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.