Galantamine Enhances Dopaminergic Neurotransmission In Vivo Via Allosteric Potentiation of Nicotinic Acetylcholine Receptors

Abstract

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 a7 nAChR antagonist methyllycaconitine (6.0 mg/kg i.p.) as well as the N-methyl-Daspartate 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.

Galantamine Postischemia Provides Neuroprotection and Memory Recovery against Transient Global Cerebral Ischemia in Gerbils

“…Galantamine is an acetylcholinesterase inhibitor that also shows allosteric potentiation of the nicotinic receptor (Schrattenholz et al, 1996) and N-methyl-D-aspartate recep-tor (Moriguchi et al, 2004) and facilitation of synaptic transmission (Santos et al, 2002;Schilström et al, 2007). Our laboratory demonstrated the antiapoptotic and neuroprotective effects of galantamine, which acts on ␣-7 neuronal nicotinic receptors and also induces antiapoptotic protein B-cell leukemia/lymphoma 2 expression in cultured chromaffin cells and human neuroblastoma cells (Arias et al, 2004(Arias et al, , 2005.…”

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

“…Eight of 13 participants were rated as responders on the basis of their improvement scores on the Clinical Global Impressions scale. The allosteric properties of galantamine could directly lead to increased release of acetylcholine and activation of postsynaptic nAChRs (Samochocki et al, 2003) or act indirectly through its effects on the release of other neurotransmitters, especially glutamate and dopamine (Schilström et al, 2007;Wang et al, 2007). It has been demonstrated that amyloid- precursor protein (APP) is upregulated in a mouse model for Fragile X mental retardation (FXS) (Westmark et al, 2008) and two clinical studies have reported higher levels of APP in children with autism.…”

“…Galantamine is an acetylcholinesterase inhibitor that also acts as a positive allosteric modulator at the 42 and 7 nAChRs (Dajas-Bailador et al, 2003;Samochocki et al, 2003;Schilström et al, 2007). In two studies with small numbers of subjects it has been reported that galantamine showed potential benefits for attention, memory, and psychomotor speed in schizophrenia (Schubert et al, 2006;Lee et al, 2007).…”

Pharmacological Aspects of the Acetylcholinesterase Inhibitor Galantamine

“…Schilström et al (32) found using in vivo Up-pointing arrow: increase or potentiation, down-pointing arrow: decrease or reversal, ±: no effect. single unit recordings that systemic administration of galantamine at low doses of 0.01 and 0.1 mg/kg increased firing activity of dopaminergic cells in the ventral tegmental area of anesthetized rats.…”