Blockade of mGLUR5 receptors differentially alters amphetamine-induced enhancement of locomotor activity and of brain stimulation reward

Abstract

This study was aimed at determining the role of mGLUR5 glutamate receptors on amphetamine-induced enhancement of locomotion and of brain stimulation reward (BSR). The effect of different doses of the mGLUR5 antagonist, MPEP (0, 1, 3 and 9 mg/kg, i.p.), was assessed on reward induced by electrical stimulation of the lateral hypothalamus, and on the enhancement of reward by amphetamine (1 mg/kg, i.p.) in adult male Long Evans rats. The effect of a single dose of MPEP (0 and 9 mg/kg) on amphetamine-induced increase in locomotor activity was also assessed. Systemic injection of MPEP alone did not alter reward threshold and maximum rate of responding. Amphetamine produced a 25-30% decrease in reward threshold, an effect not altered by the highest dose of MPEP. At this dose, MPEP produced a weak inhibition of spontaneous locomotion and a significant attenuation of the enhanced locomotor activity induced by amphetamine. These findings show that mGLUR5 glutamate receptors are unlikely to constitute important elements of the reward-relevant pathway, and do not intervene in the enhancement effect of amphetamine. They also show, however, that these glutamate receptors play a key role in amphetamine-induced increased locomotor activity, providing additional evidence for a dissociation between the substrates that mediate these two behaviours.

RGS4 overexpression in the rat dorsal striatum modulates mGluR5- and amphetamine-mediated behavior and signaling

“…As such, systemic administration of mGluR5 antagonists inhibited Amph-induced hyperactivity (Gormley and Rompre 2011; McGeehan et al 2004; Pietraszek et al 2004) and expression of Amph-induced conditioned place preference (Herzig et al 2005). However, some studies provided contradictory evidence regarding the role of mGluR5 in regulating rewarding and locomotor-stimulating effects of psychostimulants (Gormley and Rompre 2011; McGeehan and Olive 2003; Veeneman et al 2011). Discrepancies could stem from the fact that whereas different drugs exert region-specific effects on the brain, a population of mGluR1/5 receptors in the whole brain was typically blocked in these studies.…”

The effects of mGluR2/3 activation on acute and repeated amphetamine-induced locomotor activity in differentially reared male rats.

“…While mGluR 2/3 is localized presynaptically and perisynaptically, reducing transmission at glutamatergic synapses (Anwyl, 1999; Cartmell & Schoepp, 2000; Gass & Olive, 2008), it appears that mGluR 5 is primarily localized postsynaptically (Romano et al, 1995; Rodrigues et al, 2005; Gormley & Rompre, 2010). Both mGluR 2/3 and mGluR 5 are involved in the development of sensitivity to psychostimulants (McGeehan & Olive, 2003; Rahman & Bardo, 2008; Schwendt & McGinty, 2007).…”

“…Both mGluR 2/3 and mGluR 5 are involved in the development of sensitivity to psychostimulants (McGeehan & Olive, 2003; Rahman & Bardo, 2008; Schwendt & McGinty, 2007). Group I mGluR 5 s play a key role in amphetamine-induced increases in locomotor activity (Gormley & Rompre, 2010; Veeneman et al, 2011). Both the stimulant function of amphetamine and the reinforcing effects of amphetamine are reduced by the mGluR 5 antagonist MTEP (Kumaresan et al, 2009; Martin-Fardon et al, 2009).…”

Differential modulation of thresholds for intracranial self-stimulation by mGlu5 positive and negative allosteric modulators: implications for effects on drug self-administration

“…These latter observations are in agreement with previous studies showing that acute administration of the less selective mGlu5 NAM MPEP (3 and 9 mg/kg) also elevates ICSS thresholds (Harrison et al, 2002; Kenny et al, 2003, 2005). However, a more recent study found that these doses of MPEP did not alter brain stimulation reward (Gormley and Rompre, 2011). These discrepant results are likely due to differences in the ICSS procedures employed.…”

“…In the present study and others (Harrison et al, 2002; Kenny et al, 2003, 2005), a current–intensity threshold determination procedure was used, which varies the intensity of the stimulation current delivered to the electrode while keeping the stimulation frequency constant. On the other hand, Gormley and Rompre (2011) utilized a rate–frequency analysis procedure which varies the frequency of the stimulation current delivered to the electrode while keeping the current–intensity constant. It is therefore of interest to conduct future studies to determine if MTEP or fenobam produce any effects on brain stimulation reward using this rate–frequency approach.…”