Relationship between the Serotonergic Activity and Reinforcing Effects of a Series of Amphetamine Analogs

Abstract

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.

Estimating the relative reinforcing strength of (±)-3,4-methylenedioxymethamphetamine (MDMA) and its isomers in rhesus monkeys: comparison to (+)-methamphetamine

“…Among amphetamine-like drugs that are not as selective for 5-HT releasing activity, Ritz and Kuhar (1989) reported a negative correlation between potency as a reinforcer and binding affinity at the 5-HT transporter (SERT). We have recently reported self-administration results with a series of amphetamine analogs in monkeys that reached similar conclusions (Wee et al 2005).…”

A Reduced Rate of In Vivo Dopamine Transporter Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants

“…Serotonergic activity of stimulants has been proposed to influence relative reinforcing efficacy of compounds with mixed monoamine actions (Roberts et al, 1999;Wee et al, 2005). It, however, seems unlikely that differences in the serotonergic activity of the drugs in the present study contributed to the differences in relative reinforcing efficacy observed under the PR schedule.…”

Serotonin is involved in the psychostimulant and hypothermic effect of 4-methylamphetamine in rats

“…This compound is equipotent as a releaser of dopamine, norepinephrine and 5-HT [4], It also shows low affinity for 5-HT 2 receptors [15]. However, with respect to 5-HT release, 4-MA was significantly more potent compared to amphetamine [4].…”

“…Green et al studied the effect of MDMA on body temperature and found that its administration to rats produces hyperthermia if animals are housed in normal or warm ambient room temperature conditions ( 20°C), but hypothermia when in cool conditions ( 17°C) [19]. Perhaps the difference between both drugs is that the potency and selectivity of 4-MA as serotonin releaser is higher than other amphetamine derivatives [4]. A slight tachyphylaxis to this effect was found because after a repeated administration schedule, the maximum of hypothermia after the fourth administration significantly differed from the first one.…”

“…There are very few published studies on the pharmacology of 4-MA in laboratory animals [4,5]. It has been speculated that, compared to amphetamine, the most pronounced serotonergic action of 4-MA could diminish the psychoactive effects of amphetamine leading to the consumption of repeated and higher doses of contaminated amphetamine [2].…”