New Drugs, Old Targets: Tweaking the Dopamine System to Treat Psychostimulant Use Disorders

Abstract

The abuse of illicit psychostimulants such as cocaine and methamphetamine continues to pose significant health and societal challenges. Despite considerable efforts to develop medications to treat psychostimulant use disorders, none have proven effective, leaving an underserved patient population and unanswered questions about what mechanism(s) of action should be targeted for developing pharmacotherapies. As both cocaine and methamphetamine rapidly increase dopamine (DA) levels in mesolimbic brain regions, leading to euphoria that in some can lead to addiction, targets in which this increased dopaminergic tone may be mitigated have been explored. Further, understanding and targeting mechanisms underlying relapse are fundamental to the success of discovering medications that reduce the reinforcing effects of the drug of abuse, decrease the negative reinforcement or withdrawal/negative affect that occurs during abstinence, or both. Atypical inhibitors of the DA transporter and partial agonists/antagonists at DA D3 receptors are described as two promising targets for future drug development.

Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap?

“…In recent years, this important limitation of MOD efficacy has stimulated the development of new structural analogs of MOD to extend therapeutic actions to a broader population and, thus, maximize the effects of the parent drug for use in treatment of PSUD. Some of these novel agents showing atypical DAT blocker properties, have been highlighted in recently published reviews ( Newman et al, 2021 ; Tanda et al, 2021 ). Among them, some have been shown to bind with high affinity to DAT, and those that promote an inward facing conformation of DAT have shown behavioral and neurochemical preclinical activities different from those of typical abused psychostimulants ( Cao et al, 2010 , 2016 ; Okunola-Bakare et al, 2014 ).…”

“…Among them, some have been shown to bind with high affinity to DAT, and those that promote an inward facing conformation of DAT have shown behavioral and neurochemical preclinical activities different from those of typical abused psychostimulants ( Cao et al, 2010 , 2016 ; Okunola-Bakare et al, 2014 ). Such effects suggest an atypical DAT blocker profile ( Keighron et al, 2019a ; Newman et al, 2019 , 2021 ; Tanda et al, 2021 ) and their potential as novel agents for use in the treatment of PSUD.…”

Effect of Chaihu-jia-Longgu-Muli decoction on withdrawal symptoms in rats with methamphetamine-induced conditioned place preference

“…During the course of addiction, β-EP concentration increases due to the stimulation of methamphetamine [8][9][10] . This is a similar effect to what occurs with an influx of a large number of exogenous opiates into the body.…”

“…Methamphetamine stimulates the release of several neurotransmitters such as dopamine (DA), 5-hydroxytryptamine (5-HT), and endorphins (β-EP), which are associated with emotions [8][9][10] . Methamphetamine directly acts on the dopaminergic neurons and competes with released DA for access to DA transporters [11] .…”

Proteome-Informed Machine Learning Studies of Cocaine Addiction

“…However, currently no cocaine addiction medications have been approved by the U.S. Food and Drug Administration (FDA). 1 The psychotropic properties of cocaine primarily derive from blocking the dopamine transporter (DAT). Specifically, cocaine blocks DAT and prevents dopamine reuptake from the synaptic cleft into the presynaptic axon terminal.…”