NEUROPHARMACOLOGICAL PROFILE OF A NOVEL AND SELECTIVE LIGAND OF THE SIGMA SITE - SR 31742A

The biochemical, electrophysiological and behavioural effects of SR 31 742A, a novel and selective ligand of sigma sites in brain, labelled w ith (+)-[H-3]3PPP (K(i) = 5.3 +/- 0.3 nM), were investigated in rodent s and compared with those of DA antagonists having (haloperidol) or no t (spiroperidol) a high affinity for sigma sites. Like haloperidol but unlike spiroperidol, SR 31742A, (ED50 = 0.065 mg/kg, i.p., and 0.21 m g/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-anaesthe tized 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 a fter repeated injections. The drug SR 31742A reduced (2.5, 5, 10 mg/kg , i.p.) the hyperactivity elicited by various drugs including that pro duced by injection of (+)-amphetamine into the nucleus accumbens and i mpaired avoidance responses at doses (5, 10 mg/kg, i.p.), sparing esca pe behaviour. SR 31742A lacked affinity for DA receptors and neither d id 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 metabolis m of DA but at 10 mg/kg (i.p.) it significantly reduced the amphetamin e-induced rise in levels of 3-MT in the striatum of mice. Together, th ese results indicate a modulatory role for sigma sites upon the activi ty of hippocampal and DA systems and that sigma ligands exert effects, which suggest antipsychotic potential.