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

Abstract

Pharmacological manipulation of the type 5 metabotropic glutamate (mGlu5) receptor alters various addiction related behaviors such as drug self-administration and the extinction and reinstatement of drug-seeking behavior. However, the effects of pharmacological modulation of mGlu5 receptors on brain reward function have not been widely investigated. We examined the effects of acute administration of positive and negative allosteric modulators (PAMs and NAMs, respectively) on brain reward function by assessing thresholds for intracranial self-stimulation (ICSS). In addition, when acute effects were observed, we examined changes in ICSS thresholds following repeated administration. Male Sprague-Dawley rats were implanted with bipolar electrodes into the medial forebrain bundle and trained to respond for ICSS, followed by assessment of effects of mGlu5 ligands on ICSS thresholds using a discrete trials current–intensity threshold determination procedure. Acute administration of the selective mGlu5 NAMs MTEP (0, 0.3, 1, or 3 mg/kg) and fenobam (0, 3, 10, or 30 mg/kg) dose-dependently increased ICSS thresholds (∼70% at the highest dose tested), suggesting a deficit in brain reward function. Acute administration of the mGlu5 PAMs CDPPB (0, 10, 30, and 60 mg/kg) or ADX47273 (0, 10, 30, and 60 mg/kg) was without effect at any dose tested. When administered once daily for five consecutive days, the development of tolerance to the ability of threshold-elevating doses of MTEP and fenobam to increase ICSS thresholds was observed. We conclude that mGlu5 PAMs and NAMs differentially affect brain reward function, and that tolerance to the ability of mGlu5 NAMs to reduce brain reward function develops with repeated administration. These brain reward deficits should be taken into consideration when interpreting acute effects of mGlu5 NAMs on drug self-administration, and repeated administration of these ligands may be an effective method to reduce these deficits.

Fenobam sulfate inhibits cocaine-taking and cocaine-seeking behavior in rats: implications for addiction treatment in humans

“…The neural mechanisms underlying the antagonism of cocaine reward by mGluR5 NAMs are not fully understood. Several studies suggest that blockade of mGluR5 decreases brain reward functioning as measured by electrical intracranial self-stimulation (Cleva et al 2012; Kenny et al 2005), suggesting that a diminished rewarding response to cocaine may underlie the antagonism of cocaine self-administration after mGluR5 blockade.…”

“…Fenobam was granted orphan drug status by the FDA in 2006 and has been recently investigated as an experimental clinical treatment for Fragile X Syndrome (Berry-Kravis et al 2009) and L-DOPA-induced dyskinesias (Rylander et al 2010). Fenobam was recently reported to inhibit brain-stimulation reward (Cleva et al 2012) and attenuate methamphetamine-seeking behavior in rats (Watterson et al 2013). Considering these results, as well as the success of buprenorphine as an orphan drug approved for treating morphine dependence (Jaffe and O’Keeffe 2003), and fenobam’s superior mGluR5 selectivity compared to MPEP (Montana et al 2009), fenobam is an intriguing clinical candidate for the treatment of psychostimulant dependence.…”

Attenuation of reinstatement of methamphetamine-, sucrose-, and food-seeking behavior in rats by fenobam, a metabotropic glutamate receptor 5 negative allosteric modulator

“…Fenobam, along with the prototypic mGluR5 NAMs MPEP and MTEP, have been shown to decrease brain reward functioning as measured by intracranial self-stimulation (ICSS) (Cleva et al 2012; Harrison et al 2002; Kenny et al 2003, 2005). Specifically, doses of MPEP (1–9 mg/kg) which significantly decrease cocaine self-administration, also elevate ICSS thresholds (Harrison et al 2002; Kenny et al 2003, 2005).…”

“…route at doses of 5, 10, or 15 mg/kg in a volume of 1 ml/kg. These doses were chosen based on previous reports that they do not produce significant signs of sedation or anhedonia (Cleva et al 2012; Porter et al 2005). Fenobam (10 mg/kg) was also injected via the i.p.…”

Medication Development for the Treatment of Cocaine Addiction – Progress at Preclinical and Clinical Levels

“…Fenobam was reported to have improved mGluR5 selectivity compared to MPEP, as assessed by the use of mGluR5-KO mice, and rapidly penetrate brain-blood barrier to concentrate in the brain (Montana et al, 2009). Systemic administration of fenobam dose-dependently elevates stimulation threshold for brain-stimulation reward in rats, suggesting a reduction in brain reward function (Cleva et al, 2012). In addition, our pilot experimental data also suggest that oral administration of fenobam significantly inhibits cocaine self-administration and cocaine-or cue-, induced cocaine-seeking behaviour.…”