Schizophrenia is a debilitating chronic
psychiatric illness affecting 1% of the population. The cardinal features of
schizophrenia are positive symptoms (thought disorder,
hallucinations, catatonic behavior), negative symptoms (social withdrawal,
anhedonia, apathy) and
cognitive impairment. Although progress in elucidating the aetiology of
schizophrenia has been slow, new insights on the neurochemical and neurophysiological mechanisms underlying the pathophysiology of this illness are beginning to emerge. The
glutamate/
N-methyl-D-aspartate (
NMDA) hypofunction hypothesis of
schizophrenia is supported by observations that administration of
NMDA glutamate receptor antagonists such as
phencyclidine (PCP) or
ketamine induces
psychosis in humans; moreover, decreased levels of
glutamate and changes in several markers of glutamatergic function occur in schizophrenic brain. Administration of PCP or
ketamine to rodents elicits an increase in locomotion and stereotypy accompanied by an increase in
glutamate efflux in several brain regions. Systemic administration of group II metabotropic
glutamate (mGlu) receptor agonists suppresses PCP-induced behavioral effects and the increase in
glutamate efflux. Activation of group II mGlu receptors (mGlu2 and mGlu3) decreases
glutamate release from presynaptic nerve terminals, suggesting that group II mGlu receptor agonists may be beneficial in the treatment of
schizophrenia. In addition, pharmacological manipulations that enhance
NMDA function may be efficacious
antipsychotics. Selective activation of mGlu5 receptors significantly potentiates
NMDA-induced responses, supporting this novel approach for the treatment of
schizophrenia. The
glutamate hypothesis of
schizophrenia predicts that agents that restore the balance in glutamatergic neurotransmission will ameliorate the symptomatology associated with this illness. Development of potent, efficacious, systemically active drugs will help to address the
antipsychotic potential of these novel
therapeutics. This review will discuss recent progress in elucidating the pharmacology and function of group II mGlu and mGlu5 receptors in the context of current hypotheses on the pathophysiology of
schizophrenia and the need for new and better
antipsychotics.