Different effects of ionotropic and metabotropic glutamate receptor antagonists on attention and the attentional properties of nicotine
Introduction
Several lines of research have implicated glutamate in cognitive functions. Cognitive impairments occur in neurodegenerative conditions (e.g. Alzheimer's and Parkinson's diseases), psychiatric states (schizophrenia) and other disorders (Farber et al., 1998, Konradi and Heckers, 2003, Meldrum and Garthwaite, 1990). N-Methyl-d-aspartate (NMDA) receptor antagonists have effects that resemble psychosis and prefrontal lobe dysfunctions such as impairment of working memory (Murphy et al., 2005). Responses evoked by NMDA may be influenced by metabotropic glutamate 5 (mGlu5) receptor modulators that have also been implicated in the regulation of cortical executive functions (Homayoun and Moghaddam, 2006, Kinney et al., 2003, Lu et al., 1997). In the present studies we have used the 5-choice serial reaction time task (5-CSRTT) to explore the ability of NMDA and mGlu5 receptor antagonists to modulate the attentional properties of nicotine in rats.
Nicotine can act as a cognitive enhancer in animals and humans via the cholinergic network that controls information processing and executive functions (Everitt and Robbins, 1997, Koelega, 1993, Levin et al., 2006). Several recent reports indicate that nicotine can improve attention in normal (unlesioned) rats as shown by increased accuracy of signal detection in the 5-CSRTT, accompanied by reduced reaction times and omission errors (Hahn et al., 2002a, Hahn et al., 2002b, Hahn et al., 2003). Just as performance of the 5-CSRTT is controlled by multiple neuronal networks (Robbins, 2002), diverse neurotransmitters contribute to the nicotine-induced enhancement of attention. The nicotinic agonist isoarecolone, which has weaker effects on dopamine release than nicotine, improved stimulus detection without altering reaction times (Hahn et al., 2003). Neither the dopamine D1-antagonist SCH 23390 nor the D2-antagonist raclopride impaired response accuracy, although raclopride weakened the effect of nicotine on reaction times (Hahn et al., 2002a, Hahn et al., 2002b). Contrastingly, the β-noradrenaline receptor antagonist propranolol weakened the effect of nicotine on stimulus detection (Hahn and Stolerman, 2005). Rezvani et al. (2005) found that the serotonin 5-HT2A receptor antagonist ketanserin blocked the ability of nicotine given acutely or chronically to improve accuracy in a two-lever signal detection task. These studies suggest that neurotransmitters other than dopamine may play a crucial role in the attention-enhancing properties of nicotine.
Glutamate acts at both ionotropic and metabotropic G-protein-coupled receptors (mGluR). There are three major subtypes of the tetrameric ionotropic receptors: N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoazole-propionic acid (AMPA) receptors, and kainate receptors (Danbolt, 2001, Rosenmund et al., 1998). NMDA receptor subunits are up-regulated after continuous nicotine self-administration (Wang et al., 2006) and correspondingly, NMDA receptor antagonists can weaken some behavioural and neurochemical effects of nicotine (Fu et al., 2000b, Glick et al., 2001, Shoaib et al., 1994). Mammalian metabotropic glutamate receptors are divided into eight subtypes (Schoepp et al., 1999) and may play an important role in nicotine dependence (Kenny and Markou, 2004). The selective mGlu5 receptor antagonist MPEP weakened nicotine self-administration (Paterson and Markou, 2005, Tessari et al., 2004) but not the effect of nicotine on brain stimulation reward (Harrison et al., 2002).
Some studies have evaluated the role of endogenous glutamate in visuospatial attention. Experiments with antagonists suggest that physiological activation of NMDA receptors may influence some measures of attentional performance. The non-competitive NMDA receptor antagonist dizocilpine impaired performance of a two-lever operant signal detection task and nicotine attenuated this effect (Rezvani and Levin, 2003, Rezvani et al., 2007). Infusion of the competitive NMDA receptor antagonist (+)3-(2-carboxypiperazin-4-propyl)-1-propenyl-1-phosphonic acid (CPP) into the prefrontal cortex reduced accuracy and increased omission errors and perseverative responding in rats performing the 5-CSRTT (Higgins et al., 2003a, Higgins et al., 2003b, Mirjana et al., 2004, Murphy et al., 2005). However, the effects of systemically administered CPP on the 5-CSRTT seem not to have been examined whereas the metabotropic glutamate receptor antagonist MPEP impaired the speed of responding and decreased the numbers of anticipatory responses (Semenova and Markou, 2007). The effects of manipulating either ionotropic or metabotropic glutamatergic mechanisms on nicotine-stimulated attentional performance have not been reported.
The present study analysed the effects of competitive antagonists at ionotropic NMDA and metabotropic mGlu5 glutamate receptors on attentional performance and on the attentional effects of nicotine. These studies were carried out both under standard conditions involving detection of visual stimuli of 1 s duration and under conditions where attentional demands were increased by the use of shorter (0.5 s) stimuli (Hahn et al., 2002a). The use of short stimuli typically degrades performance and minimises ceiling effects that are problematic in studies with cognitive enhancers.
Section snippets
Subjects
Male hooded Lister rats (Harlan, UK) originally weighing 250–300 g were housed individually in a temperature (20 ± 1 °C) and humidity (50 ± 10%) controlled environment on a 12 h light–dark cycle (lights on from 0730 h). Rats had restricted access to food to maintain weights at 85% of those under free feeding conditions and they had water ad libitum. A total of 40 rats were used. The treatment of animals complied with the UK Animals (Scientific Procedures) Act 1986 and the Code of Practice of the
Experiment 1: dose–response study of the combined effects of CPP and nicotine
The dose of CPP, the nicotine dose and the time period within sessions were the factors in 3-way repeated measure ANOVA. Fig. 1A indicates that nicotine in the absence of CPP increased accuracy (for main effect of nicotine F1,19 = 15.7, P < 0.0001). Although there were signs of reductions in omission errors, response latencies and anticipatory responding after administration of nicotine, these trends did not attain statistical significance (Fig. 1B–D). CPP in the absence of nicotine increased the
Discussion
The study examined the role of glutamate in performance of the 5-CSRTT and in the attentional effects of nicotine. The attention-enhancing properties of nicotine have been well documented in rodents and humans (Koelega, 1993, Levin and Simon, 1998, Mansvelder et al., 2006) and the present results confirm those reported previously (Hahn et al., 2002a, Hahn et al., 2002b, Hahn et al., 2003). Although the neurochemical substrates that underlie the attentional effects of nicotine are not fully
Acknowledgments
We thank the European Union for financial support and Novartis, Zurich, Switzerland, for the generous donation of MPEP. None of the authors has any relevant financial or other conflict of interest.
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Present address: Drug Dependence & Behavioural Neurochemistry Department, Psychiatry-CEDD, GlaxoSmithKline S.p.A., Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy.