Dopamine release in prefrontal cortex in response to β-amyloid activation of α7∗ nicotinic receptors

Abstract

The levels of soluble beta amyloid (Aβ) are correlated with symptom severity in Alzheimer's disease. Soluble Aβ has been shown to disrupt synaptic function and it has been proposed that accumulation of soluble Aβ triggers synapse loss over the course of the disease. Numerous studies indicate that soluble Aβ has multiple targets, one of which appears to be the nicotinic acetylcholine receptor, particularly for Aβ concentrations of pM-nM. Moreover, pM-nM soluble Aβ was found to increase presynaptic Ca 2+ levels, suggesting that it may have an impact on neurotransmitter release. In the present study, soluble Aβ was perfused into mouse prefrontal cortex and the effect on the release of dopamine outflow via microdialysis was assessed. In the presence of tetrodotoxin, Aβ 1-42 at 100nM evoked the release of dopamine to ∼170% of basal levels. The Aβ 1-42 -evoked dopamine release was sensitive to antagonists of α7 nicotinic receptors and was absent in mice harboring a null mutation for the α7 nicotinic subunit, but was intact in mice harboring a null mutation for the β2 nicotinic subunit. The control peptide Aβ 40-1 was without effect. In contrast, Aβ 1-42 at 1-10pM caused a profound but slowly developing decrease in dopamine outflow. These results suggest that Aβ alters dopamine release in mouse prefrontal cortex, perhaps involving distinct targets as it accumulates during Alzheimer's disease and leading to disruption of synaptic signaling.

Chronic Nicotine Alters Nicotinic Receptor-induced Presynaptic Ca2+ Responses in Isolated Nerve Terminals

“…Increased presynaptic [Ca 2+ ]i likely underlies the nicotine-evoked release of neurotransmitter from cortical synaptosomes described previously to involve predominantly α7 nAChRs whose activation, in turn, triggers the opening of N-and P/Q-type VGCCs [25,26], though β2 nAChRs are likely involved as well [27,28]. In addition, increased presynaptic [Ca 2+ ]i also likely underlies nicotine enhancement of neurotransmitter release measured in cortical slices [29][30][31][32][33] and the intact cortex using microdialysis [19,34,35].…”

Dopamine Modulates Cholinergic Cortical Excitability in Alzheimer's Disease Patients

“…In particular, the reduced levels of dopamine transporters restricted to the NAcc together with altered receptors expression for dopamine recently described (McNeill et al, 1984;Kumar and Patel, 2007), provide sufficient evidence that dopamine content deficit also occurs during the neurodegenerative process of AD. These alterations, in association with the changes because of the progressive neurodegenerative processes (aberrant growth of dendritic trees and amyloid deposit) (Arendt et al, 1995;Preda et al, 2008;Wu et al, 2007) can induce, as a consequence a perturbation in the balance of the other neurotransmitter systems, leading to altered cortical excitability and cognitive decline. In this view, the prompt effect of L-dopa on SLAI has to be interpreted as the result of a momentarily restored transmitter deficiency, leading to restored electrophysiological patterns.…”

Impact of Sustained Exposure to β-Amyloid on Calcium Homeostasis and Neuronal Integrity in Model Nerve Cell System Expressing α4β2 Nicotinic Acetylcholine Receptors

“…Acute application of pico-to nanomolar A␤ evokes increases in Ca 2ϩ and neurotransmitter release via presynaptic nAChRs (12)(13)(14). Mutation of a key tyrosine residue in the agonist-binding site of ␣7 nAChRs eliminates the A␤ effect on presynaptic Ca 2ϩ (15), directly confirming the agonist-like action of A␤.…”