Methamphetamine Regulation of Firing Activity of Dopamine Neurons

Abstract

Methamphetamine (METH) is a substrate for the dopamine transporter that increases extracellular dopamine levels by competing with dopamine uptake and increasing reverse transport of dopamine via the transporter. METH has also been shown to alter the excitability of dopamine neurons. The mechanism of METH regulation of the intrinsic firing behaviors of dopamine neurons is less understood. Here we identified an unexpected and unique property of METH on the regulation of firing activity of mouse dopamine neurons. METH produced a transient augmentation of spontaneous spike activity of midbrain dopamine neurons that was followed by a progressive reduction of spontaneous spike activity. Inspection of action potential morphology revealed that METH increased the half-width and produced larger coefficients of variation of the interspike interval, suggesting that METH exposure affected the activity of voltage-dependent potassium channels in these neurons. Since METH has been shown to affect Ca 2ϩ homeostasis, the unexpected findings that METH broadened the action potential and decreased the amplitude of afterhyperpolarization led us to ask whether METH alters the activity of Ca 2ϩ -activated potassium (BK) channels. First, we identified BK channels in dopamine neurons by their voltage dependence and their response to a BK channel blocker or opener. While METH suppressed the amplitude of BK channel-mediated unitary currents, the BK channel opener NS1619 attenuated the effects of METH on action potential broadening, afterhyperpolarization repression, and spontaneous spike activity reduction. Live-cell total internal reflection fluorescence microscopy, electrophysiology, and biochemical analysis suggest METH exposure decreased the activity of BK channels by decreasing BK-␣ subunit levels at the plasma membrane.

HIV, Tat and dopamine transmission

“…While further investigation is necessary to determine the mechanism(s)by which Tat regulates DAT activity and the firing activity of dopamine neurons, the existing literature suggest that Tat alters dopamine neurotransmission within the CNS. This is consistent with the susceptibility of HIV-1 infected patients to abuse of illicit drugs, such as cocaine and methamphetamine, that target monoaminergic systems such as midbrain dopamine neurons (Goodwin et al, 2009; Lin et al, 2016; Saha et al, 2014), and to the higher sensitivity of (GT-tg bigenic mice) mice to psychostimulants (Kesby et al, 2016a; Mediouni et al, 2015a; Paris et al, 2014a). Further developing our understanding of the precise mechanism(s) by which of Tat regulates DAT might be a key in the development of effective therapeutic approaches designed to ameliorate the damaging and disruptive effects of Tat and HIV infection on DAT activity and the dopaminergic system.…”

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

“…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.…”

Mechanism of manganese dysregulation of dopamine neuronal activity

“…The mechanistic relationship between manganese-regulation of Ca 2+ signaling and excitability of dopamine neurons has remained unclear. Recently, we have shown changes in Ca 2+ homeostasis in the dopamine neurons influence neuronal activity indirectly through Ca 2+ -activated potassium channels (Lin et al, 2016). In the current study, we report a mechanistic link between manganese regulation of the excitability of dopamine neurons and manganese modulation of Ca 2+ channels.…”