O-RECEPTOR PSYCHOTOMIMETICS: ACTIONS ON SINGLE NEURONS

In a classical series of experiments, Martin and coworkers described the
responses of the chronic spinal dog to several classes of opiate compounds
(1-2). From these responses he described three types of opiate receptor
designated mu, kappa, and sigma. The sigma receptor was proposed to account
for the response observed with the experimental drug, SKF10047. This
benzomorphan opiate produced an increase in respiratory and heart rate,
mydriasis, and a striking behavioral syndrome suggesting a "canine
delirium". The sigma-binding site has now been shown to be a unique,
non-opioid binding protein present in the central and peripheral nervous
system. Compounds that have high affinity for this site such as
haloperidol, phenothiazines and even SKF10047, have interactions with other
receptors making it difficult to accurately assess the physiologic and
pharmacologic role of the sigma-binding site. Recently several high
affinity ligands have become available that are selective for the
sigma-site. This should make it possible to study the cellular effects of
the interaction between sigma-ligands and the binding site. In the present proposal the action of sigma-ligands on single neurons in
the locus coeruleus and dorsal raphe will be studied using intracellular
recording in brain slices. The action of sigma-ligands on resting
properties, spontaneous activity, membrane currents, synaptic potentials
and ligand activated currents will be studied. Studies of specific
intrinsic and ligand activated membrane currents in isolation will be
carried out with the single electrode voltage clamp. As there has been
little work done with selective sigma-ligands at the cellular level, this
study will lead to an understanding of the cellular actions of this class
of psychotomimetic compounds. Equally important, the results may lead to a
better understanding of the pathogenesis of and new therapies for
schizophrenia.