https://www.ncbi.nlm...pubmed/18845194 Synergistic effect of galantamine on nicotine-induced neuroprotection in hemiparkinsonian rat model.
Recent studies have reported that smokers tend to be less susceptible to Parkinson's disease (PD) and the stimulation of nicotinic acetylcholine receptor (nAChR) is considered to confer a neuroprotective effect. Galantamine is an acetylcholinesterase inhibitor and an allosteric potentiating ligand for nAChRs. However, the effects of galantamine and nicotine on dopaminergic neurons remain unclear. This study evaluated the neuroprotective effects of galantamine and nicotine in a rat 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian model. 6-OHDA with or without galantamine and/or nicotine were injected into unilateral substantia nigra of rats. Although methamphetamine-stimulated rotational behavior and dopaminergic neuronal loss induced by 6-OHDA were not inhibited by galantamine alone, those were moderately inhibited by nicotine alone. In addition, 6-OHDA-induced neuronal loss and rotational behavior were synergistically inhibited by co-injection of galantamine and nicotine. These protective effects were abolished by mecamylamine, an nAChR antagonist. We further found that alpha7 nAChR was expressed on both tyrosine hydroxylase (TH)-immunopositive and TH-immunonegative neurons in the SNpc. A combination of galantamine and nicotine greatly suppressed 6-OHDA-induced reduction of TH-immunopositive/alpha7 nAChR-immunopositive neurons. These results suggest that galantamine synergistically enhances the neuroprotective effect of nicotine against 6-OHDA-induced dopaminergic neuronal loss through an allosteric modulation of alpha7 nAChR activation.
Galantamine Enhances Dopaminergic Neurotransmission In Vivo Via Allosteric Potentiation of Nicotinic Acetylcholine Receptors
Bjo ¨rn Schilstro ¨m*,1, Vladimir B Ivanov1, Charlotte Wiker1 and Torgny H Svensson1 1Section of Neuropsychopharmacology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Clinical studies suggest that adjunct galantamine may improve negative and cognitive symptoms in schizophrenia. These symptoms may be related to impaired dopaminergic function in the prefrontal cortex. Indeed, galantamine has been shown to increase dopamine release in vitro. Galantamine is an allosteric modulator of nicotinic acetylcholine receptors (nAChRs) and, at higher doses, an acetylcholine esterase (AChE) inhibitor. We have previously shown that nicotine, through stimulation of nAChRs in the ventral tegmental area (VTA), activates midbrain dopamine neurons and, hence, potentiation of these receptors could be an additional mechanism by which galantamine can activate dopaminergic pathways. Therefore, the effects of galantamine (0.01–1.0mg/kg s.c.) on dopamine cell firing were tested in anaesthetized rats. Already at a low dose, unlikely to result in significant AchE inhibition, galantamine increased firing activity of dopaminergic cells in the VTA. The effect of galantamine was prevented by the nAChR antagonist mecamylamine (1.0mg/kg s.c.), but not the muscarinic receptor antagonist scopolamine (0.1mg/kg s.c.), and it was not mimicked by the selective AChE inhibitor donepezil (1.0mg/kg s.c.). Our data thus indicate that galantamine increases dopaminergic activity through allosteric potentiation of nAChRs. Galantamine’s effect was also prevented by the a7 nAChR antagonist methyllycaconitine (6.0mg/kg i.p.) as well as the N-methyl-Daspartate antagonist CGP39551 (2.5mg/kg s.c.), indicating a mechanism involving presynaptic facilitation of glutamate release. In parallel microdialysis experiments, galantamine was found to increase extracellular levels of dopamine in the medial prefrontal cortex. These results may have bearing on the enhancement of negative and cognitive symptoms in schizophrenia.
