Glial Modulators as Potential Treatments of Psychostimulant Abuse

Abstract

Glia (including astrocytes, microglia and oligodendrocytes), which constitute the majority of cells in the brain. have many of the same receptors as neurons, secrete neurotransmitters and neurotrophic and neuroinflammatory factors, control clearance of neurotransmitters from synaptic clefts, and are intimately involved in synaptic plasticity. Despite their prevalence and spectrum of functions, appreciation of their potential general importance has been elusive since their identification in the mid-1800s, and only relatively recently have they been gaining their due respect. This development of appreciation has been nurtured by the growing awareness that drugs of abuse, including the psychostimulants, affect glial activity, and glial activity, in turn, has been found to modulate the effects of the psychostimulants. This developing awareness has begun to illuminate novel pharmacotherapeutic targets for treating psychostimulant abuse, for which targeting more conventional neuronal targets has not yet resulted in a single, approved medication. In this chapter, we discuss the molecular pharmacology, physiology and functional relationships that the glia have especially in the light in which they present themselves as targets for pharmacotherapeutics intended to treat psychostimulant abuse disorders. We then review a cross section of preclinical studies that have manipulated glial processes whose behavioral effects have been supportive of considering the glia as drug targets for psychostimulant-abuse medications. We then close with comments regarding the current clinical evaluation of relevant compounds for treating psychostimulant abuse, as well as the likelihood of future prospects.

Glial and neuroinflammatory targets for treating substance use disorders

“…It has recently come to light that nearly all drugs of abuse also influence non-neuronal glial cells (Beardsley and Hauser, 2014; Crews and Vetreno, 2016; Hutchinson and Watkins, 2014). Glial cells make up the majority of cells in the brain where they play an active role in a variety of brain functions including neurotransmitter release and clearance, synaptic development and maturation, synaptic plasticity, neuronal cell survival, immune responding, and many others (Sofroniew and Vinters, 2010).…”

Interactions of HIV and Drugs of Abuse

“…MOR-expressing microglia and astroglia appear to contribute to the interactive neurotoxicity of morphine and Tat in the striatum (Zou et al, 2011; Sorrell & Hauser, 2014). In addition, e.g., GABA and fractalkine may serve as “off” signals—switching off overactive microglia (Beardsley & Hauser, 2014), and opiates can possibly modify these signals (Krebs, Gauchy, Desban, Glowinski, & Kemel, 1994; You et al, 1996; Steiner & Gerfen, 1998; McQuiston, 2007; Bagley et al, 2011; Suzuki et al, 2011). Thus, the innate immune and neurotransmitter signals disrupted by opiates and HIV strategically converge and are integrated into a unique “neuroimmune” logic by microglia.…”

“…DAMPs are released from stressed or injured cells (Bianchi, 2007; Srikrishna & Freeze, 2009) and trigger innate immune activation. Multiple classes of PRRs appear to be triggered through drug and alcohol abuse (Crews et al, 2011; Yakovleva, Bazov, Watanabe, Hauser, & Bakalkin, 2011; Beardsley & Hauser, 2014). Methamphetamine also reportedly affects subpopulations through the activation of trace aminoacid associated receptor-1 (TAAR1) (Bunzow et al, 2001; Reese et al, 2007; Xie & Miller, 2009).…”

“…Glutamate overflow, especially at extrasynaptic sites (Sattler, Xiong, Lu, MacDonald, & Tymianski, 2000; Hardingham, Fukunaga, & Bading, 2002), can induce excitotoxic neuronal injury and even death through overactivation of extrasynaptic GluN2B NMDA receptors (Ivanov et al, 2006; Liu et al, 2007). The NMDA receptor antagonists MK-801 or dextromethorphan can attenuate methamphetamine neurotoxicity (Thomas & Kuhn, 2005), suggesting that microglial activation and dopamine terminal losses may be intimately linked to excitotoxic glutamatergic transmission and imbalances in synaptic and extrasynaptic glutamate (Beardsley & Hauser, 2014). …”

Ibudilast (AV411), and its AV1013 analog, reduce HIV-1 replication and neuronal death induced by HIV-1 and morphine

“…Both AV411 and its amidated analogue, AV1013, have a low molecular weight (230 Da), with the ability to readily cross the blood brain barrier [13], and have pronounced anti-inflammatory and anti-nociceptive effects [14–17] that are reported to be principally mediated by glia [16, 18–20]. AV411 reduces neuroinflammation by elevating cAMP [21–23] and by decreasing tumor necrosis factor-α (TNF-α) release, which restricts the activity of glia, while promoting the production of the anti-inflammatory cytokine interleukin (IL)-10 and increasing the release of various neurotrophic factors by astrocytes and microglia [18–20]. In addition, AV411 has been shown to be neuroprotective against LPS-activated microglia and in neuronal injury from excitotoxic ischemia [24, 25].…”