Potassium, but not atropine-stimulated cortical acetylcholine efflux, is reduced in aged rats

doi:10.1016/0197-4580(96)00075-9

Neurobiology of Aging

Volume 17, Issue 4, July–August 1996, Pages 565-571

https://doi.org/10.1016/0197-4580(96)00075-9 Get rights and content

Abstract

Using in vivo microdialysis, cortical acetylcholine (ACh) efflux was measured in freely moving Brown Norway/Fischer 344 F1 rats, aged 4 or 22 months. The effects of local, intracortical perfusion of atropine (1.0 or 100.0 μM) via the dialysis probe were compared to local K⁺ (100.0 mM) stimulation in the presence of elevated extracellular Ca²⁺ (2.5 mM). Basal cortical ACh efflux in aged rats was similar to that of young animals. Administration of atropine (1.0 or 100.0 μM) via the cortical dialysis probe substantially increased cortical ACh efflux, but did not differentially stimulate ACh efflux in young and aged rats. In contrast, ACh efflux stimulated locally with K⁺ and Ca²⁺ was significantly reduced in aged rats relative to young adults. The implications of the dissociable effects of K⁺-depolarization and muscarinic blockade for local regulation of cortical ACh efflux in aged animals are discussed.

References (72)

F.A. Abdulla et al.
Importance of forebrain cholinergic and GABAergic systems to the age-related deficits in water maze performance of rats
Neurobiol. Aging
(1995)
M.C. Altavista et al.
Aging is associated with a diffuse impairment of forebrain cholinergic neurons
Brain Res.
(1990)
D.M. Armstrong et al.
Morphologic alterations of choline acetyltransferase-positive neurons in the basal forebrain of aged behaviorally characterized Fisher 344 rats
Neurobiol. Aging
(1993)
A. Biegon et al.
Aging and brain cholinergic muscarinic receptor subtypes: An autoradiographic study in the rat
Neurobiol. Aging
(1989)
M.J. Blake et al.
Muscarinic acetylcholine receptor subtype mRNA expression and ligand binding in the aged rat forebrain
Neurobiol. Aging
(1991)
F. Casamenti et al.
Phosphatidylserine reverses the age-dependent decrease in cortical acetylcholine release: A microdialysis study
Eur. J. Pharmacol.
(1991)
S. Consolo et al.
In vivo and in vitro studies on the regulation of cholinergic neurotransmission in striatum, hippocampus and cortex of aged rats
Brain Res.
(1986)
G.L. Dunbar et al.
Hippocampal choline acetyltransferase activity correlates with spatial learning in aged rats
Brain Res.
(1993)
S. Dunnett
Cholinergic grafts, memory and aging
Trends Neurosci.
(1991)
W. Fischer et al.
Progressive decline in spatial learning and integrity of forebrain cholinergic neurons in rats during aging
Neurobiol. Aging
(1992)

W. Fischer et al.

In vivo acetylcholine release as measured by microdialysis is unaltered in the hippocampus of cognitively impaired aged rats with degenerative changes in the basal forebrain

Brain Res.

(1991)

G. Forloni et al.

Decreased [³H]hemicholinium binding to high-affinity choline uptake sites in aged rat brain

Brain Res.

(1992)

H. Hartmann et al.

Aging enhances the calcium sensitivity of central neurons of the mouse as an adaptive response to reduced free intracellular calcium

Neurosci. Lett.

(1993)

R. Hellweg et al.

Nerve growth factor levels and choline acetyltransferase activity in the brain of aged rats with spatial memory impairments

Brain Res.

(1990)

A. Huidobro et al.

Age-related changes in calcium homeostatic mechanisms in synaptosomes in relation with working memory deficiency

Neurobiol. Aging

(1993)

S. Ikegami

Behavioral impairment in radial-arm maze learning and acetylcholine content of the hippocampus and cerebral cortex in aged mice

Behav. Brain Res.

(1994)

Z.L. Jin et al.

Age-dependent change in the inhibitory effect of an adenosine agonist on hippocampal acetylcholine release in rats

Brain Res. Bull.

(1993)

B.J. Johnson et al.

Dopaminergic modulation of striatal acetylcholine release in rats depleted of dopamine as neonates

Neuropharmacology

(1995)

T. Kadar et al.

Age-related changes in the cholinergic components within the central nervous system. II. working memory impairment and its relation to hippocampal muscarinic receptors

Mech. Aging Dev.

(1990)

M. Kurosawa et al.

Well-maintained responses of acetylcholine release and blood flow in the cerebral cortex to focal electrical stimulation of the nucleus basalis of Meynert in aged rats

Neurosci. Lett.

(1989)

C. Lebrun et al.

A comparison of the working memory performances of young and aged mice combined with parallel measures of testing and drug-induced activations of septo-hippocampal and nbm-cortical cholinergic neurons

Neurobiol. Aging

(1990)

A.S. Lippa et al.

Conformational changes in muscarinic receptors may produce diminished cholinergic neurotransmission and memory deficits in aged rats

Neurobiol. Aging

(1985)

A.S. Lippa et al.

Brain cholinergic dysfunction and memory in aged rats

Neurobiol. Aging

(1980)

J.K. Liu et al.

Effect of physostigmine on relative acetylcholine output induced by systemic treatment with scopolamine in in vivo microdialysis of rat frontal cortex

Neurochem. Int.

(1994)

V. Luine et al.

Spatial memory deficits in aged rats: Contributions of the cholinergic systems assessed by ChAT

Brain Res.

(1990)

V.N. Luine et al.

Age and sex-dependent decreases in ChAT in basal forebrain nuclei

Neurobiol. Aging

(1986)

E.M. Meyer et al.

Effects of aging on rat cortical presynaptic cholinergic processes

Neurobiol. Aging

(1984)

M.L. Michaelis et al.

Regulation of calcium levels in brain tissue from adult and aged rats

Mech. Ageing Dev.

(1992)

H. Michalek et al.

Age-related differences in brain choline acetyltransferase, cholinesterases and muscarinic receptor sites in two strains of rats

Neurobiol. Aging

(1989)

T. Mizuno et al.

Spontaneous acetylcholine release in the hippocampus exhibits a diurnal variation in both young and old rats

Neurosci. Lett.

(1994)

H. Moore et al.

Age-dependent modulation of in vivo cortical acetylcholine release by benzodiazepine receptor ligands

Brain Res.

(1992)

O.G. Nilsson et al.

Anticholinergic sensitivity in the aging rat septohippocampal system as assessed in a spatial memory task

Neurobiol. Aging

(1993)

A.B. Norman et al.

Effects of aging and cholinergic deafferentation on putative muscarinic cholinergic receptor subtypes in rat cerebral cortex

Neurosci. Lett.

(1986)

F.J. Pedata et al.

Acetylcholine release from rat cortical slices during postnatal development and aging

Neurobiol. Aging

(1983)

E.K. Perry et al.

Convergent cholinergic activities in aging and Alzheimer's disease

Neurobiol. Aging

(1992)

R.D. Schwarz et al.

Loss of muscarinic M₁ receptors with aging in the cerebral cortex of Fisher 344 rats

Pharmacol. Biochem. Behav.

(1990)

Cited by (34)

Behavioral-cognitive targets for cholinergic enhancement
2015, Current Opinion in Behavioral Sciences
Citation Excerpt :
Together, it is difficult to see how these effects of AChE inhibitors enhance cholinergic neurotransmission and related functions, particularly if it is the case that cholinergic neurotransmission is not primarily characterized by volume-transmission [10]. Likewise, administration of non-selective mAChR antagonists such as scopolamine or atropine results in extremely high extracellular concentrations of ACh as these drugs block presynaptic M2 mAChRs (e.g., [11]). While also blocking postsynaptic mAChRs, high extracellular ACh levels resulting from M2 antagonism extensively stimulate postsynaptic nAChRs.
Cholinergic mechanisms have long been considered a promising target for enhancing cognitive functions. Two distinct yet interacting components of cholinergic activity have been proposed to mediate specific cognitive functions. Transient spikes in cholinergic activity mediate the detection of cues in situations involving attentional mode shifts. More slowly changing cholinergic neuromodulation of cortical circuitry regulates task compliance specifically in response to performance challenges. Increases in cholinergic neuromodulation enhances the generation of cholinergic transients via stimulation of α4β2* nicotinic acetylcholine receptors. Stimulation of these receptors stabilizes attentional performance and increases cue detection rates. Adjunctive treatment with agonists or modulators at these receptors is predicted to benefit unstable attentional performance and low cue detection rates that are common to several brain disorders.
The effects of postnatal alcohol exposure and galantamine on the context pre-exposure facilitation effect and acetylcholine efflux using invivo microdialysis
2015, Alcohol
Citation Excerpt :
We have previously used high K+/Ca2+ to reveal age-related differences in hippocampal glutamate and GABA release (Stanley, Fadel, & Mott, 2012). Finally, Moore et al. (1996) used a similar protocol to reveal age-related differences in prefrontal cortical ACh release. Importantly, in our work, these conditions did reveal differences in depolarization-induced hippocampal ACh release as a function of prenatal ethanol exposure, at least relative to non-treated control animals.
Fetal alcohol spectrum disorders (FASD) are characterized by damage to multiple brain regions, including the hippocampus, which is involved in learning and memory. The acetylcholine neurotransmitter system provides major input to the hippocampus and is a possible target of developmental alcohol exposure. Alcohol (3.0 g/kg/day) was administered via intubation to male rat pups (postnatal day [PD] 2–10; ethanol-treated [ET]). Controls received a sham intubation (IC) or no treatment (NC). Acetylcholine efflux was measured using in vivo microdialysis (PD 32–35). ET animals were not different at baseline, but had decreased K⁺/Ca²⁺-induced acetylcholine efflux compared to NC animals and an enhanced acetylcholine response to galantamine (acetylcholinesterase inhibitor; 2.0 mg/kg) compared to both control groups. A separate cohort of animals was tested in the context pre-exposure facilitation effect task (CPFE; PD 30-32) following postnatal alcohol exposure and administration of galantamine (2.0 mg/kg; PD 11-30). Neither chronic galantamine nor postnatal alcohol exposure influenced performance in the CPFE task. Using immunohistochemistry, we found that neither alcohol exposure nor behavioral testing significantly altered the density of vesicular acetylcholine transporter or alpha7 nicotinic acetylcholine receptor in the ventral hippocampus (CA1). In the medial septum, the average number of choline acetyltransferase (ChAT+) cells was increased in ET animals that displayed the context-shock association; there were no changes in IC and NC animals that learned the context-shock association or in any animals that were in the control task that entailed no learning. Taken together, these results indicate that the hippocampal acetylcholine system is significantly disrupted under conditions of pharmacological manipulations (e.g., galantamine) in alcohol-exposed animals. Furthermore, ChAT was up‑regulated in ET animals that learned the CPFE, which may account for their ability to perform this task. In sum, developmental alcohol exposure may disrupt learning and memory in adolescence via a cholinergic mechanism.
Monitoring cholinergic activity during attentional performance in mice heterozygous for the choline transporter: A model of cholinergic capacity limits
2013, Neuropharmacology
Citation Excerpt :
The detection limit of this system averaged 5 fmol/15 μL. The muscarinic acetylcholine receptor (mAChR) blocker atropine is a potent ACh releaser, by blocking presynaptic mAChR (e.g., Moore et al., 1996). Atropine administration served to challenge the capacity of ACh release in CHT+/− mice.
Reductions in the capacity of the human choline transporter (SLC5A7, CHT) have been hypothesized to diminish cortical cholinergic neurotransmission, leading to risk for cognitive and mood disorders. To determine the acetylcholine (ACh) release capacity of cortical cholinergic projections in a mouse model of cholinergic hypofunction, the CHT+/− mouse, we assessed extracellular ACh levels while mice performed an operant sustained attention task (SAT). We found that whereas SAT-performance-associated increases in extracellular ACh levels of CHT+/− mice were significantly attenuated relative to wildtype littermates, performance on the SAT was normal. Tetrodotoxin-induced blockade of neuronal excitability reduced both dialysate ACh levels and SAT performance similarly in both genotypes. Likewise, lesions of cholinergic neurons abolished SAT performance in both genotypes. However, cholinergic activation remained more vulnerable to the reverse-dialyzed muscarinic antagonist atropine in CHT+/− mice. Additionally, CHT+/− mice displayed greater SAT-disrupting effects of reverse dialysis of the nAChR antagonist mecamylamine. Receptor binding assays revealed a higher density of α4β2* nAChRs in the cortex of CHT+/− mice compared to controls. These findings reveal compensatory mechanisms that, in the context of moderate cognitive challenges, can overcome the performance deficits expected from the significantly reduced ACh capacity of CHT+/− cholinergic terminals. Further analyses of molecular and functional compensations in the CHT+/− model may provide insights into both risk and resiliency factors involved in cognitive and mood disorders.
Galanthamine plus estradiol treatment enhances cognitive performance in aged ovariectomized rats
2011, Hormones and Behavior
Citation Excerpt :
The function of cholinergic afferents declines with age (Baskerville et al., 2006; Fischer et al., 1992b) as well as with specific neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (Lanari et al., 2006; Linstow and Platt, 1999; Smith et al., 1999). This is demonstrated by decreases in the number and size of cholinergic neurons in the MS, DBB, and NBM (Altavista et al., 1990; Fischer et al., 1989, 1992a; Mesulam et al., 1987; Stroessner-Johnson et al., 1992), decreases in high affinity choline uptake (Kristofiková et al., 1992; Sherman and Friedman, 1990), acetylcholine release (Araujo et al., 1990; Moore et al., 1996; Takei et al., 1989; Wu et al., 1988), and cholinergic synaptic transmission (Taylor and Griffith, 1993). These neurons also are adversely affected by loss of ovarian function as demonstrated by decreases in ChAT and TrkA expression beyond the effects of normal aging (reviewed in Gibbs, 2010).
We hypothesize that beneficial effects of estradiol on cognitive performance diminish with age and time following menopause due to a progressive decline in basal forebrain cholinergic function. This study tested whether galanthamine, a cholinesterase inhibitor used to treat memory impairment associated with Alzheimer's disease, could enhance or restore estradiol effects on cognitive performance in aged rats that had been ovariectomized in middle-age. Rats were ovariectomized at 16–17 months of age. At 21–22 months of age rats began receiving daily injections of galanthamine (5 mg/day) or vehicle. After one week, half of each group also received 17ß-estradiol administered subcutaneously. Rats were then trained on a delayed matching to position (DMP) T-maze task, followed by an operant stimulus discrimination/reversal learning task. Treatment with galanthamine + estradiol significantly enhanced the rate of DMP acquisition and improved short-term delay-dependent spatial memory performance. Treatment with galanthamine or estradiol alone was without significant effect. Effects were task-specific in that galanthamine + estradiol treatment did not significantly improve performance on the stimulus discrimination/reversal learning task. In fact, estradiol was associated with a significant increase in incorrect responses on this task after reversal of the stimulus contingency. In addition, treatments did not significantly affect hippocampal choline acetyltransferase activity or acetylcholine release. This may be an effect of age, or possibly is related to compensatory changes associated with long-term cholinesterase inhibitor treatment. The data suggest that treating with a cholinesterase inhibitor can enhance the effects of estradiol on acquisition of a DMP task by old rats following a long period of hormone deprivation. This could be of particular benefit to older women who have not used hormone therapy for many years and are beginning to show signs of mild cognitive impairment. Potential mechanisms for these effects are discussed.
Regulation of cortical acetylcholine release: Insights from in vivo microdialysis studies
2011, Behavioural Brain Research
Citation Excerpt :
While some investigations have demonstrated decreased basal cortical ACh release [21,162] in animal models, others have not shown such a phenomenon in either cerebral cortex or hippocampus [48,99]. Stimulated release, whether by behavioral or pharmacological manipulations, tend to more consistently show age-related deficits [56,103] that may correlate with cognitive impairment [135,136]. Similarly, partial lesions of basal forebrain cholinergic neurons comparably reduce basal ACh release in young and old animals, while only young lesioned animals are able to maintain increased release in response to an appetitive stimulus [46].
Acetylcholine release links the activity of presynaptic neurons with their postsynaptic targets and thus represents the intercellular correlate of cholinergic neurotransmission. Here, we review the regulation and functional significance of acetylcholine release in the mammalian cerebral cortex, with a particular emphasis on information derived from in vivo microdialysis studies over the past three decades. This information is integrated with anatomical and behavioral data to derive conclusions regarding the role of cortical cholinergic transmission in normal behavioral and how its dysregulation may contribute to cognitive correlates of several neuropsychiatric conditions. Some unresolved issues regarding the regulation and significance of cortical acetylcholine release and the promise of new methodology for advancing our knowledge in this area are also briefly discussed.
Donepezil treatment restores the ability of estradiol to enhance cognitive performance in aged rats: Evidence for the cholinergic basis of the critical period hypothesis
2009, Hormones and Behavior
Recent studies suggest that the ability of estradiol to enhance cognitive performance diminishes with age and/or time following loss of ovarian function. We hypothesize that this is due, in part, to a decrease in basal forebrain cholinergic function. This study tested whether donepezil, a cholinesterase inhibitor, could restore estradiol effects on cognitive performance in aged rats that had been ovariectomized as young adults. Rats were ovariectomized at 3 months of age, and then trained on a delayed matching to position (DMP) T-maze task, followed by a configural association (CA) operant condition task, beginning at 12–17 or 22–27 months of age. Three weeks prior to testing, rats started to receive either donepezil or vehicle. After one week, half of each group also began receiving estradiol. Acclimation and testing began seven days later and treatment continued throughout testing. Estradiol alone significantly enhanced DMP acquisition in middle-aged rats, but not in aged rats. Donepezil alone had no effect on DMP acquisition in either age group; however, donepezil treatment restored the ability of estradiol to enhance DMP acquisition in aged rats. This effect was due largely to a reduction in the predisposition to adopt a persistent turn strategy during acquisition. These same treatments did not affect acquisition of the CA task in middle-aged rats, but did have small but significant effects on response time in aged rats. The data are consistent with the idea that estrogen effects on cognitive performance are task specific, and that deficits in basal forebrain cholinergic function are responsible for the loss of estradiol effect on DMP acquisition in aged ovariectomized rats. In addition, the data suggest that enhancing cholinergic function pharmacologically can restore the ability of estradiol to enhance acquisition of the DMP task in very old rats following long periods of hormone deprivation. Whether donepezil has similar restorative effects on other estrogen-sensitive tasks needs to be explored.

View all citing articles on Scopus

View full text

Potassium, but not atropine-stimulated cortical acetylcholine efflux, is reduced in aged rats

Abstract

Neurobiol. Aging

Brain Res.

Neurobiol. Aging

Neurobiol. Aging

Neurobiol. Aging

Eur. J. Pharmacol.

Brain Res.

Brain Res.

Trends Neurosci.

Neurobiol. Aging

Brain Res.

Brain Res.

Neurosci. Lett.

Brain Res.

Neurobiol. Aging

Behav. Brain Res.

Brain Res. Bull.

Neuropharmacology

Mech. Aging Dev.

Neurosci. Lett.

Neurobiol. Aging

Neurobiol. Aging

Neurobiol. Aging

Neurochem. Int.

Brain Res.

Neurobiol. Aging

Neurobiol. Aging

Mech. Ageing Dev.

Neurobiol. Aging

Neurosci. Lett.

Brain Res.

Neurobiol. Aging

Neurosci. Lett.

Neurobiol. Aging

Neurobiol. Aging

Pharmacol. Biochem. Behav.