Evolving knowledge about important plant-derived memory enhancer
Neurotransmitter Spiral …
… and may be a key for providing significant benefits for psychiatric diseases
By Will Block
t happens all the time. We think we know the answer to a biomedical question, and then in a flash, we really know the answer—beyond everything we knew before—and we understand it on a profoundly different level. That process has been called the spiral theory of knowledge. In widening your knowledge about a particular subject, you find yourself revisiting many of the facts you knew, as well as encountering new ones. This may propel you to employ your higher faculties with a greater intensity than usual. Since the fields of knowledge are unified, both hierarchically and chronologically, new knowledge will have implications, some of which will significantly alter your earlier knowledge, often with a broader perspective and higher integration. Can you say, “Eureka?”
Revisiting What is Known about Dementia
Consider the dementia Alzheimer’s disease (AD) for example, an even more complicated and mysterious subject than had long been thought. We now know that most neurons in the brain have receptors for not just one type of neurotransmitter, but several or many. That means that all such neurons are part of multiple “ergic” systems and can respond in exceedingly complex and variable ways—including opposite ways, depending on the circumstances. In AD, the two primary systems are believed to be the cholinergic and glutamatergic, but the disease also involves dysfunctions in the dopaminergic, noradrenergic, and serotonergic systems (which utilize dopamine, noradrenaline, and serotonin, respectively as neurotransmitters), and perhaps others as well.
Improving Neural Signals Helps Cognition
Now, a new review conducted at Osaka University in Japan reports on the accumulated findings for the phytonutrient galantamine on neurotransmitter release and pharmacological studies, principally in animal models of psychiatric disorders. The primary current use of galantamine is for the treatment AD. However, judging from a variety of evidential approaches reported by the review, there are strong indications that resolving cholinergic deficits can lessen or abate the pathophysiology* of psychiatric disorders, and that galantamine can help. How can this wider spectrum of benefits be explained?
Improved Cognitive Function and Psychiatric Health
There is growing clinical evidence that galantamine may improve cognitive dysfunction and psychiatric illness in schizophrenia, major depression, and bipolar disorder. As well, it may be useful for treating cocaine and alcohol abuse. Although galantamine has rather weak acetylcholinesterase inhibitor (AChEI) properties, it also has additional allosteric
potentiating effects at nicotinic receptors. Accordingly, it affects not only cholinergic transmission, but also other neurotransmitter systems such as monoamines, glutamate, and γ-aminobutyric acid (GABA) through its allosteric mechanism. The researchers point out that these effects may result in additional benefits.
There are strong indications
that cholinergic deficits
contribute to the pathophysiology of
psychiatric disorders, and that
galantamine can help.
In order to understand the underlying mechanism for the clinical effectiveness of galantamine, neuropharmacological studies have been conducted in animal models for a number of psychiatric disorders. These studies make the case
that it is not only the nicotinic receptor-modulating properties, but also the muscarinic receptor* activation, that contributes to the antipsychotic effect and improvement of cognitive dysfunction by galantamine. This idea is not new to readers of this publication.
The Uniqueness of Galantamine
Reduced central cholinergic neurotransmission is generally considered to be the core pathophysiological feature in AD. Thus, the inhibition of acetylcholinesterase (AChE) is the most successful strategy for current symptomatic treatments for the disease. The common AChEIs used to treat AD patients are the drugs donepezil and rivastigmine, along with the phytonutrient galantamine. Important to note, like the other AChEIs, galantamine is a selective and rapidly-reversible acetylcholinesterase inhibitor, but it is also an allosterically potentiating ligand (binder) of neuronal nicotinic receptors. Among the commonly used AChEIs, this later mechanism is unique to galantamine.
Galantamine interacts with the nicotinic receptor at binding sites separate from those for acetylcholine (ACh) and nicotinic agonists
and acts specifically to enhance and sensitize the activity of nicotinic receptors in the presence of ACh. This effect appears to be beneficial for the treatment of AD, in view of the previous findings that the severity of cognitive impairment in AD correlates with loss of nicotinic receptors and prolonged direct agonism for nicotinic receptors, which may cause desensitization rather than increased activation of the receptors.
The Role of Cholinergic Function in Psychiatric Diseases
Cholinergic changes are also involved in several psychiatric disorders. In schizophrenia, alterations in nicotinic and muscarinic receptor subtypes are thought to contribute to cognitive impairment and reduced choline acetyltransferase activity in the brain, which in turn is negatively correlated with the severity of such cognitive impairment. Decreased muscarinic receptor availability (binding activity) in other areas of the brain is associated with both bipolar disorder and major depressive disorder. With genetic variation in the CHRNA5 gene, which encodes the α5 subunit of the nicotinic receptors, mRNA levels are affected and this is associated with risk of alcohol dependence. These observations suggest that deficits in the cholinergic system, including nicotinic receptors, are implicated in the pathophysiology of psychiatric disorders, as well as AD.
Studies have shown that the use of galantamine adjunctively can improve negative and cognitive symptoms in schizophrenia, although there are a few negative reports. Also, galantamine improves mood in some patients with major depression or hastens the antidepressant treatment response in patients with late-life depression. In bipolar disorders, galantamine reduces manic symptoms and improves cognitive dysfunction. Improvement of cognitive dysfunction by galantamine is also observed in cocaine users. Finally, the Osaka researchers reported that galantamine reduced the alcohol consumption of relapsed patients with alcohol dependence. Altogether, these findings suggest that galantamine has great therapeutic promise for psychiatric disorders.
Effects of Galantamine on Neurotransmitter Release
Nicotinic receptors are located not only on cholinergic terminals, but also on the terminals of non-cholinergic neurons, and when activated, nicotinic receptors stimulate ACh release as well as the release of other neurotransmitters. Indeed, systemic administration of nicotine stimulates in vivo release of dopamine, noradrenaline, 5-HT, and glutamate in several brain regions including the prefrontal cortex, striatum, nucleus accumbens,* and hippocampus. Therefore, the allosteric modulating action of galantamine on nicotinic receptors could enhance the release of these neurotransmitters in the brain.
Galantamine may improve
cognitive dysfunction and psychiatric
illness in schizophrenia, major
depression, and bipolar disorder.
As well, it may be useful for
treating cocaine and alcohol abuse.
Some antipsychotic drugs increase ACh release in the prefrontal cortex and hippocampus, and thus it may be inferred that increased ACh contributes to the ability of improving cognition and negative symptoms. It is likely, too, that increased cholinergic neurotransmission is responsible for the clinical effects of galantamine, as several reports using rat tissue indicate and rat in vivo studies agree. These and other observations suggest that there are other mechanisms than AChEI involved in the galantamine-induced increases in ACh levels in the prefrontal cortex. There is also a report that galantamine increased extracellular dopamine concentrations in the prefrontal cortex, and that the effect of galantamine on ACh levels was partially blocked by a dopamine-D1-receptor antagonist. This suggests that a dopamine-mediated mechanism may contribute to galantamine-induced increase in prefrontal ACh levels.
Different mechanisms may
underlie the increasing effect of
galantamine on prefrontal
dopamine release, depending on
the dose and animal species used.
In another of the papers reviewed and analyzed by the Osaka University researchers, it was shown that galantamine increased dopamine release from nerve terminals in mouse striatal slices. This study suggests that galantamine activates midbrain dopaminergic neurons via nicotinic α7-receptor stimulation. In addition, a microdialysis study* demonstrated that galantamine at low doses of 0.1 mg/kg, but not 1 mg/kg, significantly increased extracellular dopamine levels in the medial prefrontal cortex of rats.
Also, the Osaka researchers reported that coadministration of galantamine and risperidone (an atypical antipsychotic drug), at their non-effective doses of 0.05 mg/kg, caused significant increases in the extracellular dopamine levels in the medial prefrontal cortex of mice pretreated with saline and a non-competitive NMDA-receptor antagonist. Prevention of this by mecamylamine (a nonselective and noncompetitive antagonist of the nicotinic acetylcholine receptors) indicates the involvement of nicotinic receptors.
Acetylcholine acts in many
cognitive functions such as
sensory information processing,
attention, memory and learning.
However, in another study, higher doses of galantamine (1 mg/kg and 3 mg/kg) increased extracellular dopamine levels in the prefrontal cortex of mice. Curiously, this increase was not affected by mecamylamine, suggesting the involvement of an independent nicotinic receptor mechanism. All in all, it remains to be determined just how galantamine increases dopamine release in the prefrontal cortex of mice.
Elsewhere in a referenced paper, galantamine potentiated neurotransmitter release by blocking small conductance calcium (Ca2+)-activated potassium (K+) channels. Because galantamine at low doses binds allosterically to nicotinic receptors and potentiates their function, and at high doses also acts as a weak acetylcholinesterase inhibitor, different mechanisms may underlie the increasing effect of galantamine on prefrontal dopamine release, depending on the dose and animal species used.
On another neurotransmitter front, it was reported that galantamine significantly increased noradrenaline release from hippocampal slices and that it potentiated nicotine-evoked noradrenaline release. Noradrenaline is the brain’s version of adrenaline. In another in vivo microdialysis study, it was shown that galantamine with nicotine given at ineffective doses increased noradrenaline release, although galantamine (3 mg/kg) alone did not affect the release in the hippocampus of rats. This study also demonstrated that galantamine enhanced nicotine-stimulated noradrenaline release. It is important to remember that dopamine is the immediate precursor of noradrenaline, and that when noradrenaline is insufficiently present, a person’s mood or energy levels may decline, even bottom out—for example, in depression.
On the basis of the studies reviewed, galantamine does not appear to affect serotonin (5-HT) release in the brain. Systemic administration of galantamine at doses of 1 and 3 mg/kg did not affect the extracellular 5-HT levels in the prefrontal cortex of mice. Nevertheless, the cholinergic and serotonergic systems are intertwined, so the proper study may not yet have been done.
Glutamate and GABA Release
There are a few reports on the effect of galantamine on in vivo release of glutamate and GABA in the brain. In rat brain tissue, galantamine potentiated excitatory postsynaptic current amplitude, thus indicating the enhancement of glutamatergic synaptic neurotransmission. Furthermore, galantamine-induced facilitation of glutamatergic neurotransmission was eliminated in the presence of an anti-nicotinic receptor antibody.
Regarding in vivo release of glutamate, galantamine reversed the decrease in the extracellular glutamate levels induced by a metabolite that inhibits α7 nicotinic receptors in the prefrontal cortex of rats. The suppression of glutamatergic neurotransmission by galantamine may be responsible for its clinical effect in schizophrenia.
Another more recent paper showed that four months of galantamine treatment (8 mg daily dose for the first month; 16 mg daily dose for the remaining three months) increased absolute glutamate levels and the ratio of glutamate to creatine in the right hippocampus of patients with AD.
The same researchers also demonstrated that these changes were associated with increased cognitive performance in AD patients. Regarding GABA-ergic transmission, another paper showed that galantamine potentiated the field stimulation or ACh-induced inhibitory postsynaptic current amplitude in rat hippocampal slices. Galantamine also potentiates that same type of amplitude via nicotinic receptors in human cerebral cortical slices. But, galantamine did not affect this increase in amplitude and frequency in the primary cortical neurons.
Effects of Galantamine on
Animal Models of Psychiatric Disorders
ACh acts in many cognitive functions such as sensory information processing, attention, memory and learning. Most studies on galantamine appear to focus on the effect on cognitive or memory impairment in animal models of schizophrenia and other psychiatric disorders.
Two papers by Wang et al. examined the effects of galantamine alone and in combination with risperidone (remember, an atypical antipsychotic drug) in a phencyclidine* (PCP)-induced model. PCP induces psychotomimetic states in humans and rodents. Since PCP psychosis incorporates not only positive symptoms but also negative symptoms and cognitive dysfunction, PCP-treated animals have been proposed as a preclinical model of schizophrenia. Galantamine significantly improved the impairment of social interaction and of latent visuospatial learning and memory in PCP-treated mice.
John Nash, a U.S. mathematician and joint winner of the 1994 Nobel Prize for Economics, suffered from schizophrenia. His life has been the subject of the 2001 Academy Award-winning film A Beautiful Mind.
Furthermore, co-administration of risperidone and galantamine at lower doses significantly improved the impairment, but not when administered alone. These results suggest that galantamine may be effective in treating the negative symptoms and cognitive dysfunction of schizophrenia and that it may have a synergistic effect with risperidone. Co-administration of galantamine and risperidone also increased extracellular dopamine levels in the medial prefrontal cortex of PCP-treated mice.
The ability to block this behavior indicates that the combined effect of galantamine and risperidone may be mediated by activation of nicotinic receptor- and dopamine-D1 receptor-mediated neurotransmission. The synergistic effect of galantamine is also demonstrated in the conditioned avoidance response test, an animal model of antipsychotic activity having a high predictive validity.
Galantamine inhibited the
expression of cocaine-induced
locomotor sensitization in mice.
Yet another paper reported that galantamine alone at doses of 5 mg/kg attenuated the conditioned avoidance response, and at lower doses (1 mg/kg) potentiated a typical antipsychotic antagonist-induced avoidance response in rats. In addition, adjunctive galantamine (1.25 mg/kg) also enhanced the antipsychotic-like effects of haloperidol (a typical antipsychotic) and risperidone in the conditioned avoidance response test.
Other reviewed papers show that galantamine (3 mg/kg) improves prepulse inhibition—the normal inhibition of the startle response when a weak stimulus (the prepulse) immediately precedes an intense startling stimulus (the pulse)—deficits induced by a non-selective dopamine-receptor agonist, in rats. There are other examples of this.
Clinical studies show that adjunctive galantamine can improve cognitive symptoms in schizophrenia, while donepezil does not, at least not significantly. From these and other studies, the authors conclude that the effect of galantamine in increasing extracellular ACh levels may result in activation of muscarinic receptors.
Psychostimulant-Induced Behaviors (Psychosis/Cognitive Deficits)
In nonhuman primates, the ability of galantamine to counteract dextroamphetamine-induced behavioral effects was reported. At doses of 0.6 and 1 mg/kg, galantamine attenuated dextroamphetamine-induced arousal, unrest, and repetitive movement in Cebus monkeys.
Similar to dextroamphetamine is methamphetamine, a highly addictive drug of abuse, and chronic methamphetamine users show psychotic signs such as hallucinations and delusions. These are indistinguishable from those of paranoid schizophrenia. Chronic use of methamphetamine also causes long-term cognitive deficits. A paper by Noda et al. showed that galantamine (3 mg/kg) ameliorated the impairment of recognition memory in mice repeatedly pretreated with methamphetamine. From this and other similar papers, these improvements by galantamine may be mediated by a kind of kinase (a phosphate transferring enzyme) signaling in a nicotinic receptor- and dopamine-D1 receptor-mediated mechanism.
Repeated intermittent administration of cocaine can enhance the stimulating effect on locomotor activity, a phenomenon called behavioral sensitization. This behavioral model has been used extensively to analyze the neural modification associated with repeated cocaine exposure and withdrawal. Another report found that galantamine (1 mg/kg) inhibited the expression of cocaine-induced locomotor sensitization in mice. Although the mechanism for the effect of galantamine remains to be clarified, this inhibition may be derived from increased ACh levels in the nucleus accumbens because donepezil also inhibited cocaine-induced locomotor sensitization and the depletion of ACh sources by cholinergic cell elimination markedly attenuated the inhibitory effect of donepezil.
Alcohol Addiction (Preference/Memory Impairment)
Alcohol is more commonly abused than any other drug. For all heavy drinkers, an increased health risk exists, although only some of them develop addiction. Anything that could help reduce ethanol consumption would help block the development of disease and derail the developmental processes leading to addiction.
In one paper, it was reported that higher doses (5 and 10 mg/kg) of galantamine inhibited ethanol intake in alcohol-preferring rats. Previous work showed that prolonged alcohol intake in rats led to memory impairment and decreases in ACh content and the activities of choline acetyltransferase and AChE.
In addition, it was shown that administration of galantamine (2.5 mg/kg) to prolonged alcohol-intake rats improved the speed of learning and short-term memory in two widely used tests.
Depression and Anxiety
As far as we know, there are no preclinical studies indicating the effect of galantamine on behavioral models of depression. Nonetheless, the effects on neurogenesis and neurotrophic factor expression have been studied. Newly generated neurons in the adult mouse hippocampus may be integrated into the neuronal circuitry and can display functional properties similar to those found in mature brain cells. Thus, neurogenesis plays a crucial role in behavioral, physiological and cognitive processes, and much attention has been focused on hippocampal neurogenesis in relation to the pathophysiology and treatment of depression.
Another paper investigated the effect of galantamine on neurogenesis in mouse cerebral cortical cultures in vitro and in the certain brain zones of mice in vivo. Galantamine (0.01 – 10 μM) was found to be valuable for enhanced cell proliferation. Brain-derived neurotrophic factor (BDNF) plays a key role in adult hippocampal neurogenesis, antidepressant treatment, and depressive-like behavior.
Galantamine treatment improved
acquisition performance with
the retrieval of both the immediate-
early gene and the precursor of brain-
derived neurotrophic factor levels in
In a very recent unpublished paper, the Osaka researchers report, a selective cholinergic immunotoxin, when administered into the third ventricle, impaired spatial acquisition memory in the Morris water maze test and decreased hippocampal protein levels of an immediate-early gene and proBDNF (the precursor of BDNF), leading to a diminished potential to consolidate new synapses.
The neurotransmitter effects of
galantamine may be the basis for
the improvement of abnormal
behaviors in animal models of
Galantamine (2.5 mg/kg) treatment improved acquisition performance with the retrieval of both the immediate-early gene and the precursor of BDNF levels in immunotoxin-treated rats. This study also showed that the activation of muscarinic, but not nicotinic, receptors caused a rapid induction of the immediate-early gene and BDNF production in hippocampal primary neurons. These findings imply that galantamine regulates synthesis of the immediate-early gene and BDNF by activation of muscarinic receptors and thus promotes synapse consolidation and learning ability.
The Spiral Does Not End
Summarizing the findings of the review, in addition to AD, deficits in cholinergic function have been identified in schizophrenia, major depression, and bipolar disorder, along with alcohol abuse and cocaine use. As well, current evidence suggests that galantamine may have a potential to provide the beneficial effects for these diseases, as well as others not yet on the map.
Clarification will come with further clinical trials with larger samples. Like the AChEI drug donepezil, the phytonutrient galantamine is a selective and rapidly reversible acetylcholinesterase inhibitor, but unlike it, galantamine also acts as an allosterically potentiating ligand of nicotinic receptors. It is this action that contributes not only to the neuronal protection against several neurotoxic stimuli, but also to the enhancement of neurotransmitter release such as dopamine, noradrenaline, glutamate, and GABA.
The neurotransmitter effects of galantamine may be the basis for the improvement of abnormal behaviors in animal models of psychiatric disorders. Yet there is more. Galantamine’s muscarinic receptor activation, by increasing brain ACh levels, may mediate in part anti-psychotic effects and improve cognitive dysfunction by galantamine. When considered as the multifunction nutrient that it is, galantamine may offer a unique therapeutic profile in psychiatric disorders. Now, if you’ve succeeded in slogging through this article, and ascended your way up the spiral, it may be time to say, “Cheers,” and of course, “Eureka!”
- Ago Y, Koda K, Takuma K, Matsuda T. Pharmacological Aspects of the Acetylcholinesterase Inhibitor Galantamine. J Pharmacol Sci 2011 Apr 16. [Epub ahead of print]
- Wang JC, Grucza R, Cruchaga C, Hinrichs AL, Bertelsen S, Budde JP, et al. Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence. Mol Psychiatry 2009;14:501–10.
- Allen TB, McEvoy JP. Galantamine for treatment-resistant schizophrenia. Am J Psychiatry 2002;159:1244–5.
- Buchanan RW, Conley RR, Dickinson D, Ball MP, Feldman S, Gold JM, et al. Galantamine for the treatment of cognitive impairments in people with schizophrenia. Am J Psychiatry 2008;165:82–9.
- Norén U, Björner A, Sonesson O, Eriksson L. Galantamine added to antipsychotic treatment in chronic schizophrenia: cognitive improvement? Schizophr Res 2006;85:302–304.
- Rosse RB, Deutsch SI. Adjuvant galantamine administration improves negative symptoms in a patient with treatment-refractory schizophrenia. Clin Neuropharmacol 2002;25:272–5.
- Schubert MH, Young KA, Hicks PB. Galantamine improves cognition in schizophrenic patients stabilized on risperidone. Biol Psychiatry 2006;60:530–3.
- Elgamal S, MacQueen G. Galantamine as an adjunctive treatment in major depression. J Clin Psychopharmacol 2008;28:357–9.
- Holtzheimer PE 3rd, Meeks TW, Kelley ME, Mufti M, Young R, McWhorter K, et al. A double blind, placebo-controlled pilot study of galantamine augmentation of antidepressant treatment in older adults with major depression. Int J Geriatr Psychiatry 2008;23:625–31.
- Snorrason E, Stefánsson JG. Galanthamine hydrobromide in mania. Lancet 1991;337:557.
- Sofuoglu M. Cognitive enhancement as a pharmacotherapy target for stimulant addiction. Addiction 2010;105:38–48.
- Dajas-Bailador FA, Heimala K, Wonnacott S. The allosteric potentiation of nicotinic acetylcholine receptors by galantamine is transduced into cellular responses in neurons: Ca2+ signals and neurotransmitter release. Mol Pharmacol 2003;64:1217–26.
- Sharp BM, Yatsula M, Fu Y. Effects of galantamine, a nicotinic allosteric potentiating ligand, on nicotine-induced catecholamine release in hippocampus and nucleus accumbens of rats. J Pharmacol Exp Ther 2004;309:1116–23.
- Penner J, Rupsingh R, Smith M, Wells JL, Borrie MJ, Bartha R. Increased glutamate in the hippocampus after galantamine treatment for Alzheimer disease. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:104-10.
- Wang D, Noda Y, Zhou Y, Nitta A, Furukawa H, Nabeshima T. Synergistic effect of galantamine with risperidone on impairment of social interaction in phencyclidine-treated mice as a schizophrenic animal model. Neuropharmacology 2007;52:1179-87.
- Wang D, Noda Y, Zhou Y, Nitta A, Furukawa H, Nabeshima T. Synergistic effect of combined treatment with risperidone and galantamine on phencyclidine-induced impairment of latent visuospatial learning and memory: Role of nAChR activationdependent increase of dopamine D1 receptor-mediated neurotransmission. Neuropharmacology 2007;53:379-89.
- Wiker C, Schilström B, Sandbäck C, Wadenberg ML, Svensson TH. Adjunctive galantamine, but not donepezil, enhances the antipsychotic-like effect of raclopride in rats. Int J Neuropsychopharmacol 2008;11:845–50.
- Gerlach J, Casey DE. Remoxipride, a new selective D2 antagonist, and haloperidol in cebus monkeys. Prog Neuropsychopharmacol Biol Psychiatry 1990;14:103-12.
- Noda Y, Mouri A, Ando Y, Waki Y, Yamada SN, Yoshimi A, et al. Galantamine ameliorates the impairment of recognition memory in mice repeatedly treated with methamphetamine: involvement of allosteric potentiation of nicotinic acetylcholine receptors and dopaminergic-ERK1/2 systems. Int J Neuropsychopharmacol 2010;13:1343-54.
- Gil-Bea FJ, Solas M, Mateos L, Winblad B, Ramírez MJ, Cedazo-Mínguez A. Cholinergic hypofunction impairs memory acquisition possibly through hippocampal Arc and BDNF downregulation. Hippocampus 2010 Jun 2. doi: 10.1002/hipo.20812. [Epub ahead of print]
Will Block is the publisher and editorial director of Life Enhancement magazine.