Elsevier

Neuropharmacology

Volume 53, Issue 3, September 2007, Pages 421-430
Neuropharmacology

Different effects of ionotropic and metabotropic glutamate receptor antagonists on attention and the attentional properties of nicotine

https://doi.org/10.1016/j.neuropharm.2007.05.023Get rights and content

Abstract

Distinct lines of evidence indicate that glutamate plays a primary role in modulating cognitive functions. Notably, competitive glutamate receptor antagonists acting at ionotropic N-methyl-d-aspartate (NMDA) or metabotropic glutamate 5 (mGlu5) receptors impair cognitive performance. Conversely, nicotine and other psychostimulants stimulate glutamatergic mechanisms and can act as cognitive enhancers. Hence we analysed the role of glutamate in performance of an attentional task and in nicotine-induced enhancement of attention by using the rodent five-choice serial reaction time task (5-CSRTT). Rats were trained to criterion performance and were then pre-dosed with either vehicle, the NMDA receptor antagonist (+)3-(2-carboxypiperazin-4-propyl)-1-propenyl-1-phosphonic acid (CPP, 0.3–2.0 mg/kg) or the mGlu5 antagonist 2-methyl-6-phenylethynyl-pyridine (MPEP, 1.0–9.0 mg/kg) and challenged with nicotine (0.2 mg/kg). Nicotine improved attentional performance, an effect that was weakened by doses of CPP that themselves had little impact on performance; importantly, CPP dose-dependently blunted the ability of nicotine to improve response accuracy, the major measure of signal detection in the paradigm. MPEP dose-dependently impaired signal detection under conditions with a high attentional load, an effect that was reversed by nicotine; thus, MPEP did not block nicotine-induced attentional enhancement. Co-administration of either CPP or MPEP with nicotine also produced a general slowing of performance characterised by increases in omission errors and response latencies and reduced anticipatory responding. It is concluded that activation of NMDA receptors may be an important determinant of the effects of nicotine in the 5-CSRTT. Stimulation of nicotinic receptors may also reverse attentional deficits associated with the impaired function of the glutamate network.

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.

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