1. ¹Department of Experimental and Applied Pharmacology, Centre of Excellence in Applied Biology, University of Pavia, Pavia, Italy
2. ²Section of Pharmacology and Toxicology, Department of Experimental Medicine, University of Genoa, Genoa, Italy

Correspondence: Professor S Govoni, Department of Experimental and Applied Pharmacology, Centre of Excellence in Applied Biology, University of Pavia, Viale Taramelli, 14, 27100 Pavia, Italy. Tel: +39 0382 987394; Fax: +39 0382 987405; E-mail: govonis@unipv.it

Received 26 January 2007; Revised 14 May 2007; Accepted 18 May 2007; Published online 20 June 2007.

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 -amyloid (A) 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 A 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. A 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 A on DA release and, in turn, A impaired PKC activation by CCh. We can suggest that, in nucleus accumbens, A disrupted in vivo and in vitro cholinergic control of DA release by acting on muscarinic transduction machinery.