mGlu5 Signaling: A Target for Addiction Therapeutics?

Abstract

The role of metabotropic glutamate 5 (mGlu5) receptors in substance abuse disorders has been a focus of research for over a decade. In animal models, mGlu5 antagonists not only decrease drug taking but also drug seeking. It follows that mGlu5 antagonists are promising potential pharmacotherapeutic agents for the treatment of substance abuse. More recently, however, evidence has emerged that such compounds may in fact interfere with cognitive behavioral strategies for treatment of such disorders. mGlu5 receptors are linked to N-methyl-D-aspartate (NMDA) receptors via scaffold proteins and consequently are critical for NMDA receptor-dependent neural plasticity, giving them a prominent role in learning and memory. This is important because these processes are critical for rehabilitation treatment during recovery from substance abuse disorders. Therefore, although an antagonist or negative allosteric modulator (NAM) for mGlu5 may serve to decrease the reinforcing value of drugs such as cocaine or methamphetamine, it may also interfere with the process of behavioral change during treatment. Conversely, mGlu5 stimulation may actually serve to enhance this process. This chapter will follow the line of evidence supporting the idea that compounds that enhance mGlu5 receptor function may serve as useful adjuncts to behavioral therapy for substance abuse. We will also discuss the effects of chronic drug use on mGlu5 expression and function. We propose that mGlu5 PAMs in fact show promise as short-term adjuncts to behavioral therapy and could improve the long-term prognosis of such strategies.