Sigma receptors were defined originally in terms of opiate responses and later became associated with the phencyclidine (PCP) receptor. PCP's psychotomimetic effects suggested a possible role of sigma receptors in psychiatric processes. Drugs originally classified as sigma opioids are neither effectively analgesic nor substantially addictive. At appropriate doses, however, they can cause psychotomimetic effects such as delusions, hallucination, depersonalization and dysphoria which are not blocked by the mu/kappa opiate antagonist naloxone. Binding profiles of prototypical sigma drugs such as n-allylnormetazocine have shown that there is a population of high affinity binding sites which is distinct from the PCP binding sites. This high affinity site is now referred to as the sigma receptor. Although many selective sigma ligands have been developed, agonist/antagonist interactions for these ligands have not been delineated and a physiological role for this receptor has yet to be elucidated. The proposed studies are designed to test the hypothesis that high-affinity sigma ligands such as d-pentazocine influence the physiology of hippocampal neurons. Preliminary studies indicate that bath application of relatively low concentrations of d-pentazocine (PENT) enhanced evoked field potentials in area CA1 of the rat hippocampal slice. The effect of PENT was not influenced by naloxone or the NMDA antagonist amino-phosphovaleric acid (APV) added to the bath. Enhanced field potentials were not observed when PENT was applied in the presence of the antipsychotic drug haloperidol. The proposed studies are aimed at extending these studies to other agents with demonstrated affinity for the sigma site. Planned experiments will also determine the selectivity of the effects observed by including known antagonists of other receptor sites. Possible mechanisms underlying the increased amplitude of evoked field potentials seen in the presence of PENT include increased synchrony of firing, increased number of cells firing, or an increased amount of repetitive firing due to depression of inhibitory synaptic input. A selected set of these possible mechanisms will be tested by means of intracellular recordings from CA1 neurons.
