title: Acute beta-amyloid administration disrupts the cholinergic control of dopamine release in the nucleus accumbens.
abstract: The clinical presentation of Alzheimer's disease is characterized by memory deficits but it also involves the impairment of several cognitive functions. Some of these cognitive and executive functions are mediated by limbic areas and are regulated by dopaminergic neurotransmission. Furthermore, literature data suggest that beta-amyloid (Abeta) can influence synaptic activity in absence of neurotoxicity and in particular can impair cholinergic modulation of other neurotransmitter actions. In the present study, we evaluated whether small concentrations of Abeta could disrupt cholinergic control of dopamine (DA) release in nucleus accumbens using in vivo (brain dialysis) and in vitro (isolated synaptosomes) models. The cholinergic agonist carbachol (CCh) greatly enhanced DA release from dopaminergic nerve endings in nucleus accumbens both in vivo and in vitro. This effect was mainly exerted on muscarinic receptors because it was inhibited by the muscarinic antagonist atropine and it was unaffected by the nicotinic antagonist mecamylamine. Also the nicotinic agonists epibatidine and nicotine evoked a dopaminergic outflow in nucleus accumbens, which, however, was lower. Abeta 1-40 in absence of neurotoxicity fully inhibited the DA release evoked by CCh and only marginally affected the DA release evoked by epibatidine. The PKC inhibitor GF109203X mimicked the effect of Abeta on DA release and, in turn, Abeta impaired PKC activation by CCh. We can suggest that, in nucleus accumbens, Abeta disrupted in vivo and in vitro cholinergic control of DA release by acting on muscarinic transduction machinery.
authors.affiliation: Department of Experimental and Applied Pharmacology, Centre of Excellence in Applied Biology, University of Pavia, Pavia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Preda
authors.forename: Stefano
authors.initials: S
authors.lastname: Govoni
authors.forename: Cristina
authors.initials: C
authors.lastname: Lanni
authors.forename: Marco
authors.initials: M
authors.lastname: Racchi
authors.forename: Elisa
authors.initials: E
authors.lastname: Mura
authors.forename: Massimo
authors.initials: M
authors.lastname: Grilli
authors.forename: Mario
authors.initials: M
authors.lastname: Marchi
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004563:Electrochemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D017551:Microdialysis; D018722:Nicotinic Agonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage*; D011493:Protein Kinase C / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018679:Cholinergic Agonists; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D018722:Nicotinic Agonists; D010446:Peptide Fragments; D011725:Pyridines; C078592:amyloid beta-protein (1-40); D002217:Carbachol; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; C082748:epibatidine; D000109:Acetylcholine; D004298:Dopamine