Galantamine, a
drug for
Alzheimer's disease, is a novel
cholinergic agent with a dual mode of action, which inhibits
acetylcholinesterase and allosterically modulates
nicotinic acetylcholine receptors (nAChRs), as a result stimulates
catecholamine neurotransmission. In the present study, we investigated whether
galantamine exerts cognitive improving effects through the allosteric modulation of nAChR in the intracerebroventricular
beta amyloid (Abeta)(25-35)-injected animal model of
Alzheimer's disease.
Galantamine (3 mg/kg p.o.) significantly increased the extracellular
dopamine release in the hippocampus of saline- and Abeta(25-35)-injected mice. The effects of
nicotine on the extracellular
dopamine release were potentiated by
galantamine, but antagonized by
mecamylamine, a nAChR antagonist. Abeta(25-35)-injected mice, compared with saline-injected mice, could not discriminate between new and familiar objects in the novel object recognition test and exhibited less freezing response in the fear-conditioning tasks, suggesting Abeta(25-35) induced
cognitive impairment.
Galantamine improved the Abeta(25-35)-induced
cognitive impairment in the novel object recognition and fear-conditioning tasks. These improving effects of
galantamine were blocked by the treatment with
mecamylamine,
SCH-23390, a
dopamine-D1 receptor antagonist, and
sulpiride, a
dopamine-D2 receptor antagonist, but not by
scopolamine, a
muscarinic acetylcholine receptor antagonist. This study provides the first in vivo evidence that
galantamine augments dopaminergic neurotransmission within the hippocampus through the allosteric potentiation of nAChRs. The improving-effects of
galantamine on the Abeta(25-35)-induced
cognitive impairment may be mediated through the activation of, at least in part, dopaminergic systems, and the enhancement of
dopamine release may be one of multiple mechanisms underlying the therapeutic benefit of
galantamine.