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