Research reportMGlu5 antagonism impairs exploration and memory of spatial and non-spatial stimuli in rats
Introduction
Metabotropic glutamate receptor 5 (mGlu5) is a G-protein coupled receptor that is linked to different ion channels and uses multiple intracellular signalling pathways [11], [19]. MGlu5 receptors have been implicated in synaptic plasticity, learning, and memory [2], [38], [41]. Among the learning tasks in which systemic applications of selective mGlu5 antagonists, 2-methyl-6-(phenylethynyl)-pyridine (MPEP) [15] or [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) [12] has impaired learning are a number of procedures using aversive unconditioned stimuli or response consequences: conditioned fear-potentiation of a startle response [40], contextual and auditory fear conditioning [16], LiCl-induced conditioned taste aversion [7], [39], and passive avoidance [17]. Some learning tasks using non-aversive unconditioned stimuli or response outcomes have also shown sensitivity to systemically applied MPEP or MTEP although performance in some such tasks has been found unimpeded. For instance, acquisition in a light-nosepoke association task for rats was significantly impaired by MPEP [20]. However, one study using rats in a water maze task reported no effect [3], while another obtained a relatively small deficit produced by MPEP [45]. In a color—key response association task, MPEP failed to affect both within-session and between-session learning in rats [10]. Effects of MPEP were also absent in mice tested for long-term spatial learning in the elevated plus maze [36]. In an appetitive and spatial three-hole learning task for rats, long-term acquisition was unimpeded by systemically applied MPEP in doses up to 10 mg/kg [33]. It is therefore clear that MPEP can impact aversive learning whereas the effect in non-aversive tasks remains equivocal. Thus, further studies are necessary to elucidate the specific functions of mGlu5 receptors in specific learning and memory tasks. This goal was presently pursued using two non-aversive learning tasks: the cross-maze and the object recognition task, in which effects of systemically administered MPEP were analyzed.
With respect to the role of mGlu5 in specific brain structures in non-aversive learning, little information is available. One study found that working and reference memory in the eight-arm maze was reduced after i.c.v. injections of MPEP which binds to hippocampal receptors [30]. The hippocampus is connected to the prelimbic cortex via a monosynaptic glutamatergic pathway [22], [23] and this cortex has been implicated in both working and reference memory [27]. However, with respect to memory-functions of prelimbic mGlu5, no information is available. The possible involvement of prelimbic mGlu5 in both spatial and non-spatial retention was therefore presently tested by using prelimbic infusions of MPEP before training in the cross-maze and the object recognition task.
The capacity of rodents to explore stimuli that are to be remembered is an essential factor in all learning tasks. It is therefore customary to verify that impacting mGlu5 function with an experimental treatment does not affect the capacity for exploratory locomotor activity. Most reports have found that systemic administrations of MPEP or MTEP have no direct effect on spontaneous locomotion [10], [18], [20], [24], [46], but at higher doses (MPEP: 100 mg/kg p.o. for mice and 30–100 mg/kg p.o. for rats, 100 mg/kg i.p. for rats; MTEP: 10–100 mg/kg i.p. for rats) both antagonists have attenuated spontaneous activity [31], [34], [43], [44], [47]. However, one investigation with mice found that doses of 5 and 20 mg/kg MPEP induced hyperactivity [29]. In order to test the possible effects of mGlu5 antagonism on exploration of spatial and non-spatial cues, the influence of MPEP-administration on exploratory locomotion was observed in cross-maze, object recognition task and open field.
In previous investigations of the behavioral consequences of mGlu5 antagonism, the interval between administration of the antagonist and behavioral testing has varied between 20 min [33], 25 min [39], 30 min [16], [17] and 60 min [40], [46]. Since no pharmacokinetic information is available to verify a constant pharmacological impact throughout this range, the varying intervals used in previous research prevent direct comparisons of dose-effects among the different reports. In order to elucidate the possible effects of the interval, exploratory locomotion was presently observed in the open field task at intervals ranging from 5 to 180 min after MPEP-administration. The open field task was used since it proved the most dose-sensitive among the tasks employed in this study.
Section snippets
Subjects
Male Sprague–Dawley rats were housed in pairs in a vivarium with a 12 h light/12 h dark cycle (lights on at 0700). Experiments were initiated near the beginning of the light period. For cross-maze experiments, the animals weighed between 200 g and 250 g on the first experimental day. The weight of the rats in the object recognition experiment was 250–300 g. The rats had ad libitum access to food and water except for those used for training in the cross-maze (in which solutions were used as reward).
Experiment 1: exploration and alternation behavior in the cross-maze (i.p. MPEP)
Early exploratory locomotion in the cross-maze is shown in Fig. 1A which depicts 6 periods of 5 min each for groups given either 0, 2, 5 or 10 mg/kg MPEP. A significant effect of drug dose was present (F(3,32) = 61.75; p < 0.0001; repeated measures dose × period ANOVA). The 2 mg/kg condition did not differ significantly from the 0 mg/kg condition but both the 5 and the 10 mg/kg groups showed significantly reduced exploratory locomotion (p < 0.0001 for both, multiple comparisons with control). The number of
Discussion
The present study found that systemically applied MPEP impaired short- and long-term appetitive spatial conditioning in the cross-maze as well as object discrimination. These findings support the existing evidence that mGlu5 is involved in both spatial and non-spatial learning [41]. However, it was also found in these tasks that MPEP reduced exploration of the stimuli to be remembered and this may have contributed to the impaired retention. However, the fact that prelimbic MPEP-administration
References (49)
Metabotropic glutamate receptors: electrophysiological properties and role in plasticity
Brain Res Rev
(1999)- et al.
Inhibition of mGluR5 blocks hippocampal LTP in vivo and spatial learning in rats
Pharmacol Biochem Behav
(2002) - et al.
Allosteric enhacement of metabotropic glutamate receptor 5 function promotes spatial memory
Neuroscience
(2006) - et al.
Effects of metabotropic glutamate receptor 5 on latent inhibition in conditioned taste aversion
Behav Brain Res
(2005) - et al.
Anxiolytic-like activity of the mGluR5 antagonist MPEP. A comparison with diazepam and buspirone
Pharmacol Biochem Behav
(2002) - et al.
[3H]-Methoxymethyl-MTEP and [3H]-methoxy-PEPy: potent and selective radioligands for the metabotropic glutamate subtype 5 (mGlu5) receptor
Bioorg Med Chem Lett
(2003) - et al.
A new one-trial test for neurobiological studies of memory in rats. 1. Behavioural data
Behav Brain Res
(1988) - et al.
2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist
Neuropharmacology
(1999) - et al.
The role of group I metabotropic glutamate receptors in acquisition and expression of contextual and auditory fear conditioning in rats—a comparison
Neuropharmacology
(2006) - et al.
The mGluR5 antagonist MPEP, but not the mGluR2/3 agonist LY314582, augments PCP effects on prepulse inhibition and locomotor activity
Neuropharmacology
(2002)
Differential effects of mGluR1- and mGluR5 antagonism on spatial learning in rats
Pharmacol Biochem Behav
MGluR5, but not mGluR1, antagonist modifies MK-801-induced locomotor activity and deficit of prepulse inhibition
Neuropharmacology
Multiple MPEP administrations evoke anxiolytic- and antidepressant-like effects in rats
Neuropharmacology
Morphine conditioned reward is inhibited by MPEP, the mGluR5 antagonist
Neuropharmacology
Glutamate receptor function in learning and memory
Behav Brain Res
MPEP, a selective glutamate receptor 5 antagonist, attenuates conditioned taste aversion in rats
Behav Brain Res
The metabotropic glutamate receptor antagonist 2-methyl-6-(phenylethyl)-pyridine (MPEP) blocks fear conditioning in rats
Neuropharmacology
Differential roles of hippocampal metabotropic glutamate receptors 1 and 5 in inhibitory avoidance learning
Neurobiol Learn Mem
Effects of the prototypical mGlu5 receptor antagonist 2-methyl-6(phenylethynyl)-pyridine on rotarod, locomotor activity and rotational responses in unilateral 6-OHDA-lesioned rats
Eur J Pharmacol
Behavioural activity of S-(3,5)-DHPG, a selective agonist of group 1 metabotropic glutamate receptors
Pharmacol Res
[3H]Methoxymethyl-3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine binding to metabotropic glutamate receptor subtype 5 in rodent brain: in vitro and in vivo charaterization
J Pharmacol Exp Therapeutics
The effect of the mGluR5 receptor antagonist MPEP in rodent tests of anxiety and cognition: a comparison
Psychopharmacology
A specific role for group I mGluRs in hippocampal LTP and hippocampus-dependent spatial learning
Learn Mem
Metabotropic glutamate receptor mGlu5 is a mediator of appetitive and energy balance in rats and mice
J Pharmacol Exp Therapeutics
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