Schizophrenia: neural mechanisms for novel therapies

Abstract

Although valuable antischizophrenic drugs exist, they only partially ameliorate symptoms and elicit substantial side effects. Classic neuroleptic drugs act by blocking dopamine receptors. They can relieve some symptoms but not behavioral withdrawal features that are designated "negative" symptoms. Clozapine and related newer atypical neuroleptics may be more efficacious in relieving negative symptoms. Understandng their actions may facilitate new drug discovery. Agents influencing glutamate neurotransmission and N-methyl-D-aspartate receptors, especially the cotransmitter D-serine, are promising. Stimulation of the alpha7 subtype of nicotinic acetylcholine receptor may also be efficacious. The search for genes linked to schizophrenia has revealed several leads that may permit development of novel therapeutic agents. Promising genes include disrupted-in-schizophrenia-1, dysbindin, and neuregulin.

Figure 1

Schematic representation of drug actions that normalize aberrant glutamate neurotransmission in the prefrontal cortex of schizophrenics. GABA neurons (pink) are depicted as synapsing upon glutamate neurons (yellow). In schizophrenics (SZ), the GABA inhibitory neurons in the prefrontal cortex may be decreased in number or functionally impaired, fitting with reports of lowered levels of the GABA-synthesizing enzyme, glutamate decarboxylase, in schizophrenic brains (17,18). PCP diminishes glutamate stimulation of the GABA neurons by blocking the NMDA subtype of glutamate receptor (NMDA-R). The GABA inhibitory neurons synapse upon glutamate neurons so that PCP causes enhanced glutamate efflux in the prefrontal cortex. d-serine is a coagonist with glutamate of NMDA-R at the so-called glycine site so that its administration enhances functions of the GABA inhibitory neurons. Agonists of the mGlu2/3 receptors block excess glutamate efflux, which occurs with PCP administration and which has been speculated to take place in schizophrenia.