Long-acting blockade of biogenic amine transporters in rat brain by administration of the potent novel tropane 2beta-propanoyl-3beta-(2-Naphthyl)-tropane.
2beta-Propanoyl-3beta-(2-naphthyl)-tropane (WF-23) is a potent cocaine analog with activity at dopamine and serotonin transporters. The purpose of these experiments was to characterize the time course of effects of acute administration of WF-23 on spontaneous locomotion and biogenic amine transporters. Rats received injections i.p. with WF-23 (1 mg/kg), cocaine (30 mg/kg) or vehicle and locomotor activity was measured at various times postinjection. Animals were killed immediately after behavioral activity. Locomotor activity was significantly increased by WF-23 administration, reaching maximum at 4 hr and persisting for 24 hr. Cocaine-elicited elevations in locomotor activity occurred only at the earliest times. WF-23 decreased DA transporter binding in striatal membranes ([125I]RTI-55 binding), with >50% loss in binding for up to 49 hr postinjection. WF-23 increased the Kd of the high affinity site, with no effect on Bmax. Cocaine depressed binding (20%) only at the earliest times. WF-23 decreased levels of [3H]WIN 35,428 binding sites up to 95% of control in both dorsal and ventral striatum with a similar time-course when assessed autoradiographically. WF-23 also reduced [3H]citalopram binding to serotonin transporter sites throughout the brain. The slow onset and very long duration of action of WF-23, taken together with its actions at dopamine and serotonin transporters, suggest a potential role for treatment of disorders characterized by their involvement of these neural systems.
Daunais
J B
JB
Department of Physiology/Pharmacology, Center for the Neurobiological Investigation of Drug Abuse, Wake Forest University School of Medicine Winston-Salem, North Carolina, USA.
Hart
S L
SL
Smith
H R
HR
Letchworth
S R
SR
Davies
H M
HM
Sexton
T
T
Bennett
B A
BA
Childers
S R
SR
Porrino
L J
LJ
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001679:Biogenic Amines / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D015283:Citalopram / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism; D014326:Tropanes / Q000494:pharmacology*
D001679:Biogenic Amines; D015283:Citalopram; D003042:Cocaine; D004298:Dopamine; D017367:Selective Serotonin Reuptake Inhibitors; D014326:Tropanes; C112780:2-propanoyl-3-(2-naphthyl)-tropane; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane