Preliminary Evidence that CBR12909 is Less Effective at Elevating Mesolimbic Dopamine Function than Cocaine
R.B. Rothman, A. Kim, N. Greig, B.R. de Costa, K.C. Rice, F.I. Carroll and A. Pert
Administration of dopamine (DA) uptake inhibitors to rats stimulates locomotor activity via elevation of mesolimbic DA levels. In the present study, rats received i.p. injections of doses of cocaine (COC, 20 mg/kg), GBR12909 (GBR, 20 mg/kg), nomifensine (NOM, 5 mg/kg), WIN-065-2 (WIN, 1 mg/kg) or saline (SAL) which preliminary studies indicated produce the same level of locomotor stimulation and stereotopy. These parameters were measured for 30 min. At the end of the 30 min test period, the subjects were sacrificed, and the brains removed and kept frozen at -70° C. The brains were homogenized in 10 ml/gm wet weight ice-cold 10 mM TRIS-HCI, pH 7.0. The homogenates were then centrifuged at 30,000 xg for 20 min, and the supernatants kept frozen at -70° C. The next day, aliquots of the supernatants were serially diluted, and assayed for inhibition of [3H]DA reuptake by a striatal synaptosomal preparation. Only supernatant prepared from GBR-injected rats strongly inhibited [3H]DA reuptake (IC50 about 100 μ1). The rank-order of potency was GBR>>NOM>WIN=COC. The brain level of GBR was calculated to be about 1 μM. Control studies determined that brain supernatant did not metabolize these agents. In vivo binding studies using [3H]BTCP to measure occupancy of the DA transporter resulted in the following rank-order of occupancy: GBR>>NOM>WIN=COC. Since COC produces the same level of response as does GBR, but at lower receptor occupancy, these data support the hypothesis that GBR is less efficacious than is COC at increasing mesolimbic DA function, and are consistent with our previous finding that GBR attenuates the ability of COC to elevate extracellular levels of DA (Rothman et al, 1989).
AFFILIATION:
1LCP, NIDA Addiction Research Center, Baltimore, MD 21224.
2LMC, NIDDK, Bethesda, MD 20892.
3LN, NIA, Bethesda, MD 20892.
4RTI, Research Triangle Park, NC 27709.
5BPB, NIMH, Bethesda, MD 20892.
