In Vitro and in Vivo Evidence for a Lack of Interaction with Dopamine D2 Receptors by the Metabotropic Glutamate 2/3 Receptor Agonists 1S,2S,5R,6S-2-Aminobicyclo[3.1.0]hexane-2,6-bicaroxylate Monohydrate (LY354740) and (−)-2-Oxa-4-aminobicyclo[3.1.0] Hexane-4,6-dicarboxylic Acid (LY379268)

Some recently published in vitro studies with two metabotropic glutamate 2/3 receptor (mGluR 2/3 ) agonists [(−)-2-oxa-4-aminobicyclo[3.1.0] hexane-4,6-dicarboxylic acid (LY379268) and 1 S ,2 S ,5 R ,6 S -2-aminobicyclo[3.1.0]hexane-2,6-bicaroxylate monohydrate (LY354740)] suggest that these compounds may also directly interact with dopamine (DA) D 2 receptors. The current in vitro and in vivo studies were undertaken to further explore this potential interaction with D 2 receptors. LY379268 and LY354740 failed to inhibit D 2 binding in both native striatal tissue homogenates and cloned receptors at concentrations up to 10 μM. LY379268 and LY354740 (up to 10 μM) also failed to stimulate [ 35 S]GTPγS binding in D 2L - and D 2S -expressing clones in the presence of NaCl or N -methyl-d-glucamine. In an in vivo striatal D 2 receptor occupancy assay, LY379268 (3–30 mg/kg) or LY354740 (1–10 mg/kg) failed to displace raclopride (3 μg/kg i.v.), whereas aripiprazole (10–60 mg/kg) showed up to 90% striatal D 2 receptor occupancy. LY379268 (10 mg/kg) and raclopride (3 mg/kg) blocked d -amphetamine and phencyclidine (PCP)-induced hyperactivity in wild-type mice. However, the effects of LY379268 were lost in mGlu 2/3 receptor knockout mice. In DA D 2 receptor-deficient mice, LY379268 but not raclopride blocked both PCP and d -amphetamine-evoked hyperactivity. In the striatum and nucleus accumbens, LY379268 (3 and 10 mg/kg) was without effect on the DA synthesis rate in reserpinized rats and also failed to prevent S -(−)-3-(3-hydroxyphenyl)- N -propylpiperidine-induced reductions in DA synthesis rate. Taken together, the current data fail to show evidence of direct DA D 2 receptor interactions of LY379268 and LY354740 in vitro or in vivo. Instead, these results provide further evidence for a novel antipsychotic mechanism of action for mGluR 2/3 agonists.