The sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission

Abstract

Dopamine neurotransmission is highly dysregulated by the psychostimulant methamphetamine, a substrate for the dopamine transporter (DAT). Through interactions with DAT, methamphetamine increases extracellular dopamine levels in the brain, leading to its rewarding and addictive properties. Methamphetamine also interacts with the sigma-1 receptor (σ1R), an inter-organelle signaling modulator. Using complementary strategies, we identified a novel mechanism for σ1R regulation of dopamine neurotransmission in response to methamphetamine. We found that σ1R activation prevents methamphetamine-induced, DAT-mediated increases in firing activity of dopamine neurons. In vitro and in vivo amperometric measurements revealed that σ1R activation decreases methamphetamine-stimulated dopamine efflux without affecting basal dopamine neurotransmission. Consistent with these findings, σ1R activation decreases methamphetamine-induced locomotion, motivated behavior, and enhancement of brain reward function. Notably, we revealed that the σ1R interacts with DAT at or near the plasma membrane and decreases methamphetamine-induced Ca2+ signaling, providing potential mechanisms. Broadly, these data provide evidence for σ1R regulation of dopamine neurotransmission and support the σ1R as a putative target for the treatment of methamphetamine addiction.

HIV‐1Tat regulation of dopamine transmission and microglial reactivity is brain region specific

“…To ensure proper identification of dopamine neurons in our recordings we used multiple complementary approaches. The dopaminergic neurons were identified 1) by expression of tyrosine hydroxylase (TH) promoter-driven red fluorescent protein, 2) morphologically by their large cell bodies with broad 2–5 first order processes, 3) electrophysiologically by their well-characterized spontaneous firing frequency of 0.3–4 Hz as described previously (Richardson et al, 2016; Saha et al, 2014; Sambo et al, 2017). The average input resistance was 320.5 ± 22.5 MΩ; membrane time constant was 832.1 ± 46.7 μs; and membrane capacitance was 65.8 ± 3.3 pF.…”

“…Adult male GT-tg bigenic mice, RFP::TH mice (Lin et al, 2016; Richardson et al, 2016; Saha et al, 2014; Sambo et al, 2017), and C57BL/6J wild-type (Jackson Labs, Bar Harbor, ME) mice (8–10 weeks of age) were maintained in the University of Florida animal facilities. All experiments were approved by the Institutional Animal Care and Use Committee.…”

“…Midbrain neuronal cultures were obtained from RFP::TH mice, a transgenic mouse strain where the dopamine neurons are rendered fluorescent (Lin et al, 2016; Richardson et al, 2016; Saha et al, 2014; Sambo et al, 2017). Mouse midbrain dopamine neurons from 0–2 day old pups of either sex were isolated and incubated in a dissociation medium at 34–36°C under continuous oxygenation for 2 hours.…”

“…The electrodes were filled with a pipette solution containing (in mM): 120 potassium-gluconate, 20 KCl, 2 MgCl 2 , 10 HEPES, 0.1 EGTA, 2 ATP, and 0.25 GTP, with pH adjusted to 7.25 with KOH. Unless indicated, all experiments were performed in the presence of a dopamine D 1 receptor antagonist SCH23390 (1 μM) and a D 2 receptor antagonist sulpiride (1μM) (Lin et al, 2016; Saha et al, 2014; Sambo et al, 2017) in the aCSF to block dopamine D 1 and D 2 receptors. All experiments were performed at 37°C.…”

The dopamine transporter: An unrecognized nexus for dysfunctional peripheral immunity and signaling in Parkinson’s Disease

“…Exogenous agents such as amphetamine and its derivatives enhance dopamine release via disruption of vesicular storage of dopamine and an efflux mechanism, while cocaine and other inhibitors such as nomifensine and GBR-12935 block both the uptake and DAT-mediated dopamine efflux (Eshleman et al, 1994; Goodwin, 2009). Research on endogenous aspects of DAT regulation exist to examine and characterize the interactions between DAT and other intracellular proteins, which may serve to mediate the regulation attributed to psychostimulants and possibly other endogenous agents (Butler et al, 2015; Sambo et al, 2017). …”