Selenoprotein P Modulates Methamphetamine Enhancement of Vesicular Dopamine Release in Mouse Nucleus Accumbens Via Dopamine D2 Receptors

Abstract

Dopamine (DA) transmission plays a critical role in processing rewarding and pleasurable stimuli. Increased synaptic DA release in the nucleus accumbens (NAc) is a central component of the physiological effects of drugs of abuse. The essential trace element selenium mitigates methamphetamine-induced neurotoxicity. Selenium can also alter DA production and turnover. However, studies have not directly addressed the role of selenium in DA neurotransmission. Selenoprotein P (SELENOP1) requires selenium for synthesis and transports selenium to the brain, in addition to performing other functions. We investigated whether SELENOP1 directly impacts (1) DA signaling and (2) the dopaminergic response to methamphetamine. We used fast-scan cyclic voltammetry to investigate DA transmission and the response to methamphetamine in NAc slices from C57/BL6J SELENOP1 KO mice. Recordings from SELENOP1 KO mouse slices revealed reduced levels of evoked DA release and slower DA uptake rates. Methamphetamine caused a dramatic increase in vesicular DA release in SELENOP1 KO mice not observed in wild-type controls. This elevated response was attenuated by SELENOP1 application through a selenium-independent mechanism involving SELENOP1-apolipoprotein E receptor 2 (ApoER2) interaction to promote dopamine D2 receptor (D2R) function. In wild-type mice, increased vesicular DA release in response to methamphetamine was revealed by blocking D2R activation, indicating that the receptor suppresses the methamphetamine-induced vesicular increase. Our data provide evidence of a direct physiological role for SELENOP1 in the dopaminergic response to methamphetamine and suggest a signaling role for the protein in DA transmission.

Regional and sex differences in spontaneous striatal dopamine transmission

“…Thus, there are likely many other factors that affect the gradient of release from evoked signals that are not contributing to spontaneously occurring release. Examining evoked DA release is extremely valuable when measuring uptake kinetics (i.e., Michaelis‐Menten measures of DAT function, Yorgason et al., 2013), psychostimulant effects on proteins expressed in DA terminals (Hedges et al., 2018; Torres et al., 2021; Yorgason et al., 2020), and examining circuitry from direct auto‐ and hetero‐receptor activity on DA terminals (Gao et al., 2019; Torres et al., 2021; Yorgason et al., 2013). However, since regional activity differs between nonstimulated (spontaneous) and evoked conditions, further pharmacological and/or genetic manipulations are necessary to describe circuit‐specific effects recruited during evoked release experiments.…”

Effectiveness and Relationship between Biased and Unbiased Measures of Dopamine Release and Clearance

“…The Michaelis–Menten K m is frequently used for describing the effects of DAT inhibitors ,,, and correlates strongly with the exponential decay measure tau . Therefore, in order to establish the relationship between exponential decay and downward velocity, the effects of tropane analogs on tau were examined (Figure E).…”

“…Another common method is to start off with a specific fixed value for K m (e.g., 160–200 nM based on previous dopamine binding studies). With this fixed K m value, only the thickness layer, release concentration, and V max are adjusted to determine baseline release and clearance values. − This second method is often combined with a third approach where the V max is constrained after drug application, and K m becomes variable in the presence of psychostimulants. − …”

Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats

“…Selenium has been implicated in mediating dopamine release and transmission within the substantia nigra [51,52] and the nucleus accumbens [53] . The presence of SELENOP1 on nucleus accumbens dopamine terminals is proposed to attenuate dopamine release into the synaptic cleft via direct mediation of the dopamine 2 autoreceptors, protecting against neurotoxic effects of drugs of abuse as evidenced for methamphetamine [53] . Ccdc152, another gene on chromosome 2, is encoded within the SELENOP1 gene, and acts to attenuate SELENOP1 levels via posttranslational modification [54] .…”