It has been reported that among drugs with mixed actions on central nervous system monoamine systems, increased serotonergic activity is associated with decreased potency as a reinforcer. The present experiment was designed to examine this relationship for amphetamine analogs that varied in serotonin releasing potency and to evaluate whether serotonergic actions can affect reinforcing efficacy. Compounds PAL 313 and 314 are para-and meta-methylamphetamine, respectively. PAL 303 and 353 are para-and meta-fluoroamphetamine, respectively. All compounds had similar potencies as in vitro releasers of dopamine (DA) and norepinephrine (NE) but differed in potency for 5-hydroxytryptamine (serotonin) (5-HT) release [EC 50 (nanomolar) PAL 313 ϭ 53.4; PAL 314 ϭ 218; PAL 303 ϭ 939; PAL 353 ϭ 1937]. When made available to rhesus monkeys (Macaca mulatta) (n ϭ 4) for self-administration under a fixed-ratio 25 schedule, all were positive reinforcers with biphasic dose-response functions (0.003-1.0 mg/kg) and were equipotent. PAL 313 was self-administered at a lower rate than the other compounds, which were indistinguishable. Under a progressive-ratio schedule (n ϭ 5), all drugs were positive reinforcers. Dose-response functions increased to a maximum or were biphasic (0.01-1.0 mg/kg), and drugs were equipotent. At maximum, PAL 313 maintained less responding than other PAL drugs, which maintained similar maxima. Thus, all compounds were positive reinforcers under both schedules, consistent with their potent DA actions. Responding was lower when 5-HT potency was higher and comparable with DA and NE potency. The results suggest that the mechanism for this effect involves a decrease in reinforcing potency and efficacy among monoamine releasing agents when 5-HT releasing potency is increased relative to DA.

Rates of delay discounting (impulsive choice) have been shown to vary among individuals, particularly people who abuse drugs relative to those who do not, but factors that may contribute to these differences have not been identified. To explore a role for possible genetic and neurochemical determinants, Lewis (n=8) and Fischer 344 (n=8) rats were allowed to choose between one food pellet delivered immediately and three food pellets delivered after increasing delays. The delays to the large reinforcer (0, 10, 20, 40, 60 s) were increased across five blocks of trials in daily experimental sessions. For both groups of rats, choice for the larger reinforcer decreased as the delay to presentation increased. However, the Lewis rats were more likely to choose the smaller, immediate reinforcer earlier in the session, i.e., at shorter large-reinforcer delays, than the Fisher 344 rats. This difference in choice was statistically significant. Repeated administration of 3.0 mg/kg, i.p. clomipramine (mean of last five sessions) did not significantly alter choice, relative to baseline, for either strain. The present findings suggest that differences in delay discounting/impulsive choice may involve genetic, e.g., neurochemical, differences.

Biological differences may underlie individual differences in impulsive behavior, such as choice for a smaller, more immediate reinforcer over a larger, more delayed reinforcer. Repeated exposure to drugs of abuse may have differing effects on such behavior. To evaluate acute and repeated effects of nicotine on impulsive choice, two strains of rats that have been shown to differ in impulsive choice were tested in a delay-discounting paradigm. Eight Lewis and eight Fischer 344 rats were allowed to choose between one food pellet delivered immediately and three food pellets delivered after a delay. The delay systematically increased in blocks of trials within each session, and the delay value at which choice for the two alternatives was equal (i.e., the indifference point) was interpolated. Effects of nicotine (0.1 – 1.0 mg/kg, s.c.) on percent choice and indifference points were determined during the acute-testing phase and during the re-determination of effects of each dose following at least 30 sessions of repeated 1.0 mg/kg nicotine exposure. Lewis rats had shorter indifference points (i.e., made fewer larger reinforcer choices) than the Fischer 344 rats. Acute nicotine administration increased mean larger-reinforcer choices at the 0.3 mg/kg dose in the Lewis rats and at the 1.0 mg/kg dose in the Fischer 344 rats. After repeated exposure to nicotine, indifference points returned to near baseline (pre-drug) levels for both strains. Strain differences were observed in rates of delay discounting and nicotine may decrease impulsive choice acutely, but this effect does not appear to be long-lasting.

Convergent lines of evidence support a dual deficit model of stimulant withdrawal, where reductions in synaptic dopamine (DA) and 5-hydroxytryptamine (serotonin) (5-HT) contribute to dysphoria, drug craving, and relapse. Thus, we predicted that a nonamphetamine compound with substrate activity at DA and 5-HT transporters (i.e., a dual DA/5-HT releaser) would be an effective medication for treating stimulant addictions. Ideally, this type of medication would alleviate withdrawal symptoms, suppress cocaine self-administration, and lack side effects commonly associated with central nervous system stimulants. In the present work, more than 350 compounds were screened in vitro for activity as substrate-type releasing agents at DA, 5-HT, and norepinephrine transporters. These efforts identified PAL-287 (1-napthyl-2-aminopropane) as a nonamphetamine compound with potent substrate activity at biogenic amine transporters. In vivo microdialysis in rats demonstrated that PAL-287 (1-3 mg/kg i.v.) increased extracellular DA and 5-HT in frontal cortex, but effects on 5-HT were somewhat greater. PAL-287 induced substantially less locomotor stimulation than (ϩ)-amphetamine, a drug that increases only extracellular DA. Administration of high-dose (ϩ)-methamphetamine or (Ϯ)-3,4-methylenedioxymethamphetamine to rats produced long-lasting depletion of cortical 5-HT, whereas PAL-287 (18 mg/kg i.p. ϫ 3) did not. PAL-287 displayed little or no reinforcing properties in rhesus monkeys trained to self-administer cocaine, yet PAL-287 produced a dose-dependent decrease in responding for cocaine when infused at a dose of 1.0 mg/kg/h. Collectively, the findings reported here demonstrate that nonamphetamine monoamine releasing agents such as PAL-287 might be promising candidate medications for the treatment of stimulant dependence.