Galantamine enhances dopaminergic neurotransmission in vivo via allosteric potentiation of nicotinic acetylcholine receptors.
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 (0.01-1.0 mg/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 (1.0 mg/kg s.c.), but not the muscarinic receptor antagonist scopolamine (0.1 mg/kg s.c.), and it was not mimicked by the selective AChE inhibitor donepezil (1.0 mg/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 alpha7 nAChR antagonist methyllycaconitine (6.0 mg/kg i.p.) as well as the N-methyl-D-aspartate antagonist CGP39551 (2.5 mg/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.
Schilström
Björn
B
Section of Neuropsychopharmacology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. bjorn.schilstrom@fyfa.ki.se
Ivanov
Vladimir B
VB
Wiker
Charlotte
C
Svensson
Torgny H
TH
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005702:Galantamine / Q000494:pharmacology*; D007189:Indans / Q000494:pharmacology; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D017551:Microdialysis / Q000379:methods; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects*; D017557:Ventral Tegmental Area / Q000166:cytology
D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D018733:Nicotinic Antagonists; D010880:Piperidines; D011978:Receptors, Nicotinic; D005702:Galantamine; C064540:CGP 39551; D008464:Mecamylamine; D015763:2-Amino-5-phosphonovalerate; D000077265:Donepezil; D004298:Dopamine