Dopamine release in prefrontal cortex in response to beta-amyloid activation of alpha7 * nicotinic receptors.
The levels of soluble beta-amyloid (Abeta) are correlated with symptom severity in Alzheimer's disease. Soluble Abeta has been shown to disrupt synaptic function and it has been proposed that accumulation of soluble Abeta triggers synapse loss over the course of the disease. Numerous studies indicate that soluble Abeta has multiple targets, one of which appears to be the nicotinic acetylcholine receptor, particularly for Abeta concentrations of pM to nM. Moreover, pM to nM soluble Abeta was found to increase presynaptic Ca(2+) levels, suggesting that it may have an impact on neurotransmitter release. In the present study, soluble Abeta was perfused into mouse prefrontal cortex and the effect on the release of dopamine outflow via microdialysis was assessed. In the presence of tetrodotoxin, Abeta(1-42) at 100 nM evoked the release of dopamine to approximately 170% of basal levels. The Abeta(1-42)-evoked dopamine release was sensitive to antagonists of alpha7 nicotinic receptors and was absent in mice harboring a null mutation for the alpha7 nicotinic subunit, but was intact in mice harboring a null mutation for the beta2 nicotinic subunit. The control peptide Abeta(40-1) was without effect. In contrast, Abeta(1-42) at 1-10 pM caused a profound but slowly developing decrease in dopamine outflow. These results suggest that Abeta 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.
Wu
Jianlin
J
Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA 19102, USA.
Khan
Ghous M
GM
Nichols
Robert A
RA
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis / Q000379:methods; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; D002038:Bungarotoxins; C579166:Chrna7 protein, mouse; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); D009538:Nicotine; D004298:Dopamine