Modulation of NMDA and dopaminergic neurotransmissions by sigma ligands: possible implications for the treatment of psychiatric disorders

Abstract

Sigma (sigma) receptors, improperly classified as belonging to the opiate receptor family when discovered in 1976, were subsequently confused with phencyclidine binding sites for several years. It's only recently, with the emergence of new selective ligands that their functional significance could be meaningfully addressed. Several subtypes of sigma receptors are present in high densities in the limbic structures as well as in motor-related areas of the CNS. Different lines of evidence suggest that a major role for sigma receptors might be to regulate the activity of the glutamatergic system via the modulation one of its subtype of receptor, the NMDA receptor. This modulation of the glutamatergic system could in turn interfere with the dopaminergic neurotransmission with which, however, sigma ligands could also interact directly. The potential involvement of sigma receptors in schizophrenia has been considered ever since their discovery. The initial suggestion to this respect emerged from the observation that several of the earliest sigma ligands induced psychotomimetic symptoms such as delusions, hallucinations and depersonalization. This link was later reinforced with the demonstration that several neuroleptics, such as haloperidol, have a high affinity for sigma receptors, whereas, some new molecules with a high affinity for sigma receptors, but a low affinity for dopaminergic receptors demonstrated a "neuroleptic-like" pharmacological profile. However, the therapeutic efficacy of selective sigma ligands in schizophrenia has not yet been established and it has even been suggested that sigma receptors might be responsible for some side effects of the classical neuroleptics. The possible implication of sigma receptors in affective disorders has also been suggested by reports showing that some antidepressant drugs have a high affinity for sigma receptors and that long-term treatments with anti- depressant drugs, even with those devoid of affinity for sigma receptors, modify their binding characteristics. In conclusion, indirect evidence suggests possible etiological and/or therapeutic roles for sigma receptors in some psychiatric disorders. However, despite several attempts, no clear indications of a therapeutic efficacy of sigma ligands has yet emerged. More selective ligands and fundamental studies on the respective role of the different subtypes of sigma receptors are needed before clear concepts can be formulated. p3