Methamphetamine Activates Trace Amine Associated Receptor 1 to Regulate Astrocyte Excitatory Amino Acid Transporter-2 via Differential CREB Phosphorylation During HIV-Associated Neurocognitive Disorders

Abstract

Methamphetamine (METH) use, referred to as methamphetamine use disorder (MUD), results in neurocognitive decline, a characteristic shared with HIV-associated neurocognitive disorders (HAND). MUD exacerbates HAND partly through glutamate dysregulation. Astrocyte excitatory amino acid transporter (EAAT)-2 is responsible for >90% of glutamate uptake from the synaptic environment and is significantly decreased with METH and HIV-1. Our previous work demonstrated astrocyte trace amine associated receptor (TAAR) 1 to be involved in EAAT-2 regulation. Astrocyte EAAT-2 is regulated at the transcriptional level by cAMP responsive element binding (CREB) protein and NF-κB, transcription factors activated by cAMP, calcium and IL-1β. Second messengers, cAMP and calcium, are triggered by TAAR1 activation, which is upregulated by IL-1β METH-mediated increases in these second messengers and signal transduction pathways have not been shown to directly decrease astrocyte EAAT-2. We propose CREB activation serves as a master regulator of EAAT-2 transcription, downstream of METH-induced TAAR1 activation. To investigate the temporal order of events culminating in CREB activation, genetically encoded calcium indicators, GCaMP6s, were used to visualize METH-induced calcium signaling in primary human astrocytes. RNA interference and pharmacological inhibitors targeting or blocking cAMP-dependent protein kinase A and calcium/calmodulin kinase II confirmed METH-induced regulation of EAAT-2 and resultant glutamate clearance. Furthermore, we investigated METH-mediated CREB phosphorylation at both serine 133 and 142, the co-activator and co-repressor forms, respectively. Overall, this work revealed METH-induced differential CREB phosphorylation is a critical regulator for EAAT-2 function and may thus serve as a mechanistic target for the attenuation of METH-induced excitotoxicity in the context of HAND.

Covid-19 interface with drug misuse and substance use disorders

“…Moreover, patients suffering from HIV-associated dementia had increased IDO activity when compared to HIV patients without dementia ( Sardar and Reynolds, 1995 ). In preclinical studies, HIV significantly increase extracellular glutamate concentrations in an in vitro astrocyte model that corresponds to clinical studies demonstrating increased excitotoxicity in patients suffering from HIV-associate neurocognitive disorders ( Cisneros and Ghorpade, 2014 ; Cisneros et al, 2020 ; Fields et al, 2013 ). Although, IDO levels and activity have not been measured in Covid-19 patients, it is likely that triggering of the immune system by SARS-CoV2 increases IDO activity and kynurenine levels thereby decreasing serotonin and dopamine levels and increasing glutamate excitotoxicity in Covid-19.…”

“…Glutamate, dopamine, and serotonin crosstalk with the immune system and maladaptive changes induced by inflammation may certainly contribute to increased vulnerability to SUDs, although direct and clear experimental designs for definitive studies are difficult to develop. For instance, TNF-α and IL-1β, classical proinflammatory cytokines, inhibit glutamate uptake in astrocytes and increase ionotropic glutamate receptor expression at the synapse ( Cisneros and Ghorpade, 2012 , 2014 ; Cisneros et al, 2020 ; Olmos and Lladó, 2014 ; Pickering et al, 2005 ) and activating glutamate transporters in glial cells reduces cocaine and methamphetamine induced CPP and significantly decreases cocaine self-administration ( Nakagawa et al, 2005 ; Northcutt et al, 2015 ). Reduced clearance and increased levels of synaptic glutamate is a central mechanism underlying SUD pathophysiology and associated cocaine- and heroin-seeking behaviors.…”

A Non-Canonical Role for IRE1α Links ER and Mitochondria as Key Regulators of Astrocyte Dysfunction: Implications in Methamphetamine use and HIV-Associated Neurocognitive Disorders

“…and/or HIV-1-relevant stimuli include astrocyte-associated neuroinflammation and glutamate excitotoxicity, which our team and others have also previously characterized Ghorpade, 2012, 2014;Borgmann and Ghorpade, 2015;Cisneros et al, 2020;Edara et al, 2020a). Moreover, astrocyte mitochondrial dysfunction may threaten the ability of astrocytes to provide essential metabolic and antioxidant support to neurons and could also contribute to the release of toxic reactive oxygen and nitrogen species (ROS/RNS) to propagate oxidative stress.…”

Synergistic Impairment of the Neurovascular Unit by HIV-1 Infection and Methamphetamine Use: Implications for HIV-1-Associated Neurocognitive Disorders

“…When HIV-1-infected cultures of human neurons and astrocytes were treated with METH, a further increase in glutamate dysregulation, as well as increased apoptosis of both cell types was observed, and METH-induced changes in astrocytic gap junctions contributed to this process [ 49 ]. Recent work indicated that METH-induced downregulation of astrocytic excitatory amino acid transporter-2 (EAAT2), which is responsible for more than 90% of glutamate uptake from the synaptic environment, was exacerbated by interleukin-1β (IL-1β) in primary human astrocytes [ 133 ]. IL-1β has been shown to be important for HIV-1 pathobiology [ 102 ].…”

“…The METH-induced EAAT2 dysfunction in astrocytes is mediated by trace amine associated receptor 1 (TAAR1). METH-induced transcription factor cyclic AMP response-binding protein (CREB) phosphorylation has been suggested as a critical mechanism for EAAT2 expression regulation, and may thus serve as a mechanistic target for the METH-induced TAAR1 activation, associated with impaired glutamate clearance capabilities in the context of HAND [ 133 ].…”