The effects of the high-affinity dopamine reuptake inhibitor, GBR 12909, were studied on responding maintained under multiple fixed ratio schedules of food and cocaine delivery in rhesus monkeys (Macaca mulatta).
GBR 12909 decreased rates of responding maintained by both events in a dose-related manner, however large decreases in cocaine-maintained responding could be obtained with doses of GBR 12909 that had little effect on food-maintained responding. This behaviorally selective effect of GBR 12909 on cocaine-maintained responding was inversely related to the unit dose of cocaine. When responding was maintained by low doses of cocaine, GBR 12909 (1 mg/kg) decreased cocaine-maintained responding almost completely. When responding was maintained by the highest dose, the same dose of GBR 12909 had little effect on responding. To the extent that higher doses of cocaine may be expected to be more reinforcing, the current results suggest that the effect of GBR 12909 on cocaine-maintained responding was determined by the reinforcing efficacy of the unit dose of cocaine.
A previous study (J.R. Glowa, F.H.E. showed that acute doses of GBR 12909 selectively decreased cocaine-maintained responding without affecting foodmaintained responding. This report extended these observations to some related drugs and to the effects of repeated administration. When responding was maintained under a multiple fixed ratio (FR) 30 food, FR 30 cocaine schedule, acute doses of GBR 12935, CFT, and d-amphetamine decreased cocaine-maintained responding more than food-maintained responding. However, in contrast to GBR 12909, none of these drugs completely decreased cocaine-maintained responding without affecting food-maintained responding. Repeated administration of GBR 12909 sustained, and of GBR 12935 improved, these selective decreases in cocaine-maintained responding. The selective effect of these dopamine reuptake inhibitors on cocaine-maintained responding is consistent with their known pharmacological selectivity for the dopamine reuptake site and can be well-maintained with repeated administration.Glowa, found that the high-affinity dopamine (DA) reuptake inhibitor, GBR 12909, could decrease responding maintained by cocaine at doses that did not have effects on comparable rates of food-maintained responding. Similar results have been reported for other drugs. For example, Mello, Mendelson, Bree, & Lucas (1989) reported that the opioid buprenorphine suppressed cocaine self-administration in rhesus monkeys at doses that had little effect on food-maintained responding. These types of effects are of interest because few studies have reported comparable differences in the effects of other drugs on food-and drugmaintained responding. To the extent that it would be desirable for a treatment drug to selectively decrease cocaineseeking behavior, this type of effect may be useful in identifying therapeutic agents comparable to those used for heroin (e.g., methadone) or nicotine (e.g., nicotine patches) abuse. In
The design, synthesis, and biological evaluation of compounds related to the dopamine (DA) uptake inhibitors: 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (1) and 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (2) (GBR 12395 and GBR 12909, respectively), directed toward the development and identification of new ligands interacting with high potency and selectivity at the dopamine transporter (DAT) is reported. The substitution of the piperazine ring in the GBR structure with other diamine moieties resulted in the retention of the high affinity of new ligands for the DAT. Some of the modified GBR analogs (e.g. 8, 10, (-)-49, or (-)-50) displayed substantially higher selectivity (4736- to 693-fold) for the dopamine (DA) versus the serotonin (5HT) reuptake site than the parent compounds. The bis(p-fluoro) substitution in the (diphenylmethoxy)ethyl fragment slightly increased the affinity of the ligands at the DA reuptake site but reduced their selectivity at this site (e.g. 9 and 8, 11 and 10, or 17 and 16, respectively). Congeners, such as the series of monosubstituted and symmetrically disubstituted piperazines and trans-2,5-dimethylpiperazines, which lack the (diphenylmethoxy)ethyl substituent lost the affinity for the DAT yet exhibited very high potency for binding to the sigma receptors (e.g.28). The chiral pyrrolidine derivatives of 1, (-)-49, and (+)-49, exhibited an enantioselectivity ratio of 181 and 146 for the inhibition of DA reuptake and binding to the DAT, respectively.
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