Abstract
Due to combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is considered a chronic disease with high prevalence of mild forms of neurocognitive impairments, also referred to as HIV-associated neurocognitive disorders (HAND). Although opiate drug use can exacerbate HIV-1 Tat-induced neuronal damage, it remains unknown how and to what extent opioids interact with Tat on the GABAergic system. We conducted whole-cell recordings in mouse striatal slices and examined the effects of HIV-1 Tat in the presence and absence of morphine (1 μM) and damgo (1 μM) on GABAergic neurotransmission. Results indicated a decrease in the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature IPSCs (mIPSCs) by Tat (5–50 nM) in a concentration-dependent manner. The significant Tat-induced decrease in IPSCs was abolished when removing extracellular and/or intracellular calcium. Treatment with morphine or damgo alone significantly decreased the frequency, but not amplitude of IPSCs. Interestingly, morphine but not damgo indicated an additional downregulation of the mean frequency of mIPSCs in combination with Tat. Pretreatment with naloxone (1 μM) and CTAP (1 μM) prevented the Tat-induced decrease in sIPSCs frequency but only naloxone prevented the combined Tat and morphine effect on mIPSCs frequency. Results indicate a Tat- or opioid-induced decrease in GABAergic neurotransmission via μ-opioid receptors with combined Tat and morphine effects involving additional opioid receptor-related mechanisms. Exploring the interactions between Tat and opioids on the GABAergic system may help to guide future research on HAND in the context of opiate drug use.
Highlights
To explore the effects of Tat on GABergic neurotransmission patch-clamp recordings were performed on striatal medium spiny neurons (MSNs) (Figure 1). spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature Inhibitory postsynaptic currents (IPSCs) (mIPSCs) were confirmed by the application of GABAA receptor antagonist bicuculline
Tat produced a significant decrease in action potential-dependent IPSCs and action potential-independent IPSCs, with altering GABAergic neurotransmission presynaptically and partially postsynaptically, depending on Tat concentration
Our findings indicate that Tat as well as opioids, including morphine and damgo, separately, decreased APdependent and action potential (AP)-independent GABA release in the striatum via a μ-opioid receptor-related mechanism, with Tat effects being dependent on extracellular and intracellular calcium
Summary
Even though severe cases of human immunodeficiency virus type 1 (HIV-1)-associated dementia have been reduced due to the introduction of combined antiretroviral therapy (cART), 30–50%-infected individuals suffer from HIV-1-associated neurocognitive disorders (HAND) (Bell et al, 1998; Dore et al, 1999; Sacktor et al, 2002; Antinori et al, 2007; Ellis et al, 2007; Heaton et al, 2011; Saylor et al, 2016). HAND is enhanced in the context of drug use, such as opiates, Tat ± Opioids Inhibit GABA Release with worsening the consequences of HIV-1 in the central nervous system (CNS) (Bell et al, 1998; Arango et al, 2004; Anthony et al, 2005; Lan et al, 2015). HIV-1 targets subcortical and cortical areas of the brain, with HIV-1 positive individuals displaying deficits in sensorimotor function, executive function, learning and memory, and attention (Berger and Nath, 1997; Berger and Arendt, 2000; Heaton et al, 2011; Scott et al, 2011). Animal in vivo and in vitro studies focusing on the striatum have identified exacerbated behavioral and structural changes by opioids in the presence of the HIV-1 transactivator of transcription (Tat) corresponding to a HAND-associated phenotype (Fitting et al, 2010, 2012, 2014)
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