcutaneously) for 10 weeks. α-Lipoic acid (50mg/kg, pos) was also co-administered in above groups. Arsenic exposure led to significant oxidative stress along, hepatotoxicity, hematotoxicity and altered brain biogenic amines levels accompanied by increased arsenic accumulation in blood and tissues. These altered biochemical variables were supported by histopathological examinations leading to oxidative stress and cell death. These biochemical alterations were significantly restored by co-administration of α-lipoic acid with arsenic and DDVP alone and concomitantly. The results indicate that arsenic and DDVP induced oxidative stress and cholinergic dysfunction can be significantly protected by the supplementation of α-lipoic acid.

Melatonin protects against alterations in hippocampal cholinergic system, trace metals and oxidative stress induced by gestational and lactational exposure to cadmium.

Dietary exposure to cadmium, even at lower doses, can lead to free radical induced neurotoxicity, neurobehavioral changes and alteration in neurotransmitters. Such changes are likely to be more pronounced in the developing brain due to incompleteness of blood brain barrier (BBB). Hippocampus being the seat of intelligence has a role in learning and cognitive behavior and any damage to hippocampus during developmental stage is likely to result in neurodegenerative changes in later life. To this end, fetal and neonatal exposure to cadmium was induced by exposing pregnant dams of Swiss albino strain throughout the period of gestation and following parturition up till 5th day post partum (pp) through drinking water (3ppm/animal/day). The neonates were sacrificed on day 6 pp and indices of oxidative stress, levels of trace elements and changes in cholinergic system were evaluated in the hippocampus. Increased lipid peroxidation, surge in reactive oxygen species (ROS), depressed antioxidant defense, increased accumulation of cadmium, differential alterations in trace elements and decreased activity of AChE were the features of cadmium toxicity. Simultaneous administration of melatonin to cadmium challenged animals offset these detrimental changes. The results suggest that melatonin co-administration can effectively protect against the adverse effects of cadmium on endogenous antioxidant status, changes in trace metal concentrations and compromised hippocampal cholinergic system.

Hyperfunction of Muscarinic Receptor Maintains Long-Term Memory in 5-HT4 Receptor Knock-Out Mice

Patients suffering from dementia of Alzheimer's type express less serotonin 4 receptors (5-HTR4), but whether an absence of these receptors modifies learning and memory is unexplored. In the spatial version of the Morris water maze, we show that 5-HTR4 knock-out (KO) and wild-type (WT) mice performed similarly for spatial learning, short- and long-term retention. Since 5-HTR4 control mnesic abilities, we tested whether cholinergic system had circumvented the absence of 5-HTR4. Inactivating muscarinic receptor with scopolamine, at an ineffective dose (0.8 mg/kg) to alter memory in WT mice, decreased long-term but not short-term memory of 5-HTR4 KO mice. Other changes included decreases in the activity of choline acetyltransferase (ChAT), the required enzyme for acetylcholine synthesis, in the septum and the dorsal hippocampus in 5-HTR4 KO under baseline conditions. Training- and scopolamine-induced increase and decrease, respectively in ChAT activity in the septum in WT mice were not detected in the 5-HTR4 KO animals. Findings suggest that adaptive changes in cholinergic systems may circumvent the absence of 5-HTR4 to maintain long-term memory under baseline conditions. In contrast, despite adaptive mechanisms, the absence of 5-HTR4 aggravates scopolamine-induced memory impairments. The mechanisms whereby 5-HTR4 mediate a tonic influence on ChAT activity and muscarinic receptors remain to be determined.

Neonatal nicotine exposure impairs development of auditory temporal processing

Accurate temporal processing of sound is essential for detecting word structures in speech. Maternal smoking affects speech processing in newborns and may influence child language development; however, it is unclear how neonatal exposure to nicotine, present in cigarettes, affects the normal development of temporal processing. The present study used the gap-induced prepulse inhibition (gap-PPI) of the acoustic startle response to investigate the effects of neonatal nicotine exposure on the normal development of gap detection, a behavioral testing procedure of auditory temporal resolution. Neonatal rats were injected twice per day with saline (control), 1 mg/kg nicotine (N-1 mg) or 5 mg/kg nicotine (N-5 mg) from postnatal day 8–12 (P8–P12). During the first month after birth, rats showed poor gap-PPI in all three groups. At P45 and P60, gap-PPI in control rats improved significantly, whereas rats exposed to nicotine exhibited less improvement. At P60, the gap-detection threshold in the N-5 mg group was significantly higher than in the control group, suggesting that neonatal nicotine exposure affects the normal development of gap-detection acuity. Additionally, 1 h after receiving an acute nicotine injection (1 mg/kg), gap-PPI recorded in adult rats from the N-5 mg group showed a temporary significant improvement. These results suggest that neonatal nicotine exposure reduces gap-PPI implying an impairment of the normal development of auditory temporal processing by inducing changes in cholinergic systems.

Pilocarpine improves olfactory discrimination and social recognition memory deficits in 24 month-old rats

Muscarinic receptor agonists have been suggested as potential drugs to counteract age-related cognitive decline since critical changes in cholinergic system occur with aging. Recently, we demonstrated that single administration of the non-selective muscarinic receptor agonist pilocarpine prevents age-related spatial learning impairments in rats. In addition, increasing evidence suggests that areas in the central nervous system processing olfactory information are affected at the early stages of age-related diseases, such as Alzheimer's disease, and that specific olfactory testing may represent an important tool in the diagnosis of these diseases. In the present study, olfactory discrimination and short-term social memory of 3 and 24 month-old rats were assessed with the olfactory discrimination and social recognition memory tasks, respectively. The actions of the repeated treatment with pilocarpine (30 mg/kg, i.p.; once per day for 21 days) in relation to age-related effects on olfactory and cognitive functions were also studied. The 24 month-old rats exhibited significantly impaired performance in both models, demonstrating deficits in their odour discrimination and in their ability to recognize a juvenile rat after a short period of time. The treatment with pilocarpine improved in a specific manner these age-related deficits in 24 month-old rats without altering their motor performance. The present results extend the notion of the participation of muscarinic receptors in control of olfactory functions and reinforce the potential of muscarinic receptor agonists for the treatment of age-related cognitive decline.

Cholinergic regulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) but not neurotrophin-3 (NT-3) mRNA levels in the developing rat hippocampus

In previous experiments it has been demonstrated that the synthesis of BDNF (brain-derived neurotrophic factor) and NGF in neurons of the hippocampus is regulated by neuronal activity. The glutamate system is predominantly responsible for upregulation and the GABAergic system for downregulation both in vitro and in vivo (Zafra et al., 1990, 1991). The aim of the present study is to examine the extent to which the cholinergic system is also involved in the regulation of NGF and BDNF mRNA and whether the regulatory contribution of the cholinergic system changes during development. Partial transection of the fimbria fornix bundle in the second postnatal week resulted in a reduction of BDNF and NGF mRNA levels in the hippocampus, suggesting that septal cholinergic input is involved in the regulation of hippocampal BDNF and NGF mRNA levels. Because the fimbria fornix bundle also contains fibers other than cholinergic ones, we further evaluated the importance of the cholinergic influence by injecting pilocarpine, a muscarinic agonist. Pilocarpine markedly increased hippocampal BDNF and NGF mRNA levels in both early postnatal and adult rats. In situ hybridization experiments demonstrated that pilocarpine led to an increase in BDNF expression in the CA1-CA4 regions of the hippocampus and in the dentate gyrus. However, pilocarpine increased NGF mRNA only in those neurons of the dentate gyrus and CA1-CA4 regions that also expressed NGF mRNA in the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional analysis of age-related changes in the cholinergic system of the hippocampal formation and basal forebrain of the rat

In an attempt to clarify conflicting reports of age-related changes in cholinergic systems of the rat hippocampal formation and basal forebrain, we compared aged (40 months) and adult (12 months) male rats using quantitative, regional receptor autoradiography in addition to radiolabelled assays of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE). The activities of ChAT and AChE in Ammon's horn/subiculum are 24% and 38% lower, respectively, in the aged brains. There is also a drop in both ChAT (38%) and AChE (28%) activities in the septum, and a 46% drop in ChAT activity in the nucleus basalis of aged rats. In the septal pole of the hippocampal formation there is no significant change with age in binding of the muscarinic antagonist, tritiated quinuclidinyl benzylate ( 3H-QNB) in any hippocampal subregion. However, specific binding in the temporal pole is higher in the subiculum (40%), CA 1 (27%), and dentate gyrus (25%) of the aged animals. Because some of the neurons of the diagonal band of Broca project to the temporal areas of the hippocampal formation by way of a ventral pathway, it is possible that with age this septohippocampal pathway is selectively affected. Particularly in Ammon's horn and the subicular regions of the aged rat hippocampus, postsynaptic muscarinic receptors may upregulate to compensate for decreases in presynaptic cholinergic activity.

Pharmacologic Induction of Cholinergic System Up-regulation and Supersensitivity in Affective Disorders Research

Phenomenological, physiological, biochemical, and receptor binding measures are useful as dependent variables in affective disorders research. Abnormalities of these measures can result from up-regulation and supersensitivity of cholinergic systems and disturbances of cholinergic-monoaminergic interaction. These deviations are safely and inexpensively produced by pharmacologic induction of up-regulation and supersensitivity of central muscarinic cholinergic systems. Techniques for inducing these changes in cholinergic systems are reviewed, and principles governing their application to specific problems are illustrated.