Atypical antipsychotic-like effects of the dopamine D-3 receptor agonist, (+)-PD 128,907

Anti-schizophrenia agents with improved efficacy and side-effect profiles are required. A dopamine D-3 receptor agonist, R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol HCl ((+)-PD 128,907), displayed an atypical antipsychotic profile comparable to that of clozapine. (+)-PD 128,907 blocked stereotypy produced by dizocilpine (MK-801) at 12-fold lower doses than those affecting apomorphine-induced stereotypes in mice and did not produce catalepsy. These effects of(+)-PD 128,907 were stereospecific and were blocked by a D-3 antagonist. These data suggest a role for D-3 receptors in antipsychotic drug action. Published by Elsevier Science B.V

GBR12909 ANTAGONIZES THE ABILITY OF COCAINE TO ELEVATE EXTRACELLULAR LEVELS OF DOPAMINE

Rats were administered various IP doses of the high-affinity dopamine (DA) reuptake inhibitor 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[phenylpropyl]piperazine (GBR12909). The caudate nuclei were removed 60 min after drug administration and stored at -70-degrees-C. Striatal membranes were prepared later. The results demonstrated that GBR12909 produced a dose-dependent decrease in the binding of [H-3]cocaine or [H-3]GBR12935 to the DA transporter (ED50 about 10 mg/kg). Saturation binding studies with [H-3]GBR12935 showed that this was due to both an increase in the K(d), due to residual drug, and to a decrease in the B(max). At a dose of 25 mg/kg IP, GBR12909 produced a 50% decrease in the B(max), and a 3.4-fold increase in the K(d). In the in vivo microdialysis studies, GBR12909 (25 mg/kg IP) produced a modest, long-lasting and stable elevation of extracellular DA. Administration of cocaine through the microdialysis probe to rats pretreated with either saline or GBR12909 (25 mg/kg IP) produced a dose-dependent increase in extracellular DA in both groups. GBR12909 inhibited cocaine-induced increases in extracellular DA by about 50% at all doses. These data collectively indicate that at a dose sufficient to decrease by 50% the B(max) of [H-3]GBR12935 binding sites, GBR12909 antagonizes the ability of cocaine to elevate extracellular DA by 50%. Further studies will be needed to evaluate a possible role for GBR12909 in the medical treatment of cocaine addiction