Metabotropic glutamate mGlu1 receptor stimulation and blockade: therapeutic opportunities in psychiatric illness

Abstract

Metabotropic glutamate mGlu(1) receptors play a modulatory role in the nervous system. They enhance cell excitability, modulate synaptic neurotransmission and are involved in synaptic plasticity. During the last 10 years, several selective metabotropic glutamate mGlu(1) receptor competitive antagonists and potentiators have been discovered. These pharmacological tools, together with early and later work in metabotropic glutamate mGlu(1) receptor mutant mice have allowed studying the role of the receptor in various aspects of psychiatric illnesses such as anxiety, depression and schizophrenia. We here review the data on selective metabotropic glutamate mGlu(1) receptor antagonists in support of their potential as anxiolytic and antidepressant treatments. We propose a rationale for the development of metabotropic glutamate mGlu(1) receptor positive allosteric modulators for the treatment of schizophrenia. Potential side effects of blockade and activation of metabotropic glutamate mGlu(1) receptors are addressed, with special focus on the differential effects of metabotropic glutamate mGlu(1) receptor antagonists in cognition models with positive reinforcement versus those that use aversive learning procedures. Further development of negative allosteric modulators and more drug-like positive allosteric modulators will be required in order to decipher the therapeutic efficacy and safety margin of these compounds in the clinic.