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

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 to nM. Moreover, pM to nM soluble Aβ was found to increase presynaptic Ca2+ 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, Aβ1–42 at 100 nM evoked the release of dopamine to ∼ 170% of basal levels. The Aβ1–42-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 Aβ40–1 was without effect. In contrast, Aβ1–42 at 1–10 pM 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.