Methamphetamine and HIV-1-induced neurotoxicity: Role of trace amine associated receptor 1 cAMP signaling in astrocytes

Abstract

Methamphetamine (METH) is abused by about 5% of the United States population with approximately 10–15% of human immunodeficiency virus-1 (HIV-1) patients reporting its use. METH abuse accelerates the onset and severity of HIV-associated neurocognitive disorders (HAND) and astrocyte-induced neurotoxicity. METH activates G-protein coupled receptors such as trace amine associated receptor 1 (TAAR1) increasing intracellular cyclic adenosine monophosphate (cAMP) levels in presynaptic cells of monoaminergic systems. In the present study, we investigated the effects of METH and HIV-1 on primary human astrocyte TAAR1 expression, function and glutamate clearance. Our results demonstrate combined conditions increased TAAR1 mRNA levels 7-fold and increased intracellular cAMP levels. METH and beta-phenylethylamine (β-PEA), known TAAR1 agonists, increased intracellular cAMP levels in astrocytes. Further, TAAR1 knockdown significantly reduced intracellular cAMP levels in response to METH/β-PEA, indicating signaling through astrocyte TAAR1. METH +/− HIV-1 decreased excitatory amino acid transporter-2 (EAAT-2) mRNA and significantly decreased glutamate clearance. RNA interference for TAAR1 prevented METH-mediated decreases in EAAT-2. TAAR1 knockdown significantly increased glutamate clearance, which was further heightened significantly by METH. Moreover, TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance that were further reduced by METH. Taken together, our data show that METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function. To our knowledge this is the first report implicating astrocyte TAAR1 as a novel receptor for METH during combined injury in the context of HAND.

TAAR1 modulates cortical glutamate NMDA receptor function

“…Alternatively, as TAAR1 is expressed in the layer V of PFC, where significant deficiency in NMDA receptor-mediated glutamate transmission was observed, it is possible that glutamate transmission deficits could be a direct consequence of the absence of cortical TAAR1. Intriguingly, a recent report indicated that TAAR1 can modulate the function of the glutamate transporter EAAT2 leading to alterations in glutamate clearance suggesting a direct connection between TAAR1 and glutamate transmission (Cisneros and Ghorpade, 2014). Finally, we cannot exclude an involvement of other monoaminergic systems and signaling pathways (ie, serotonin-mediated, (Lindemann et al, 2008)) that might be involved in TAAR1-mediated functions and behaviors.…”

Trace Amines and Their Receptors

“…Such an effect has potentially significant functional consequences for Parkinson disease-related abnormalities. Interestingly, methamphetamine-induced activation of TAAR1 leads to intracellular cAMP accumulation in human astrocytes, an effect that decreased glutamate clearance abilities due to a downregulation of excitatory amino acid transporter 2 (EAAT-2) (Cisneros and Ghorpade, 2014). Although methamphetamine has a promiscuous pharmacology, molecular alterations in astrocyte TAAR1 levels also induced changes in EAAT-2 levels and function, consistent with the methamphetamine response being TAAR1 mediated (Cisneros and Ghorpade, 2014).…”

“…Such a distribution is generally seen in both rodents and primates and is consistent with the effects of TAAR1-directed ligands described in other sections. At least in humans, expression may not be limited to neurons with one report of astrocytic TAAR1 (Cisneros and Ghorpade, 2014). Spinal cord expression may also occur, at least in rats (Gozal et al, 2014).…”

“…Interestingly, methamphetamine-induced activation of TAAR1 leads to intracellular cAMP accumulation in human astrocytes, an effect that decreased glutamate clearance abilities due to a downregulation of excitatory amino acid transporter 2 (EAAT-2) (Cisneros and Ghorpade, 2014). Although methamphetamine has a promiscuous pharmacology, molecular alterations in astrocyte TAAR1 levels also induced changes in EAAT-2 levels and function, consistent with the methamphetamine response being TAAR1 mediated (Cisneros and Ghorpade, 2014). More recently, it has been shown that high concentrations of dopamine upregulate TAAR1, consistent with TAAR1 acting to prevent dopamine hyperactivity, and this also leads to reduced EAAT-2 expression and glutamate clearance in primary cortical astrocytes (Ding et al, 2017).…”

In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1

“…The location of TAAR1 expression is mostly intracellular in neurons (Miller, 2011) and also in glial cells (Cisneros and Ghorpade, 2014). Because the substances need to reach the location of expression of TAAR1 to bind to the receptor, the intracellular availability of the ligands is also relevant.…”