It has been suggested that
sigma receptors may be involved in the etiology of
psychosis and that 5-hydroxytryptamine2 (5-HT2) antagonists may have utility in treating the negative symptoms of
psychosis as well as reducing the side effects associated with the typical
antipsychotic haloperidol. We have evaluated the potential
antipsychotic effects of 1-(cyclopropylmethyl)-4-(2'(4''-fluorophenyl)-2'-oxoethyl)piper i din e HBr (
DuP 734), a selective and potent sigma and 5-HT2 receptor
ligand with weak affinity for D2 receptors, in behavioral animal models that are not necessarily dependent on
dopamine antagonism.
DuP 734 potently blocked
mescaline-induced scratching (ED50 = 0.35 mg/kg, p.o.) and aggressive activity (ED50 = 1.9 mg/kg, p.o.) and was relatively much weaker as an
apomorphine antagonist (ED50 = 12 mg/kg, p.o.). This was in contrast to the typical
antipsychotic agents such as
haloperidol and
chlorpromazine, which were very potent in all three tests. In rats,
DuP 734 did not antagonize avoidance behavior or induce
catalepsy, and, therefore, differed from the potent
dopamine receptor antagonist antipsychotics. It did, however, reduce lever response rates in a random interval 60-sec food reward schedule of reinforcement (ED50 = 6.0 mg/kg, p.o.) in rats. The results suggest that
DuP 734 may have
antipsychotic activity without the liability of motor side effects typical of
neuroleptics. Although
DuP 734 itself did not antagonize avoidance activity, it significantly enhanced the potency of
haloperidol in blocking avoidance behavior by 3-fold (by shifting the ED50 from 0.94 to 0.36 mg/kg, p.o.), whereas the ED50 of
haloperidol for blockade of escape behavior and induction of
catalepsy was not affected.(ABSTRACT TRUNCATED AT 250 WORDS)