Psychiatric and substance use disorders pose significant public health burdens across the globe. An estimated 970 million people worldwide were living with a mental disorder in 2019 (World mental health report: Transforming mental health for all, 2022). Recent estimates suggest a high global prevalence of substance use disorders as well, with 283 million people struggling with an alcohol use disorder (World Health Organization, 2018) and another 38.6 million with another drug use disorder (United Nations Office on Drugs and Crime, 2022). Moreover, prevalence of each of these afflictions has been exacerbated by the COVID-19 pandemic. The widespread burden of psychiatric and substance use disorders is compounded by a lack of effective treatments. Selective serotonin reuptake inhibitors (SSRIs) comprise frontline therapeutics for treatment of most mood and anxiety disorders. However, although individual reports vary, it has been estimated that as many as 50% of patients prescribed SSRIs for major depressive disorder or generalized anxiety disorder fail to achieve successful remission of symptoms (Ansara, 2020; Voineskos et al., 2020). Additionally, although three Food and Drug Administration (FDA)-approved pharmacotherapies are available for treatment of alcohol use disorders, the use of pharmacotherapy alongside psychosocial intervention is limited in application and the efficacy of these compounds is only relatively modest at best (Anton et al., 2006; Ray et al., 2019). Even with combined psychosocial intervention and pharmacotherapy, relapse rates remain high at >70% (Anton et al., 2006). Finally, there are currently no FDA-approved medications for psychostimulant (e.g., cocaine, amphetamine-type stimulant) use disorders. Altogether, the relatively poor efficacy of existing therapeutics for treatment of mood, anxiety, and alcohol use disorders and the sheer lack of therapeutics available for treatment of psychostimulant use disorder underscores a dire need to identify and explore novel pharmacological targets to improve treatment. In this review, we summarize evidence for the role that organic cation transporters (OCTs), including three paralogs of OCTs (OCT1/SLC22A1, OCT2/SLC22A2, and OCT3/SLC22A3) and the plasma membrane monoamine transporter (PMAT/SLC29A4), play in regulation of monoaminergic neurotransmission and subsequent neurobiology of psychiatric and substance use disorders, with a focus on mood and anxiety disorders, alcohol use disorder, and psychostimulant use disorder.

Neurotransmitter transporters play an integral role in monoaminergic neurotransmission through their function of removal of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) from the extracellular milieu, thus terminating transmission. For this reason, neurotransmitter transporters are instrumental in maintaining monoamine homeostasis, as well as shaping normal physiological and psychological function in circuits controlling mood and reward behavior. High-affinity, low-capacity ‘uptake 1’ monoamine transporters, including the serotonin transporter (SERT/SLC6A4), the norepinephrine transporter (NET/SLC6A2), and the dopamine transporter (DAT/SLC6A3), are located in the plasma membrane of neurons and glia in the perisynaptic area, as well as along axons and dendrites (Miner, Schroeter, Blakely and Sesack, 2000, Miner, Schroeter, Blakely and Sesack, 2003; Nirenberg, Vaughan, Uhl, Kuhar and Pickel, 1996, Nirenberg et al., 1997; Pickel & Chan, 1999; Schroeter et al., 2000; Sur et al., 1996; Zhou et al., 1998). The perisynaptic location of neurotransmitter transporters shapes their modulation of behavioral effects primarily via volume transmission (for review see Fuxe et al., 2007). Uptake 1 transporters serve as the primary site of action of many psychoactive compounds including those commonly used to treat mood and anxiety disorders (e.g., SSRIs, other related classes of antidepressants) and commonly abused psychostimulant drugs (e.g., cocaine, amphetamine-type stimulants). These transporters have received great attention for their roles in monoamine homeostasis and possible dysregulation in psychiatric and substance use disorders due to their high-affinity transport of monoamine substrates and thus will not be discussed in further detail here (for reviews see Aggarwal & Mortensen, 2017; Howell & Negus, 2014; Kristensen et al., 2011).

A second low-affinity, high-capacity transport system for monoamines was first discovered in the 1960s (Bertler et al., 1964; Burgen & Iversen, 1965; Butler et al., 1988; Fuxe & Ungerstedt, 1967; Lichtensteiger et al., 1967; Shaskan & Snyder, 1970). Despite their discovery nearly six decades ago, these transporters, referred to as ‘uptake 2’ transporters, remained largely unstudied until relatively recently, likely because in foundational studies uptake 2 transport mechanisms did not become apparent until substrate concentrations reached the micromolar range, which was believed to be supraphysiological at the time. However, synaptic monoamine concentrations have been estimated to reach the millimolar range, meaning extrasynaptically located transporters would be exposed to concentrations exceeding the capacity of high-affinity, low-capacity uptake 1 transport mechanisms under normal physiological conditions (Bunin & Wightman, 1998; Clements, 1996; Garris et al., 1994). Thus, an in-depth investigation into the functional role of uptake 2 transporters commenced. Now a growing body of literature discussed in this review supports the notion that uptake 2 transporters also play a central role in regulating monoaminergic neurotransmission and shaping behavior relevant to psychiatric and substance use disorders.

Broadly speaking, OCTs are widely expressed in numerous cell types in the central nervous system and are capable of transporting monoamines well within physiological concentration ranges. Detailed expression and function of OCTs in the central nervous system is reviewed in depth elsewhere (see Sweet, 2021). Briefly, uptake 2 transporters are found in almost all cell types of the brain (including neurons, astrocytes and glial cells, primary vascular endothelial cells, and brain microvessels), particularly in limbic regions important for controlling mood and reward processing (e.g., hippocampus, hypothalamus, amygdala, striatum) (reviewed in Sweet, 2021). OCT1 expression is relatively limited in the central nervous system compared to OCT2, OCT3, and PMAT. Although its presence has not been detected in neurons, OCT1 has been shown to be expressed in astrocytes (Inazu et al., 2005). OCT2 is expressed richly in neurons of the limbic system (Bacq et al., 2012; Couroussé et al., 2015), and both OCT3 and PMAT are very widely expressed in many cell types of the central nervous system including neurons and glia (Cui et al., 2009; Dahlin et al., 2007; Gasser et al., 2017; Hill & Gasser, 2013; Mayer et al., 2018; Miura et al., 2017; Schmitt et al., 2002; Vialou et al., 2008, Vialou, Balasse, Dumas, Giros and Gautron, 2007; Wu et al., 2015). A number of studies have demonstrated that all of the OCTs (OCT1–3 and PMAT) are capable of transporting monoamines well within physiological concentration ranges (Amphoux et al., 2006; Boxberger et al., 2014; Breidert et al., 1998; Busch et al., 1998; Engel et al., 2004; Gründemann et al., 1999; Miura et al., 2017; Wu et al., 1998). In sum, OCTs are expressed abundantly in regions important for controlling mood and reward-related behaviors and contribute to monoamine clearance under normal physiological conditions. A breadth of preclinical evidence discussed here suggests these transporters play a major role in maintaining monoaminergic homeostasis and regulating neurobiology relevant to psychiatric and substance use disorders.