Behavioral consequences of the mGlu5 receptor antagonist MTEP in immature rats

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Abstract

High doses of mGluR5 antagonists have anticonvulsant effects in multiple seizure models in both adult and immature animals. Data on potential behavioral effects in immature animals are very scarce. The present study investigated whether an antagonist of mGluR5 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) in doses proven to be anticonvulsant affects behavior in immature rats. Animals aged 12, 18 and 25 days received MTEP in doses of 20 and 40 mg/kg i.p. The sensorimotor performance was tested at 15 and 60 min after dosing. Locomotor–exploratory behavior was tested at 20 and 65 min after dosing. An elevated plus maze was used to examine an adaptive form of learning and anxiety-like behavior in 18- and 25-day-old rats at 15, 60 min and 24 h. MTEP slightly affected sensorimotor performance, regardless of age. In the open field test, MTEP decreased transiently locomotor–exploratory behavior but did not affect the habituation — a simple form of nonassociative learning. In the elevated plus maze, the drug did not impair transfer latency, an indicator of an adaptive form of learning and memory. An anxiolytic-like effect was observed at 60 min after drug administration. In conclusion, no severe impairment was observed after high anticonvulsant doses of mGlu5 antagonist MTEP in immature animals.

Highlights

► Anticonvulsant doses of MTEP (20 and 40 mg/kg i.p.) in immature rats only slightly affected sensorimotor performance. ► They did not affect habituation potency in repeated exposure to open field. ► They induced an anxiolytic-like effect in elevated plus maze. ► They did not affect an adaptive form of learning and memory in elevated plus maze.

Introduction

Antagonists of mGluR5 are studied as a possible treatment in various diseases such as anxiety, depression, migraine and Parkinson (Gasparini et al., 2008). The predominant expression of mGluR5 in brain areas involved in emotional processes suggested a possible role of these receptors especially in affective disorders (for a review see Bordi and Ugolini, 1999, Gravius et al., 2010). Anxiolytic-like actions of both 2-methyl-6-(phenylethynyl) pyridine (MPEP) and 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) were found in adult (Pietraszek et al., 2005, Varty et al., 2005) as well as in immature rodents (Hodgson et al., 2008, Mikulecká and Mareš, 2009).

Additionally, antagonists of mGluR5 subtype were also shown to have anticonvulsant effects in multiple seizure models in adult rodents (Thomsen and Dalby, 1998, Chapman et al., 1999, Chapman et al., 2000). Clinical research demonstrated that approximately half of epilepsies start in infancy and childhood (Forsgren, 2004). Thus, we focused our attention on drugs acting at metabotropic glutamate receptors as potential anticonvulsants in immature rats. Our effort was substantiated by the fact that nearly one third of epileptic patients (including infants and children) are resistant to present pharmacotherapy, and many antiepileptic drugs exhibit unwanted side effects (Shorvon, 2010). In a previous study we showed that the antagonist of mGluR5, MPEP, suppressed PTZ-induced convulsions and cortical epileptic afterdischarges (Mareš and Mikulecká, 2004, Lojková and Mareš, 2005). The more specific mGluR5 antagonist MTEP (it is three orders more active on mGluR5 than on NMDA receptors — Cosford et al., 2003) exhibits an anticonvulsant action in the same two models of epileptic seizures in immature rats. Anticonvulsant effects decreased with age: doses of 20 and 40 mg/kg were active in 12- and 18-day-old rats, whereas only the 40-mg/kg dose was partly efficient in 25-day-old animals (Mareš, 2009, Lojková-Janečková et al., 2009).

The majority of studies performed in adult rodents assessing both beneficial and unfavorable effects of MTEP used low doses (Pietraszek et al., 2005, Simonyi et al., 2005, Varty et al., 2005); markedly higher doses of both mGlu5 antagonists were required to demonstrate anticonvulsant action in immature rats (Mareš and Mikulecká, 2004, Mareš, 2009). Therefore, the possible harmful side effects of such high doses of the mGluR5 antagonist have to be carefully considered. The present study was designed to determine the effects of an mGluR5 antagonist (MTEP) on different aspects of behavior in immature rats using doses that were shown to have anticonvulsant effects in our models of epileptic seizures. Therefore, we exposed animals to three age-appropriate behavioral paradigms: (a) sensorimotor tests to assess motor abilities (Mikulecká and Mareš, 2002, Mareš, 2009), (b) open field (OF) to assess locomotor–exploratory behavior and habituation potency (Cerbone and Sadile, 1994, Mikulecká and Mareš, 2009), and (c) an elevated plus maze (EPM) to measure an adaptive form of spatial memory and anxiety-like behavior (Itoh et al., 1990, Mikulecká et al., 2000).

Section snippets

Animals

Experiments were performed in three age groups of male Wistar rats: 12, 18, and 25 days old. These age groups were chosen to correspond to early postnatal infants (12 days), preschool children, and early school children (18 and 25 days — Clancy et al., 2007). The animals were housed in a room with controlled temperature (22 ± 1 °C) and humidity (50–60%) and with a 12/12 hour light regime (lights on at 6:00 AM). The animals were brought to the experimental room 1 h before testing. To control for the

Sensorimotor performance

In 12-day-old rats, a trend to a longer latency to surface righting and a significant prolongation of the time in negative geotaxis were found only 60 min after administration of either MTEP dose (H = 9.05, P = 0.011). The time spent holding the bar was not affected by MTEP in this age group.

In 18-day-old rats, the 20 mg/kg dose of MTEP significantly increased the latency to negative geotaxis response (Z = 2.12, P = 0.04) in session 1, whereas the dose of 40 mg/kg increased the latency to negative

Discussion

Given the importance of metabotropic glutamate receptors (mGluRs) in a wide variety of neurophysiological processes, the potential for adverse effects of mGluRs antagonists has to be carefully considered. The majority of studies assessing both the beneficial and unfavorable effects of mGluRs antagonists have been performed in adult animals (for reviews see Pietraszek et al., 2005, Varty et al., 2005). Our study investigated the possible side effects of a specific mGluR5 antagonist (MTEP) on

References (35)

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