Journal of Neurochemistry Lippincott—Raven Publishers, Philadelphia © 1996 International Society for Neurochemistry Dysfunction of Cholinergic and Dopaminergic Neuronal Systems in ,i3-Amyloid Protein—Infused Rats Akio Itoh, Atsumi Nitta, Masayuki Nadai, Kyoko Nishimura, *Mjtsuhjko Hirose, Takaaki Hasegawa, and Toshitaka Nabeshima Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, and *Oriental Industrial Health Associates, Inc., Nagoya, Japan Abstract: Accumulations of /3-amyloid protein are char- acteristic and diagnostic features of the brain of Alzhei- mer’s disease patients; however, the physiological role of this protein in CNS is unknown. We have previously reported that continuous infusion of /3-amyloid protein into rat cerebral ventricle impairs learning ability and de- creases choline acetyltransferase activity, a marker en- zyme of cholinergic neuron. In this study, the effects of /3-amyloid protein infusion on the release of neurotrans- mitters in cholinergic and dopaminergic neuronal systems were investigated by using an in vivo brain microdialysis method. Nicotine-stimulated release of acetylcholine and dopamine in these animals was significantly lower than that in vehicle-infused rats. Further, dopamine release induced by high-K stimulation was decreased in /3-amy- bid protein—infused rats compared with vehicle-infused rats. These results suggest that the release of the two transmitters, acetyicholine and dopamine, was de- creased by /3-amyloid protein and that learning deficits observed in the /3-amyloid protein—infused rats are partly due to the impairment of neurotransmitter release. Fur- thermore, continuous infusion of /3-amyboid protein may be a useful method to produce the animal model of AIz- heimer’s disease. Key Words: Acetylcholine—Alzhei- mer’s disease— /3-Amyloid protein—Central nervous system— Dopamine— Rats. J. Neurochem. 66, 1113—1117 (1996). Alzheimer’s disease (AD) is characterized histolog- ically by large numbers of neurofibrillary tangles (NFTs) and senile plaques (SPs) in the brain (Hardy and Allsop, 1991; Kosik, 1991). In these brains, cho- linergic dysfunction has also been found (Davies and Maloney, 1976; Rossor et al., 1982; Whitehouse et al., 1982; Coyle et al., 1983; Flynn and Mash, 1986), this being related to the severity of cognitive dysfunction and memory loss in the patients (Sims et al., 1983). However, thus far, no potent drugs suitable for clinical use have yet been developed, although treatment of AD with cholinergic agents, such as cholinesterase in- hibitors and cholinergic agonists, have been attempted. It is necessary to establish good animal models that reflect the pathological, neurochemical, and behavioral characteristics of AD, so that drugs for the treatment of AD can be developed, because the electrical or chemical lesions that have been used hitherto to pre- pare AD model animals (Le Conte et al., 1982; Flicker et al., 1983; Nabeshima et al., 1991a,b; Nitta et al., 1993, 1994b) do not show the histological and patho- logical changes (i.e., the SPs and/or NFTs) observed in the brains of AD patients. In recent years, remarkable advances have been made in the understanding of the biochemical proper- ties of SPs, which consist of extracellular accumula- tions of /3-amyloid protein (A/3) (Masters et al., 1985). However, effects of A~3 on behaviors involving learning and memory have hardly been reported. Re- cently, we reported that the continuous infusion of A~3 into the rat cerebral ventricle for 14 days, via mini- osmotic pump, causes learning deficits and decreases choline acetyltransferase (ChAT) activity in the frontal cortex and hippocampus (Nabeshima and Nitta, 1994; Nitta et al., 1 994a). In this study, to determine the effects of continuous infusion of A/3 on the mecha- nisms of neurotransmitter release in the cholinergic and dopaminergic neuronal systems, we measured re- lease of acetylcholine (ACh) and dopamine (DA) un- der two different conditions using nicotine (NIC) and high doses of potassium (high K) as stimulators; NIC activates the nicotinic ACh receptor ion channels thought to regulate neurotransmitter release (Nordberg Received June 21, 1995; revised manuscript received September 18, 1995; accepted September 21, 1995. Address correspondence and reprint requests to Dr. T. Nabeshima at Department of Neuropsychopharmacology and Hospital Phar- macy, Nagoya University School of Medicine, Tsuruma-cho 65, Showa-ku, Nagoya 466, Japan. Abbreviations used: A~, /3-amyloid protein; ACII, acetyicholine; AD, Alzheimer’s disease; ChAT, choline acetyltransferase; DA, do- pamine; DOPAC, 3,4-dihydroxyphenylacetic acid; ECD, electro- chemical detection; high K—Ringer, high potassium Ringer’s solu- tion; HVA, homovanillic acid; NFF, neurofibrillary tangle; NIC, nicotine; NIC—Ringer, Ringer’s solution containing 3 mM nicotine; SP, senile plaque. 1113