Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys

Abstract

d-Amphetamine selectively promotes release of both dopamine (DA) and norepinephrine (NE) versus serotonin (5HT), and chronic d-amphetamine treatment decreases cocaine-taking behavior in rats, nonhuman primates, and humans. However, abuse liability limits the clinical utility of amphetamine maintenance for treating cocaine abuse. One strategy to improve safety and efficacy of monoamine releasers as candidate anticocaine medications has been to develop dual DA/5HT releasers like 1-napthyl-2-aminopropane (PAL-287), but the pharmacology of this class of compounds has not been extensively examined. In particular, PAL-287 has similar potencies to release DA, 5HT, and NE, and the role of manipulating NE release potency on abuse-related or anticocaine effects of dual DA/5HT releasers is not known. To address this issue, the present study compared effects of four novel DA/5HT releasers that varied >800-fold in their selectivities to release DA/5HT versus NE: [1-(5-chloro-1H-indol-3-yl)propan-2-amine (PAL-542), 1-(5-fluoro-1H-indol-3-yl)propan-2-amine (PAL-544), 1-(1H-indol-5-yl)propan-2-amine (PAL-571), and (R)-1-(1H-indol-1-yl)propain-2-amine (PAL-569). Abuse-related effects of all four compounds were evaluated in assays of intracranial self-stimulation (ICSS) in rats and cocaine discrimination in rats and monkeys, and none of the compounds reliably facilitated ICSS or substituted for cocaine. Anticocaine effects of the compound with highest selectivity to release DA/5HT versus NE (PAL-542) were tested in an assay of cocaine versus food choice in rhesus monkeys, and PAL-542 failed to reduce cocaine choice. These results suggests that potency to release NE has minimal influence on abuse liability of dual DA/5HT releasers, and reducing relative potency to release NE versus DA/5HT does not improve anticocaine efficacy.

Figure 1

Structures of the monoamine releasers tested in this study. Potencies of these compounds to release DA, NE, and 5HT in vitro are reported in Table 1.

Figure 2

Summary effects of PAL-542, PAL-544, PAL-571, and PAL-569 on intracranial self-stimulation in rats. Group mean data are expressed as percent pre-drug baseline number of stimulations delivered across all frequencies of brain stimulation. Panel A shows potencies and efficacious of test compounds. Panel B shows time course effects for test compounds. All symbols represent mean ± s.e.m. of 5 rats. Filled symbols represent doses (A) or time (B) after test compound administration at which percent baseline stimulations were statistically (p< 0.05) different from vehicle (A) or baseline (B).

Figure 3

Cocaine-like discriminative stimulus effects of d-amphetamine, PAL-287, fenfluramine, PAL-542, PAL-544, PAL-571, and PAL-569 in a two-key food-reinforced assay of cocaine vs. saline discrimination procedure in rats (A) and rhesus monkeys (B). Abscissae: Drug dose (milligrams per kilogram, log scale). Ordinates: cumulative percentage of rats or monkeys in which complete substitution for cocaine was observed (ε90% cocaine-appropriate responding) at some dose or time. All compounds were tested in 5-6 rats and 5 rhesus monkeys.

Figure 4

Effects of continuous 7-day treatment with PAL-542 (0.032 – 0.1 mg/kg/h) on choice between cocaine and food in rhesus monkeys (N=5). Top Ordinates: percent cocaine choice (left) or the number of choices completed per component (right) during treatment with saline or increasing doses of PAL-542. Top Abscissae: unit dose of cocaine in milligrams per kilogram per injection (log scale). Bottom panels show total choices, food choices, cocaine choices and cocaine intake during choice sessions before or during 7-day treatment with PAL-542. Bottom Left Ordinate: Number of choices per session. Bottom Right Ordinate: cocaine intake in milligrams per kilogram per day during choice sessions. Bottom Abscissae: experimental endpoint. All points and bars represent group mean data ± s.e.m. obtained during days 5-7 of each 7-day treatment period. Saline points and bars represent the mean ± s.e.m. of mean data obtained during the 3 days preceding PAL-542 treatment when saline was infused through the “treatment” lumen of the double lumen catheter. Filled symbols and asterisks indicate statistical significant (p<0.05) compared to “+ saline” conditions.