Monoamine Releasers with Varying Selectivity for Dopamine/Norepinephrine versus Serotonin Release as Candidate “Agonist” Medications for Cocaine Dependence: Studies in Assays of Cocaine Discrimination and Cocaine Self-Administration in Rhesus Monkeys

Abstract

Monoamine releasers constitute one class of drugs under investigation as candidate medications for the treatment of cocaine abuse. Promising preclinical and clinical results have been obtained with amphetamine, which has high selectivity for releasing dopamine/norepinephrine versus serotonin. However, use of amphetamine as a pharmacotherapy is complicated by its high abuse potential. Recent preclinical studies suggest that nonselective monoamine releasers or serotoninselective releasers have lower abuse liability and may warrant evaluation as alternatives to amphetamine. To address this issue, the present study evaluated the effects of five monoamine releasers in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. The releasers varied along a continuum from dopamine/norepinephrine-selective to serotonin-selective [m-fluoroamphetamine (PAL-353), methamphetamine, m-methylamphetamine (PAL-314), 1-napthyl-2-aminopropane (PAL-287), fenfluramine]. In drug discrimination studies, rhesus monkeys were trained to discriminate saline from cocaine (0.4 mg/kg i.m.) in a two-key, foodreinforced drug discrimination procedure. Substitution for cocaine was positively associated with selectivity for dopamine/norepinephrine versus serotonin release. In drug selfadministration studies, rhesus monkeys responded for cocaine (0.01 and 0.032 mg/kg/injection) and food (1-g pellets) under a second-order fixed-ratio 2 (variable-ratio 16:S) schedule. In general, monoamine releasers produced dose-dependent and sustained decreases in cocaine self-administration. However, the dopamine/norepinephrine-selective releasers decreased cocaine self-administration with minimal effects on foodmaintained responding, whereas the more serotonin-selective releasers produced nonselective reductions in both cocaineand food-maintained responding. These results are consistent with the conclusion that dopamine/norepinephrine-selective releasers retain cocaine-like abuse-related effects but may also be capable of producing relatively selective reductions in the reinforcing effects of cocaine.Cocaine abuse and dependence constitute a significant public health problem, and reliable pharmacotherapies are not yet available (Mendelson and Mello, 2004;Vocci et al., 2005). One potential approach to the treatment of cocaine dependence has been suggested by the effective treatment of opioid dependence with opioid agonists such as methadone and of tobacco dependence with formulations of nicotine. These medications share pharmacological mechanisms of action with the abused drug and produce some effects in common with the abused drug, and they have been referred to as "agonist" medications (Rothman and Glowa, 1995). Cocaine blocks the reuptake of dopamine, serotonin, and norepinephrine, and the abuse-related effects of cocaine are thought to be mediated primarily by its dopaminergic effects (

Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys

“…Monoamine-releasing agents had decreased reinforcing effectiveness in rhesus monkeys when serotonin-releasing potency was increased relative to dopamine (Wee et al, 2005). In drug discrimination studies, substitution for cocaine was positively associated with selectivity for dopamine/norepinephrine versus serotonin release in rhesus monkeys (Negus et al, 2007). The behavioral and neurochemical profile of DAT inhibitors is also influenced by actions at multiple monoamine transporters in squirrel monkeys (Ginsburg et al, 2005).…”

Effects of Chronic Methylphenidate on Cocaine Self-Administration under a Progressive-Ratio Schedule of Reinforcement in Rhesus Monkeys

“…Chronic treatment with other monoamine transporter inhibitors including mazindol, RTI-112, RTI-113, and indatraline resulted in reductions in both food-and cocaine-maintained responding (Kleven and Woolverton, 1993;Negus et al, 1999Negus et al, , 2009a. On the other hand, amphetamine-like DA/NE releasers have shown more consistent selectivity in their behavioral effects (e.g., Negus et al, 2007Negus et al, , 2009b. Although the mechanisms underlying the behavioral differences between releasers and uptake inhibitors remain to be elucidated, pharmacotherapeutic approaches that reduce the abuse liability of amphetamine-like compounds, such as prodrugs (e.g., phendimetrazine; Rothman et al, 2002;Banks et al, 2012), appear to be a more promising avenue for development of "agonist" medications for cocaine dependence than DA/NE transporter inhibitors.…”

Serotonin 5-HT2Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

“…Studies utilizing such compounds have revealed an important modulatory role for 5-HT on the behavioral effects of cocaine. For example, indirect 5-HT agonists such as SERT inhibitors or 5-HT releasers have been found to attenuate the behavioral-stimulant effects (Spealman, 1993;Howell and Byrd, 1995), reinforcing effects (Kleven and Woolverton, 1993;Glowa et al, 1997;Czoty et al, 2002;Negus et al, 2007), and reinstatement effects (Ruedi-Bettschen et al, 2010;Howell and Negus, 2014) of cocaine in nonhuman primates. Interestingly, some SERT inhibitors (e.g., fluoxetine, citalopram), which evoked saline-responding when administered alone, enhanced the discriminative stimulus effects of cocaine in both monkeys (Spealman, 1993;Schama et al, 1997) and rats (Cunningham and Callahan, 1991;Callahan and Cunningham, 1997).…”