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

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.

SUBMITTER: Wu J

PROVIDER: S-EPMC2153437 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature

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

Wu Jianlin J Khan Ghous M GM Nichols Robert A RA

Brain research 20070914

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 foun ...[more]

PMID: 17935702

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Project description:IntroductionDisulfiram has been claimed to be useful in cocaine addiction therapy, its efficacy being attributed to dopamine-beta-hydroxylase (DBH) inhibition. Our previous results indicate that disulfiram and the selective DBH inhibitor nepicastat increase extracellular dopamine (DA) in the rat medial prefrontal cortex (mPFC), and markedly potentiated cocaine-induced increase. Concomitantly, in rats with cocaine self-administration history, cocaine-seeking behavior induced by drug priming was prevented, probably through overstimulation of D1 receptors due to the DA increase. The present research was aimed at studying the neurochemical mechanisms originating the enhanced DA release.MethodsNoradrenergic system ablation was attained by intracerebroventricular (i.c.v.) administration of the neurotoxin anti-DBH-saporin (aDBH-sap). DA, noradrenaline (NA), and DOPAC were assessed by HPLC after ex vivo tissue extraction or in vivo microdialysis. Control and denervated rats were subjected to microdialysis in the mPFC and caudate nucleus to evaluate the effect of nepicastat-cocaine combination on extracellular DA levels and their regulation by α2-adrenoceptors.ResultsFifteen days after neurotoxin or its vehicle administration, tissue and extracellular NA were reduced to less than 2% the control value, while extracellular DA was increased by approximately 100%. In control rats, nepicastat given alone and in combination with cocaine increased extracellular DA by about 250% and 1100%, respectively. In denervated rats, nepicastat slightly affected extracellular DA, while in combination with cocaine increased extracellular DA by 250%. No differences were found in the caudate nucleus. Clonidine almost totally reversed the extracellular DA elevation produced by nepicastat-cocaine combination, while it was ineffective in denervated rats.ConclusionsThis research shows that the increase of extracellular DA produced by nepicastat alone or in combination with cocaine was prevented by noradrenergic denervation. The results indicate that nepicastat enhances DA release from noradrenergic terminals supposedly by removing NA from α2-autoreceptors. In addition to the inhibition of DA uptake, the latter mechanism may explain the synergistic effect of cocaine on nepicastat-induced DA release.

Dataset Information

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

Publications

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

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