[Modulation of neuronal activities in the central nervous system via sigma receptors]

Sigma receptors have recently been the target of drug development related to psychiatric disorders, including schizophrenia and depression, as well as cognitive enhancers. This paper focused on the sigma-receptor-mediated modulation of neuronal activity, especially the effects on aminergic neuron and hippocampal neuron activity. Dopaminergic neuron activities in the substantia nigra and ventral tegmental area (VTA) are variously modified by the systemic administration of sigma ligands. When applied with microiontophoresis, they are reported to increase dopaminergic neuron activity in the VTA. This activity may be involved in the psychotropic or antipsychotic effects of these ligands. Moreover, serotonergic neurons in the raphe nucleus and noradrenergic neurons in the locus coeruleus were activated by sigma ligands. These effects are probably related to the antidepressant activity of sigma receptor ligands. In the hippocampus, sigma ligands suppressed CA1 neuronal activity in vitro. The effects were suggested to be due to an increase in the threshold of action potential and decreased synaptic transmission efficacy. NMDA receptor function was modified in biphasic fashion related to doses of sigma ligands, that is, a lower dose facilitated the NMDA receptor functions, and a higher dose inhibited them. These effects on the hippocampal neurons may contribute to their neuroprotective and antiamnesic actions. Further studies are needed to elucidate the relation between the physiological function of sigma receptor and psychiatric diseases by the use of sigma receptor ligands and molecular techniques.