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Nicotinic α7 Receptors Boost Cognitive Circuits in Prefrontal Cortex

July 26, 2013. Nicotinic α7 acetylcholine receptors enhance the firing of prefrontal cortex “delay cells” that underlie working memory, according to a new study published July 16, 2013, in the Proceedings of the National Academy of Sciences. Led by Min Wang at Yale University in New Haven, Connecticut, the study also found that stimulation of these receptors was necessary for the action of N-methyl-D-aspartate (NMDA) glutamate receptors in the same brain region. The results suggest a mechanism for how genetic risk variants in α7-nAChRs may lead to working memory deficits in schizophrenia.

Dysfunctional nicotinic α7 receptors (α7-nAChRs) have been proposed to underlie the cognitive deficits of schizophrenia (see SRF related news story). The gene for the receptor CHRNA7 was associated with schizophrenia in several genetic studies, and knockout mice display cognitive impairments (Stephens et al., 2012). The α7-nAChR has also emerged as a viable drug target for schizophrenia (Olincy and Freedman, 2012). For example, in a preliminary study, the agonist tropisetron improved cognitive deficits in the illness (see SRF related news story).

Behavioral studies suggest that the neurotransmitter acetylcholine is important for working memory—the short-term maintenance of small amounts of information in order to guide future thought processes—which is impaired in schizophrenia (Croxson et al., 2011). The dorsolateral prefrontal cortex (DLPFC), a brain region whose dysfunction is also well documented in the illness, appears to be central to working memory. Although animal studies have demonstrated that α7-nAChRs agonists can improve working memory deficits induced by blocking NMDA receptors, the role of α7-nAChRs in DLPFC circuits is unknown.

Delay cell pharmacology
First author Yang Yang trained monkeys to perform a spatial working memory paradigm, the oculomotor delayed response (ODR) task. A cue is flashed at one of eight locations on a screen, and the monkey must use working memory to remember this location during a 2.5-second delay. At the end of the delay, the monkey moves its eyes to the correct location to receive a reward.

To examine the physiological actions of α7-nAChRs, the researchers made electrophysiological recordings from single neurons in the DLPFC while the monkeys performed the ODR task. They concentrated on “delay cells,” those neurons with persistent firing during the delay period that are responsible for generating mental representations of visual space—a central component of visual working memory. Each of these neurons has a so-called preferred direction, a portion of visual space for which it fires most strongly.

Application of the general nAChR antagonist mecamylamine reduced neuronal firing during all timepoints of the task. In contrast, the more specific α7-nAChR antagonist methyllycaconitine reduced the delay-related firing for the neuron’s preferred direction (with no effect on its non-preferred direction or firing during the presentation of the cue). These data suggest that α7-containing nAChRs can excite DLPFC neurons and point to a role for these receptors in spatial working memory. In addition, they provide an explanation for how risk variants in CHRNA7, which presumably disrupt α7-nAChRs, could lead to cognitive deficits in schizophrenia.

In contrast with the antagonist data, application of the α7-nAChR agonist PHA543613 enhanced delay-related firing, with an inverted-U dose effect observed. The most specific boost to firing during the delay period occurred with lower doses of the drug, while higher doses produced nonspecific increases in excitability. Similarly, low doses of the drug improved performance on the ODR task, while higher doses had no effect or were impairing. Therefore, selecting the appropriate dosage will be critical to the efficacy of α7-nAChR-based cognitive-enhancing drugs to treat schizophrenia and other disorders, say the authors.

Mingling of glutamate and acetylcholine
Given that NMDA receptors are also involved in the spatial tuning of delay-related firing, the authors next examined the interactions between these glutamate receptors and α7-nAChRs. Consistent with a previous report from the authors (Wang et al., 2013), blockade of NR2B NMDA receptors with the selective antagonist Ro256981 reduced delay-related firing. However, this reduction was reversed with co-application of PHA543613. Coupled with their electron microscopy findings that α7-nAChRs are prominent in the postsynaptic density of glutamatergic synapses, where NR2B-NMDARs are also located, the authors conclude that their findings are consistent with a “spatial and functional interaction of the two receptors.”

Given the proximity of the receptors at the postsynaptic density, the authors hypothesized that α7-nAChRs may provide the depolarization necessary for NMDA receptor neurotransmission. Consistent with their hypothesis, pharmacological blockade of α7-nAChRs abolished the NMDA application-associated increase in delay cell firing, demonstrating that stimulation of α7-nAChRs is required for NMDA action. The results suggest a mechanism by which acetylcholine shapes mental states, say the authors. They suggest that because the neurotransmitter modulates arousal—it is released during wakefulness but not sleep—α7-nAChRs may act to bring NMDA receptor higher cortical circuits online, thereby generating a “conscious cognitive state.”—Allison A. Curley.

Reference:
Yang Y, Paspalas CD, Jin LE, Picciotto MR, Arnsten AF, Wang M. Nicotinic a7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex. Proc Natl Acad Sci U S A . 2013 Jul 16 ; 110(29):12078-83. Abstract

Comments on Related News


Related News: Cholinergic Drug Improves Cognition in Nonsmokers With Schizophrenia

Comment by:  Britta Hahn
Submitted 7 October 2012
Posted 7 October 2012

The study by Zhang et al. (2012) provides further evidence for the therapeutic potential of partial α7 nicotinic acetylcholine receptor (nAChR) agonists in the treatment of the cognitive deficits associated with schizophrenia. Given the impact of this symptom group on psychosocial functioning (Green et al., 2004; Tan, 2009) and the current absence of effective treatments, the importance of such findings is easily seen. Tropisetron administered over 10 days improved immediate and delayed memory subscales of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and improved P50 auditory gating deficits in 40 non-smoking inpatients with schizophrenia.

The evidence for enhanced auditory gating was strong, with the reduction in the S2/S1 ratio being entirely due to a decrease in S2 amplitude with no change in S1. By limiting the study sample to patients who displayed P50 gating deficits at baseline (~40 percent of all screened patients), the authors may have selected a subpopulation of patients particularly prone to showing benefits from α7 nAChR agonist treatment, possibly due to a larger incidence of genetic mutations reducing α7 nAChR subunit expression (Leonard et al., 2002) in this subsample. This type of pre-screening may indeed be a clinical approach to be considered prior to α7 agonist treatment. However, the measurement reliability of the P50 S2/S1 ratio tends to be low, and the degree to which P50 gating deficits predict treatment success with α7 agonists remains to be determined. Despite the large role that this ERP has played as an endophenotype of schizophrenia guiding drug development, evidence that P50 gating deficits are related to higher cognitive functions is still sparse (Potter et al., 2006). Zhang et al. found that changes in P50 gating from baseline to day 10 were correlated with changes in RBANS scores, collapsing data across all four treatment groups (including placebo). However, such correlations may be based on day-to-day fluctuations in cognitive state that could affect both measures in the same manner. More evidence is needed to clarify the clinical significance of improvements in P50 gating.

The finding that effects of tropisetron were seen mostly on memory indices differs from studies with the partial α7 agonist DMXB-A (Olincy et al., 2006; Freedman et al., 2008) and a previous study with tropisetron (Shiina et al., 2010), which reported effects predominantly on attention/vigilance indices. Larger trials may be able to determine more conclusively the cognitive domains beneficially affected by α7 agonists. Relatively flat dose-response curves were observed with tropisetron, consistent with a partial agonist mode of action. The finding that the largest dose (20 mg) produced no added benefits but tended to be associated with more side effects argues for the choice of lower doses.

Caution is warranted to not let positive findings with α7 agonists convey the impression that non-α7 nAChR subtypes are irrelevant for the treatment of cognitive deficits in schizophrenia. Indeed, non-α7 subtypes such as α4β2 mediate beneficial effects of nAChR agonists on cognitive performance (e.g., Dunbar et al., 2007; Grottick et al., 2003; Hahn et al., 2003; Levin, 2002), including improvements in sensory gating (Radek et al., 2006). The advantage of targeting α7 over other nAChR subtypes remains to be established by direct comparison. There is also a need for direct comparisons of α7-selective agonists with broader acting nAChR agonists to determine whether this subtype captures all cognitive benefit to be harvested from nAChR modulation in the treatment of schizophrenia.

References:

Dunbar G, Boeijinga PH, Demazières A, Cisterni C, Kuchibhatla R, Wesnes K, Luthringer R (2007) Effects of TC-1734 (AZD3480), a selective neuronal nicotinic receptor agonist, on cognitive performance and the EEG of young healthy male volunteers. Psychopharmacology 191: 919-29. Abstract

Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L, Allensworth D, Guzman-Bonilla A, Clement B, Ball MP, Kutnick J, Pender V, Martin LF, Stevens KE, Wagner BD, Zerbe GO, Soti F, Kem WR. (2008) Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry 165: 1040-7. Abstract

Green MF, Kern RS, Heaton RK (2004) Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res 72: 41-51. Abstract

Grottick AJ, Haman M, Wyler R, Higgins GA (2003) Reversal of a vigilance decrement in the aged rat by subtype-selective nicotinic ligands. Neuropsychopharmacology 28: 880-7. Abstract

Hahn B, Sharples CG, Wonnacott S, Shoaib M, Stolerman IP (2003) Attentional effects of nicotinic agonists in rats. Neuropharmacology 44: 1054-67. Abstract

Leonard S, Gault J, Hopkins J, Logel J, Vianzon R, Short M, Drebing C, Berger R, Venn D, Sirota P, Zerbe G, Olincy A, Ross RG, Adler LE, Freedman R (2002) Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. Arch Gen Psychiatry 59: 1085-96. Abstract

Levin ED (2002) Nicotinic receptor subtypes and cognitive function. J Neurobiol 53: 633-640. Abstract

Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, Ellis J, Zerbe GO, Leonard S, Stevens KE, Stevens JO, Martin L, Adler LE, Soti F, Kem WR, Freedman R. (2006) Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 63: 630-8. Abstract

Potter D, Summerfelt A, Gold J, Buchanan RW (2006) Review of clinical correlates of P50 sensory gating abnormalities in patients with schizophrenia. Schiz Bull 32: 692-700. Abstract

Radek RJ, Miner HM, Bratcher NA, Decker MW, Gopalakrishnan M, Bitner RS (2006) Alpha4beta2 nicotinic receptor stimulation contributes to the effects of nicotine in the DBA/2 mouse model of sensory gating. Psychopharmacology 187: 47-55. Abstract

Shiina A, Shirayama Y, Niitsu T, Hashimoto T, Yoshida T, Hasegawa T, Haraguchi T, Kanahara N, Shiraishi T, Fujisaki M, Fukami G, Nakazato M, Iyo M, Hashimoto K (2010) A randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia. Ann Gen Psychiatry 9: 27. Abstract

Tan BL (2009) Profile of cognitive problems in schizophrenia and implications for vocational functioning. Aust Occup Ther J 56: 220-228. Abstract

View all comments by Britta Hahn

Related News: Cholinergic Drug Improves Cognition in Nonsmokers With Schizophrenia

Comment by:  Georg Winterer (Disclosure)
Submitted 30 October 2012
Posted 30 October 2012

The paper of Zhang et al. once more presents promising findings suggesting that nicotinic α7 (partial) agonists may eventually be used as cognition enhancers in schizophrenia. Since several completed studies about the effect of nicotinic agonists on P50 gating and cognitive parameters are now around, we should try to figure out what distinguishes the negative and positive studies.

In the particular case of tropisetron, it certainly needs to be acknowledged that this drug also is a serotonin 5-HT3 antagonist. Previous studies (e.g., Adler et al., 2005) have already suggested that drugs that act as antagonists at this receptor improve P50 gating. Since antagonism of 5-HT3 increases release of acetylcholine, this may add to the direct partial agonist effect of tropisetron at the (low affinity) α7 nicotinic receptor as well as other nicotinic receptors, including high-affinity α4β2 receptors. In this regard, we should also acknowledge that agonists that act at other nicotinic receptors (α4β2) are now under investigation and show promising results when it comes to cognition enhancement in schizophrenia (e.g., varenicline).

Varenicline is primarily a partial agonist of the α4β2 subtype (although agonism at α7 has also been reported). Notably, other than tropisetron, varenicline is an agonist of 5-HT3 receptors. This is puzzling, adding to the confusion about the true cognition-enhancing effect in cholinergic drugs. It might be (exclusively) α7, but it is too early to jump to this conclusion. For instance, we recently published a negative proof-of-mechanism study on allosteric α7 nicotinic receptor modulation and P50 sensory gating in schizophrenia (Winterer et al., 2013).

In my opinion, what we need now is to go back to healthy probands (Phase 1) and select a range of drugs with different receptor profiles, but which have in common that they all act directly or indirectly at nicotinic receptors. These drugs then should be systematically tested for their effects on electrophysiological surrogate measures, including P50 gating, as well as cognitive measures, followed by corresponding investigations (using a preselected subset of compounds) in schizophrenia patients. Of course, this would require collaboration between R&D of different pharmaceutical companies—in other words: an industrial network approach is the unmet need!

References:

Adler LE, Cawthra EM, Donovan KA, Harris JG, Nagamoto HT, Olincy A, Waldo MC. Improved p50 auditory gating with ondansetron in medicated schizophrenia patients. Am J Psychiatry . 2005 Feb ; 162(2):386-8. Abstract

Winterer G, Gallinat J, Brinkmeyer J, Musso F, Kornhuber J, Thuerauf N, Rujescu D, Favis R, Sun Y, Franc MA, Ouwerkerk-Mahadevan S, Janssens L, Timmers M, Streffer JR. Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: A proof-of-mechanism study. Neuropharmacology . 2013 Jan ; 64(1):197-204. Abstract

View all comments by Georg Winterer