Development of a Rationally Designed, Low Abuse Potential, Biogenic Amine Releaser That Suppresses Cocaine Self-Administration

Abstract

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.

Interaction of Amphetamines and Related Compounds at the Vesicular Monoamine Transporter

“…As reviewed previously, being a serotonin transporter substrate is necessary, but not sufficient, for a drug to produce long-term serotonin depletion (Rothman and Baumann, 2002a). For example, 1-naphthyl-2-aminopropane, mCPP, and TFMPP are serotonin transporter substrates ) that do not deplete brain serotonin Rothman et al, 2005). Thus, in the present study we explored the hypothesis that neurotoxic serotonin transporter substrates (MDMA and fenfluramine) differ from non-neurotoxic serotonin transporter substrates in their VMAT 2 interactions.…”

In Vivo Effects of Amphetamine Analogs Reveal Evidence for Serotonergic Inhibition of Mesolimbic Dopamine Transmission in the Rat

“…Studies dating back to the 1980s (Lyness, 1983) demonstrate that increasing serotonergic tone can decrease stimulant self-administration. In addition, drug treatments that simultaneously elevate extracellular DA and 5-HT are not as readily self-administered as drug treatments that elevate DA alone (Roberts et al, 1999;Rothman et al, 2005;Wee and Woolverton, 2006;Howell et al, 2007). In a representative study, Wee and Woolverton (2006) examined the self-administration of mixtures containing the 5-HT releaser fenfluramine and the DA releaser (ϩ)-amphetamine.…”

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

“…For example, d-amphetamine, a monoamine releaser, has shown positive effects in human cocaine abusers (Grabowski et al, 2004) and in rodent (Chiodo et al, 2008;Chiodo and Roberts, 2009;Thomsen et al, 2013) and monkey (Negus, 2003;Negus and Mello, 2003;Czoty et al, 2010Czoty et al, , 2011 models. Although efforts are ongoing to develop novel DA indirect agonists for this purpose (e.g., Carroll et al, 1999;Platt et al, 2002;Lile and Nader, 2003;Rothman et al, 2005;Howell and Kimmel, 2008), one currently approved drug for use in humans is methylphenidate (MPD), a DA and norepinephrine (NE) transporter inhibitor used to treat attentiondeficit hyperactivity disorder (ADHD) (Holmes, 1995). MPD has pharmacological and behavioral effects that overlap considerably with those of cocaine (e.g., Bergman et al, 1989;Volkow et al, 1999).…”