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α7 Nicotinic Receptor Agonists as Cognitive Treatments: Is Less (or Less Often) More?
␣7 Nicotinic Receptor Agonists as Cognitive Treatments: Is Less (or Less Often) More? Robert W. Buchanan and Robert Schwarcz here is considerable interest in the development of nicotinic agents for the treatment of cognitive impairments in schizophrenia. This interest stems, in part, from the observation that the acute administration of nicotine improves various aspects of cognition, including attention, learning and memory, and working memory in both patients and healthy control subjects. The beneficial effect of nicotine suggests that drugs, which target either ␣42 or ␣7 nicotinic receptors (nAChRs), might be useful for enhancing cognition. However, although preclinical studies have repeatedly documented the cognitive benefits of agents that act at these receptors, there has been limited success with nicotinic agents in people with schizophrenia. There are several possible reasons why clinical effects might not be as pronounced as those observed in animal models. Two studies published in the current issue of Biological Psychiatry provide new information on the procognitive effects of ␣7 nAChR partial agonists in nonhuman primates and people with schizophrenia, raising interesting questions related to the optimal use of such agents as cognition enhancers. The first study was based on the earlier demonstration that acute administration of very low doses of the selective ␣7 nAChR partial agonist AZD0328 improves learning and attentional processes in rats and mice (1). Castner et al. (2) evaluated the procognitive effects of similarly low AZD0328 doses in rhesus monkeys, which had been trained to stability on a spatial delayed response task. Acute drug administration revealed significant but modest improvements in this assay of prefrontal cortical function. However, efficacy in the primates was not seen at the higher doses used—in contrast with rodents, where cognition-enhancing effects increase dose-dependently and are maintained at higher doses. In fact, the compound induced significant cognitive impairments when administered at the highest dose. Interestingly, similar cognitive worsening was seen at the ultralow dose. The inverted U-shaped dose response curve seen in these experiments could not be explained by unorthodox pharmacokinetics, and the apparent species difference was not caused by different AZD0328 affinities to rodent and primate ␣7 nAChRs (Ki ⫽ 3–5 nmol/L) (1). Although the detrimental consequences of the highest dose can be attributed to off-target effects—possibly involving 5-HT3 receptor inhibition (3)— or to the functional antagonist properties of high-dose partial agonists (4), the cognitive deterioration caused by the very low dose is difficult to explain. In the earlier rat study, selective inhibition of ␣7 nAChRs prevented effects of the drug (1). Therefore, it is quite likely that the cognitive worsening seen after low-dose ADZ0328 was caused by interference with ␣7 nAChR function. Whether this effect was related to receptor desensitization or internalization, as suggested by the authors, remains to be investigated. Interestingly, a subset of monkeys showed statistically significant improvement in spatial working memory when tested several weeks after acute AZD0328 administration. Castner et al. therefore
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From the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland. Address correspondence to Robert W. Buchanan, M.D., University of Maryland School of Medicine, Department of Psychiatry, PO Box 21247, Baltimore, MD 21228; E-mail: [email protected]. Received Nov 3, 2010; accepted Nov 3, 2010.
0006-3223/$36.00 doi:10.1016/j.biopsych.2010.11.004
designed a second experiment in which the animals were subjected to a multiple escalating dosing schedule. In this paradigm, the monkeys received each dose of AZD0328 in two bouts, with a 1-week interval between the bouts, followed by a 2-week washout period. This intermittent regimen resulted in persistent cognitive improvement, lasting for 2 months or more after treatment. Remarkably, the beneficial effect persisted for more than 6 months in three of the experimental animals. Even though enduring consequences of brief exposures to nicotine or selective nAChR agonists have been repeatedly described over the past 2 decades, this result is truly impressive, pushing the envelope on both the time- and dose-scale. A range of mechanisms has been credibly invoked to explain this phenomenon, including changes in gene expression, altered function of neurotrophic factors, or modified receptor regulation and intracellular signaling (5). Unfortunately, the authors did not evaluate these mechanisms with acute pharmacological challenges and/or in vivo imaging studies. In the second study, Tregellas et al. (6) examined the effects of two doses of the ␣7 nAChR partial agonist 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB-A) on “default network” activity in people with schizophrenia. The default network comprises multiple brain regions, including the posterior cingulate gyrus, cuneus/precuneus, medial prefrontal and temporal lobes, and the inferior parietal cortex (6,7). These functionally connected regions are hypothesized to be active during periods of “rest” (i.e., when the person is engaged in reflective activity). Default network connectivity and activity have previously been shown to be altered in schizophrenia (7). Tregellas et al. found that both DMXB-A doses decreased default network activity in the posterior cingulate, inferior parietal cortex, and medial frontal gyrus and increased activity in the precuneus. In addition, they examined whether the rs3087454 A/C single nucleotide polymorphism, located in the 5= regulatory sequence of the CHRNA7 gene, affected the DMXB-A effect on default network activity. They found a significant association with genotype, with DMXB-A exerting a smaller effect on posterior cingulate activity in participants who were homozygous for the minor allele. Tregellas et al. conducted their study in the context of a threearm, double-blind, double-cross-over, placebo-controlled randomized clinical trial (8). In this trial, which was designed to examine the effects of repeated DMXB-A administration on cognitive impairments and positive and negative symptoms (8), no overall significant effect of DMXB-A on cognition was observed. However, when analyses were limited to subjects who had completed the first phase of the study, both doses of DMXB-A showed selective benefits on cognition. Moreover, DMXB-A significantly improved negative symptoms, with a trend for significant improvement in Brief Psychiatric Rating Scale total score. In combination, these two DMXB-A studies raise a number of interesting issues. First, in secondary analyses, Tregellas et al. (6) found that decreased posterior cingulate activity was significantly correlated with decreased Brief Psychiatric Rating Scale total score, and increased precuneus activity was significantly correlated with decreased Scale for the Assessment of Negative Symptoms total score. These results support the hypothesis that abnormal default network activity might be associated with symptom severity (7) and BIOL PSYCHIATRY 2011;69:5– 6 © 2011 Society of Biological Psychiatry
6 BIOL PSYCHIATRY 2011;69:5– 6 suggest that normalization of network activity might be associated with decreased symptoms. An examination of the relationship between changes in default network activity and changes in cognition observed in the first phase of the Freedman et al. study (8) would be of similar interest. Second, the association between the minor allele of the rs3087454 A/C single nucleotide polymorphism and default network and hippocampal activity indicates that the beneficial clinical effects observed by Freedman et al. might be most pronounced in individuals with the major allele. In a retrospective analysis, the authors indeed noted that the minor allele was associated with smaller changes in the cognitive measure (6). Finally, there was no significant dose effect on default network activity. If—as suggested by Castner et al. (2)—␣7 nAChR partial agonists exhibit an inverted U-shaped dose response curve, with doses at each end of the continuum adversely affecting cognition, the lack of DMXB-A dose effect might simply indicate that both doses were within the effective range. Further studies, with lower and higher DMXB-A doses, would be useful to determine whether inverted U-shaped pharmacodynamics are of relevance for the use of partial agonists to treat cognition in people with schizophrenia. The monkey study of Castner et al. (2) illustrates a potential drawback to the use of partial agonists to enhance cognition. The effect of partial agonists on receptor function is dependent on the concentration of the endogenous neurotransmitter (4). Thus, the high AZD0328 dose and subsequent increased ␣7 nAChR receptor occupancy might have interfered with receptor activation by the endogenous full agonist, acetylcholine, causing the impaired performance observed on the spatial delayed response task. If these considerations also apply to human cognitive processes, it seems prudent to pay attention to possible cognitive worsening when using high doses of ␣7 nAChR partial agonists for the enhancement of cognition in people with schizophrenia. The finding that ␣7 nAChR activation by an extremely low dose of AZD0328 has deleterious effects on cognition raises a different type of concern (2). One caveat here is that this conclusion was based on a single data point so that independent confirmation is necessary. However, if the low-dose effect can be generalized, its molecular and cellular underpinnings clearly need to be elucidated, with in vivo and in vitro approaches. The discovery and development of promising novel cognitive enhancers might otherwise be impeded by (too) low dosing of test compounds in early clinical studies, leading to type II errors (false negatives). Finally, the current studies raise the provocative possibility that intermittent dosing might be more effective than continuous dosing when using partial agonists to treat cognition (the half-life of DMXB-A is 2 hours; twice daily dosing is probably not sufficient to continuously occupy the receptor). There are several instances in
www.sobp.org/journal
Commentary psychopharmacology where single or intermittent dosing has produced significant and long-lasting benefits, including the use of a dopamine D1 receptor agonist to reverse haloperidol-induced working memory impairments (9) and the differential benefits of once weekly administration of D-cycloserine for negative symptoms in schizophrenia (10). These remarkable results need to be explored further in studies that evaluate the relative efficacy of intermittent and continuous dosing in head-to-head comparisons. Dr. Buchanan has served as a data and safety monitoring board member for Cephalon, Otsuka, and Pfizer; a consultant to Abbott, GlaxoSmithKline, Sanofi-Aventis, and Schering-Plough; and an advisory board member for Abbott, AstraZeneca, Cypress Bioscience, Merck, Pfizer, Roche, Solvay Pharmaceuticals, and Wyeth. He has received grant support from Janssen Pharmaceutica. Dr. Schwarcz has received research support from Mitsubishi-Tanabe and Bristol-MyersSquibb. 1. Sydserff S, Sutton EJ, Song D, Quirk MC, Maciag C, Li C, et al. (2009): Selective ␣7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes. Biochem Pharmacol 78:880 – 888. 2. Castner SA, Smagin GN, Piser TM, Wang Y, Smith JS, Christian EP, et al. (2011): Immediate and sustained improvements in working memory after selective stimulation of ␣7 nicotinic acetylcholine receptors. Biol Psychiatry 69:12–18. 3. Widzowski DV, Maier D, McLaughlin J, Neilson K, Bock MJ, Wang Y, et al. (2007): AZD0328 and AZ11943872: ␣7 nicotinic agonists that reverse fimbria-fornix-transection-induced working memory deficits following acute or chronic administration. Soc Neurosci Abstr 906:21. 4. Hogg RC, Bertrand D (2007): Partial agonists as therapeutic agents at neuronal nicotinic acetylcholine receptors. Biochem Pharmacol 73:459 – 468. 5. Buccafusco JJ, Letchworth SR, Bencherif M, Lippiello PM (2005): Longlasting cognitive improvement with nicotinic receptor agonists: Mechanisms of pharmacokinetic-pharmacodynamic discordance. Trends Pharmacol Sci 26:352–360. 6. Tregellas JR, Tanabe J, Rojas DC, Shatti S, Olincy A, Johnson L, et al. (2011): Effects of an alpha 7-nicotinic agonist on default network activity in schizophrenia. Biol Psychiatry 69:7–11. 7. Garrity AG, Pearlson GD, McKiernan K, Lloyd D, Kiehl KA, Calhoun VD (2007): Aberrant “default mode” functional connectivity in schizophrenia. Am J Psychiatry 164:450 – 457. 8. Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L, et al. (2008): Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry 165:1040 –1047. 9. Castner SA, Williams GV, Goldman-Rakic PS (2000): Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation. Science 287:2020 –2022. 10. Goff DC, Cather C, Gottlieb JD, Evins AE, Walsh J, Raeke L, et al. (2008): Once-weekly D-cycloserine effects on negative symptoms and cognition in schizophrenia: An exploratory study. Schizophr Res 106:320 –327.
T
From the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland. Address correspondence to Robert W. Buchanan, M.D., University of Maryland School of Medicine, Department of Psychiatry, PO Box 21247, Baltimore, MD 21228; E-mail: [email protected]. Received Nov 3, 2010; accepted Nov 3, 2010.
0006-3223/$36.00 doi:10.1016/j.biopsych.2010.11.004
designed a second experiment in which the animals were subjected to a multiple escalating dosing schedule. In this paradigm, the monkeys received each dose of AZD0328 in two bouts, with a 1-week interval between the bouts, followed by a 2-week washout period. This intermittent regimen resulted in persistent cognitive improvement, lasting for 2 months or more after treatment. Remarkably, the beneficial effect persisted for more than 6 months in three of the experimental animals. Even though enduring consequences of brief exposures to nicotine or selective nAChR agonists have been repeatedly described over the past 2 decades, this result is truly impressive, pushing the envelope on both the time- and dose-scale. A range of mechanisms has been credibly invoked to explain this phenomenon, including changes in gene expression, altered function of neurotrophic factors, or modified receptor regulation and intracellular signaling (5). Unfortunately, the authors did not evaluate these mechanisms with acute pharmacological challenges and/or in vivo imaging studies. In the second study, Tregellas et al. (6) examined the effects of two doses of the ␣7 nAChR partial agonist 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB-A) on “default network” activity in people with schizophrenia. The default network comprises multiple brain regions, including the posterior cingulate gyrus, cuneus/precuneus, medial prefrontal and temporal lobes, and the inferior parietal cortex (6,7). These functionally connected regions are hypothesized to be active during periods of “rest” (i.e., when the person is engaged in reflective activity). Default network connectivity and activity have previously been shown to be altered in schizophrenia (7). Tregellas et al. found that both DMXB-A doses decreased default network activity in the posterior cingulate, inferior parietal cortex, and medial frontal gyrus and increased activity in the precuneus. In addition, they examined whether the rs3087454 A/C single nucleotide polymorphism, located in the 5= regulatory sequence of the CHRNA7 gene, affected the DMXB-A effect on default network activity. They found a significant association with genotype, with DMXB-A exerting a smaller effect on posterior cingulate activity in participants who were homozygous for the minor allele. Tregellas et al. conducted their study in the context of a threearm, double-blind, double-cross-over, placebo-controlled randomized clinical trial (8). In this trial, which was designed to examine the effects of repeated DMXB-A administration on cognitive impairments and positive and negative symptoms (8), no overall significant effect of DMXB-A on cognition was observed. However, when analyses were limited to subjects who had completed the first phase of the study, both doses of DMXB-A showed selective benefits on cognition. Moreover, DMXB-A significantly improved negative symptoms, with a trend for significant improvement in Brief Psychiatric Rating Scale total score. In combination, these two DMXB-A studies raise a number of interesting issues. First, in secondary analyses, Tregellas et al. (6) found that decreased posterior cingulate activity was significantly correlated with decreased Brief Psychiatric Rating Scale total score, and increased precuneus activity was significantly correlated with decreased Scale for the Assessment of Negative Symptoms total score. These results support the hypothesis that abnormal default network activity might be associated with symptom severity (7) and BIOL PSYCHIATRY 2011;69:5– 6 © 2011 Society of Biological Psychiatry
6 BIOL PSYCHIATRY 2011;69:5– 6 suggest that normalization of network activity might be associated with decreased symptoms. An examination of the relationship between changes in default network activity and changes in cognition observed in the first phase of the Freedman et al. study (8) would be of similar interest. Second, the association between the minor allele of the rs3087454 A/C single nucleotide polymorphism and default network and hippocampal activity indicates that the beneficial clinical effects observed by Freedman et al. might be most pronounced in individuals with the major allele. In a retrospective analysis, the authors indeed noted that the minor allele was associated with smaller changes in the cognitive measure (6). Finally, there was no significant dose effect on default network activity. If—as suggested by Castner et al. (2)—␣7 nAChR partial agonists exhibit an inverted U-shaped dose response curve, with doses at each end of the continuum adversely affecting cognition, the lack of DMXB-A dose effect might simply indicate that both doses were within the effective range. Further studies, with lower and higher DMXB-A doses, would be useful to determine whether inverted U-shaped pharmacodynamics are of relevance for the use of partial agonists to treat cognition in people with schizophrenia. The monkey study of Castner et al. (2) illustrates a potential drawback to the use of partial agonists to enhance cognition. The effect of partial agonists on receptor function is dependent on the concentration of the endogenous neurotransmitter (4). Thus, the high AZD0328 dose and subsequent increased ␣7 nAChR receptor occupancy might have interfered with receptor activation by the endogenous full agonist, acetylcholine, causing the impaired performance observed on the spatial delayed response task. If these considerations also apply to human cognitive processes, it seems prudent to pay attention to possible cognitive worsening when using high doses of ␣7 nAChR partial agonists for the enhancement of cognition in people with schizophrenia. The finding that ␣7 nAChR activation by an extremely low dose of AZD0328 has deleterious effects on cognition raises a different type of concern (2). One caveat here is that this conclusion was based on a single data point so that independent confirmation is necessary. However, if the low-dose effect can be generalized, its molecular and cellular underpinnings clearly need to be elucidated, with in vivo and in vitro approaches. The discovery and development of promising novel cognitive enhancers might otherwise be impeded by (too) low dosing of test compounds in early clinical studies, leading to type II errors (false negatives). Finally, the current studies raise the provocative possibility that intermittent dosing might be more effective than continuous dosing when using partial agonists to treat cognition (the half-life of DMXB-A is 2 hours; twice daily dosing is probably not sufficient to continuously occupy the receptor). There are several instances in
www.sobp.org/journal
Commentary psychopharmacology where single or intermittent dosing has produced significant and long-lasting benefits, including the use of a dopamine D1 receptor agonist to reverse haloperidol-induced working memory impairments (9) and the differential benefits of once weekly administration of D-cycloserine for negative symptoms in schizophrenia (10). These remarkable results need to be explored further in studies that evaluate the relative efficacy of intermittent and continuous dosing in head-to-head comparisons. Dr. Buchanan has served as a data and safety monitoring board member for Cephalon, Otsuka, and Pfizer; a consultant to Abbott, GlaxoSmithKline, Sanofi-Aventis, and Schering-Plough; and an advisory board member for Abbott, AstraZeneca, Cypress Bioscience, Merck, Pfizer, Roche, Solvay Pharmaceuticals, and Wyeth. He has received grant support from Janssen Pharmaceutica. Dr. Schwarcz has received research support from Mitsubishi-Tanabe and Bristol-MyersSquibb. 1. Sydserff S, Sutton EJ, Song D, Quirk MC, Maciag C, Li C, et al. (2009): Selective ␣7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes. Biochem Pharmacol 78:880 – 888. 2. Castner SA, Smagin GN, Piser TM, Wang Y, Smith JS, Christian EP, et al. (2011): Immediate and sustained improvements in working memory after selective stimulation of ␣7 nicotinic acetylcholine receptors. Biol Psychiatry 69:12–18. 3. Widzowski DV, Maier D, McLaughlin J, Neilson K, Bock MJ, Wang Y, et al. (2007): AZD0328 and AZ11943872: ␣7 nicotinic agonists that reverse fimbria-fornix-transection-induced working memory deficits following acute or chronic administration. Soc Neurosci Abstr 906:21. 4. Hogg RC, Bertrand D (2007): Partial agonists as therapeutic agents at neuronal nicotinic acetylcholine receptors. Biochem Pharmacol 73:459 – 468. 5. Buccafusco JJ, Letchworth SR, Bencherif M, Lippiello PM (2005): Longlasting cognitive improvement with nicotinic receptor agonists: Mechanisms of pharmacokinetic-pharmacodynamic discordance. Trends Pharmacol Sci 26:352–360. 6. Tregellas JR, Tanabe J, Rojas DC, Shatti S, Olincy A, Johnson L, et al. (2011): Effects of an alpha 7-nicotinic agonist on default network activity in schizophrenia. Biol Psychiatry 69:7–11. 7. Garrity AG, Pearlson GD, McKiernan K, Lloyd D, Kiehl KA, Calhoun VD (2007): Aberrant “default mode” functional connectivity in schizophrenia. Am J Psychiatry 164:450 – 457. 8. Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L, et al. (2008): Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry 165:1040 –1047. 9. Castner SA, Williams GV, Goldman-Rakic PS (2000): Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation. Science 287:2020 –2022. 10. Goff DC, Cather C, Gottlieb JD, Evins AE, Walsh J, Raeke L, et al. (2008): Once-weekly D-cycloserine effects on negative symptoms and cognition in schizophrenia: An exploratory study. Schizophr Res 106:320 –327.