The biochemical, electrophysiological and behavioural effects of
SR 31742A, a novel and selective
ligand of sigma sites in brain, labelled with (+)-[3H]3PPP (Ki = 5.3 +/- 0.3 nM), were investigated in rodents and compared with those of DA antagonists having (
haloperidol) or not (
spiroperidol) a high affinity for sigma sites. Like
haloperidol but unlike
spiroperidol,
SR 31742A, (ED50 = 0.065 mg/kg, i.p., and 0.21 mg/kg, p.o.) antagonized sigma-dependent turning behaviour in mice and inhibited (0.5 mg/kg, i.v.) the spontaneous firing of hippocampal (CA3) neurones in
urethane-anaesthetized rats. In
chloral hydrate-anaesthetized rats, like classical
antipsychotic compounds,
SR 31742A (0.625-5 mg/kg, i.p.) increased the number of spontaneously active A9 and
A10 DA cells after single administration and produced an opposite effect after repeated
injections. The
drug SR 31742A reduced (2.5, 5, 10 mg/kg, i.p.) the hyperactivity elicited by various drugs including that produced by injection of (+)-
amphetamine into the nucleus accumbens and impaired avoidance responses at doses (5, 10 mg/kg, i.p.), sparing escape behaviour.
SR 31742A lacked affinity for DA receptors and neither did the compound induce
catalepsy nor antagonize such effects elicited by
apomorphine as climbing,
hypothermia, stereotypy or the inhibition of firing of DA neurones.
SR 31742A did not affect the basal metabolism of DA but
at 10 mg/kg (i.p.) it significantly reduced the
amphetamine-induced rise in levels of 3-MT in the striatum of mice. Together, these results indicate a modulatory role for sigma sites upon the activity of hippocampal and DA systems and that sigma
ligands exert effects, which suggest
antipsychotic potential.