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. 2007 Nov 28:1182:82-9.
doi: 10.1016/j.brainres.2007.08.079. Epub 2007 Sep 14.

Dopamine release in prefrontal cortex in response to beta-amyloid activation of alpha7 * nicotinic receptors

Jianlin Wu  1 , Ghous M Khan, Robert A Nichols
Affiliations

Dopamine release in prefrontal cortex in response to beta-amyloid activation of alpha7 * nicotinic receptors

Jianlin Wu et al. Brain Res. .

Abstract

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.

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Figures

Fig. 1
Fig. 1
Microdialysis perfusion of β-amyloid. β-amyloid perfused into surrounding tissue via the microdialysis probe (*blank areas along right side of micrographs) placed in the prefrontal cortex for 30 min was detected via immunocytochemistry, as described in Experimental Procedures, using an anti-Aβ monoclonal antibody (right) in comparison to a control section incubated with fluorescein-conjugated secondary antibody alone (left). Images of 40μm sections around the microdialysis probe (*) were taken using confocal microscopy. Scale bar = 12 μm. Posthoc staining with Hoescht did not reveal any gross alteration in the tissue following Aβ perfusion (not shown).
Fig. 2
Fig. 2
Nicotine and β-amyloid evoke increased DA outlflow in prefrontal cortex. (A) Effect of perfusing 1μM nicotine by “reverse” dialysis into prefrontal cortex of freely moving C57B1/6 mice on the release of DA was assessed via in vivo microdialysis in the presence of TTX. The perfusate was switched to aCSF containing 1uM TTX (as control), TTX plus 1uM nicotine or TTX plus 1uM nicotine plus 2mM MLA for 5min, after which the perfusate was switched by to aCSF containing TTX alone. Under the time frame used for drug perfusion (1-3h), TTX alone did not significantly affect DA outflow. After extended perfusion (4-6h), the DA outflow dropped substantially (not shown). MLA was used a general nAChR antagonist, as its use at 2mM will block both α7 and non-α7 nAChRs (Ward et al., 1990; Mogg et al., 2002). (B) Perfusion with 100nM Aβ1-42 in aCSF in TTX for 20min in the absence or presence of BgTx (1μM) or MLA (1μM), also delivered for 20min. BgTx was delivered via a second, open cannula, implanted next to and slightly above the microdialysis probe. (C) Perfusion with 100nM Aβ12-28 in TTX, a highly soluble core fragment which strongly competes for Aβ1-42 interaction with α7 nAChRs (Wang et al., 2000a). (D) Perfusion with various concentrations of Aβ1-42 in TTX. (E) Perfusion with the peptide “Aβ40-41” in TTX, which served as a control “reverse” peptide having no effect on presynaptic Ca2+ (Dougherty et al., 2003). (Lack of effect of “Aβ42-1” on presynaptic Ca2+ has also been observed (Mehta et al., manuscript in preparation).) Dopamine (DA) content in the fractions (preloaded with perchloric acid) was determined via HPLC with an electrochemical detector, as described in the Experimental Procedures. Data are presented as averages ± s.e.m (4-6 replicates each). Mean basal values for DA: 0.5-1pg/ul, adjusted for recovery (4-10%); *p<0.05 relative to baseline.
Fig. 3
Fig. 3
β-amyloid-evoked DA outflow in prefrontal cortex of mice harboring null mutations of nAChR subunits. (A) Perfusion with 100pM or 100nM Aβ1-42 for 5min into prefrontal cortex of α7 nAChR null-mutant mice (Alpha7 KO). (B) Perfusion with 100nM Aβ1-42 into prefrontal cortex of β2 nAChR null-mutant mice (Beta2 KO). Shorter perfusion with Aβ in A and B was performed in order to reveal possible slowly developing inhibition of DA outflow resulting from the fall-off in Aβ following perfusion. (C) Perfusion with 1μM nicotine for 30min, then 100nM or 10pM Aβ1-42 with nicotine for an additional 20min. Experiments were performed as described in the legend to Fig. 2. Data are presented as averages ± s.e.m; n=3-5 replicates each, except in C where only averages are shown for clarity (n=3). Mean basal values for DA: 0.5-1pg/ul, adjusted for recovery (8-23%); *p<0.05 relative to baseline.
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