Muscarinic and nicotinic receptor modulation of object and spatial n-back working memory in humans

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Abstract

Working memory impairments in the n-back task in schizophrenia have been linked to sustained deficiency in mesocortical dopamine function. More recently, abnormalities in the cholinergic system have also been documented in schizophrenia, with cortical reductions in both nicotinic and muscarinic receptors. While the cholinergic hypothesis of memory is well established, the role of cholinergic receptors in modulating n-back working memory is not known. We investigated the effects of selective and simultaneous muscarinic and nicotinic antagonism on spatial and object n-back working memory performance. The study was a double-blind, placebo-controlled repeated-measures design in which 12 healthy subjects were tested under four acute treatment conditions; placebo (P), mecamylamine (M), scopolamine (S) and mecamylamine + scopolamine (MS). Muscarinic antagonism with scopolamine significantly impaired both object and spatial n-back working memory, whereas nicotinic antagonism with mecamylamine had little effect. Simultaneous antagonism of both muscarinic and nicotinic receptors produced greater impairments in both object and spatial n-back working memory performance than muscarinic or nicotinic antagonism alone. These results suggest that: (1) both muscarinic and nicotinic receptors may functionally interact to synergistically modulate n-back working memory, and (2) that n-back working memory impairments in schizophrenia may in part be due to reductions in both muscarinic and nicotinic receptors.

Introduction

Impairments in higher order cognitive processes are one of the most debilitating symptom dimensions of schizophrenia and thought to be a good predictor of poor clinical outcome (Green, 1996, Liddle, 2000). Working memory (i.e. processes involved in maintenance and manipulation of information over a brief period to time to guide task appropriate behaviour) is one construct that has been shown to be impaired in patients with schizophrenia (Park and Holzman, 1992, Goldman-Rakic, 1994, Fleming et al., 1995, Keefe et al., 1997, Conklin et al., 2000). Among the working memory tasks, the n-back paradigm has been extensively used to evaluate working memory function in schizophrenia, and studies have consistently found deficits in n-back working memory performance in patients with schizophrenia (Carter et al., 1998, Goldberg et al., 2003, Callicott et al., 2000, Abi-Dargham et al., 2002).

Functional neuroimaging studies have demonstrated the engagement of the dorsolateral prefrontal cortex (DLPFC) in the execution of the n-back and other working memory tasks (Cohen et al., 1994, Cohen et al., 1997, Braver et al., 1997, D'Esposito et al., 1998), and patients with schizophrenia have been shown to have abnormal working memory related activation in the DLPFC (Carter et al., 1998, Barch et al., 2001, Perlstein et al., 2001, Honey et al., 2002). Neurochemical studies in animals and humans have demonstrated a critical role for mesocortical dopamine and D1 receptors in processes relevant to working memory (Sawaguchi and Goldman-Rakic, 1991, Sawaguchi and Goldman-Rakic, 1994, Arnsten et al., 1994, Arnsten and Goldman-Rakic, 1998, Goldman-Rakic et al., 2000, Goldman-Rakic et al., 2004, Ellis and Nathan, 2001). Consistent with this, alternations in D1 receptor availability in the DLPFC (i.e. upregulation of D1 receptors) has been found in patients with schizophrenia (Abi-Dargham et al., 2002) and this increase was shown to be a strong predictor of poorer performance on an n-back working memory task (Abi-Dargham et al., 2002). Further, studies investigating functional polymorphisms of the catechol-O-methyltransferase (COMT) gene have shown that in both healthy subjects and patients with schizophrenia, those homozygous for the low enzymatic activity met allele (greater prefrontal dopamine availability) perform better on n-back working memory task than do those subjects with the high enzymatic activity val allele (lower prefrontal dopamine availability) (Goldberg et al., 2003).

While a deficiency in mesocortical dopamine has been linked with impairments in n-back working memory performance in both normal subjects and patients with schizophrenia, it is likely that other systems including the cholinergic system may also be involved. With neuropathological evidence linking a reduction in cholinergic function to the cognitive decline seen in a number of disorders such as Alzheimer's disease (Perry et al., 1978), as well as pharmacological evidence that anticholinergic drugs consistently produce impairments in learning and memory (Rusted and Warburton, 1988, Broks et al., 1988, Wesnes et al., 1988, Newhouse et al., 1992, Newhouse et al., 1994, Robbins et al., 1997, Potter et al., 2000, Edginton and Rusted, 2003, Ellis et al., 2005), the cholinergic basis of memory dysfunction has been well established (Bartus et al., 1982). In animals and healthy humans, both muscarinic and nicotinic antagonists have been shown to induce impairments in a number of cognitive domains including working memory (Levin et al., 1993, Levin et al., 1997, Rusted and Warburton, 1988, Wesnes et al., 1988, Rusted et al., 1991, Maviel and Durkin, 2003, Ellis et al., 2005).

Although the link between the cholinergic system and working memory is established, the role of this system in modulating n-back working memory is not known. Furthermore, very little is known about the functional interactions between muscarinic and nicotinic receptors, including how they may interact synergistically to modulate selective cognitive processes. Animal studies have shown some evidence for synergistic interactions between muscarinic and nicotinic receptor systems at the level of receptor regulation (i.e. sensitization and upregulation) and at a functional level on various cognitive processes (Vige and Briley, 1988, Levin et al., 1990, Riekkinen et al., 1993, Mirza and Stolerman, 2000, Leblond et al., 2002, Brown and Galligan, 2003). Further, we have recently reported in humans that similar functional synergistic interactions between muscarinic and nicotinic receptors in modulating early information processing (Erskine et al., 2004) sustained attention and working memory (Ellis et al., 2005). It is unknown if n-back working memory performance can similarly be synergistically modulated by both receptor systems.

Hence the aim of the present study was to examine the role of the cholinergic muscarinic and nicotinic receptors in modulating spatial and object n-back working memory in healthy human subjects. Based on previous animal and human working memory studies, we hypothesised that selective nicotinic and muscarinic receptor antagonism would produce impairments in performance on both object and spatial working memory. Furthermore, we hypothesised that simultaneous antagonism of both nicotinic and muscarinic receptors would impair performance on the n-back tasks, over and above the impairments produced by antagonism of either receptor alone.

Section snippets

Participants

Twelve healthy adult volunteers (4 female, 10 male) aged 19–30 years (M = 23.3, S.D. = 2.8) with a mean weight of 67.6 kg were recruited through advertisements at local universities. All subjects were university educated and proficient in English. Participants were required to pass a brief semi-structured physical and psychiatric examination and were included in the study if they were non-smokers, not currently on any medication including the oral contraceptive pill, and had no history of

Task validity

Participants performed more poorly on the 2-back compared to 1-back versions of the task for both object working memory [accuracy: F(1,11) = 12.47, p = 0.005; reaction time: F(1,11) = 3.76, p = 0.079], and spatial working memory [accuracy: F(1,11) = 18.84, p = 0.001; reaction time: F(1,11) = 7.68, p = 0.018], suggesting that for both of the n-back tasks used in the present study, 2-back load was more difficult than 1-back load (Table 1).

1-Back

A significant drug by time interaction for both accuracy [F(3,33) = 14.72, p <

Discussion

The current study is the first to examine the effects of muscarinic and nicotinic antagonism on spatial and object n-back working memory performance. Nicotinic antagonism with mecamylamine did not significantly impair n-back performance for both spatial and object working memory. As hypothesised, selective muscarinic antagonism with scopolamine significantly impaired performance on spatial (1- and 2-back) and object (2-back) working memory. Interestingly, simultaneous antagonism of both

Acknowledgements

The study was supported by the National Health and Medical Research Council (NHMRC) of Australia (Grant 345709) and Alzheimer's Australia. The authors would like to thank Layton Bioscience for providing the mecamylamine tablets.

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