Methamphetamine and neuroHIV suppress astrocytic potassium channel function in the medial prefrontal cortex via...

Methamphetamine (Meth) is a highly addictive psychostimulant that disrupts neuronal function in the medial prefrontal cortex (mPFC), inducing Meth use disorders (MUD). MUD is often complicated by HIV-associated neurocognitive disorders (HAND, a.k.a. neuroAIDS/neuroHIV), and vice versa. MUD and neuroHIV also disrupt astrocytes, altering their role in supporting normal neuron function. The mechanism(s) underlying Meth and neuroHIV's impact on astrocytes and astrocyte-neuron interplay remains unknown.

To define that, we assessed the activity of cortical astrocyte K⁺ channels that regulate extracellular K⁺ homeostasis ([K⁺]_e), and substantially neuronal excitability in the brain. HIV-1 transgenic (Tg) rats, a rodent model of neuroHIV with combined antiretroviral therapy (cART) that have no active HIV-1 replication but expression of viral proteins, were given daily repeated Meth administrations. Saline-pretreated non-Tg rats served as control. We then conducted electrophysiological assessment in mPFC astrocytes after acute Meth (20, 100 μM in bath) or daily repeated Meth administrations (5 mg/kg/day s.c. for 5 days) followed by a 3-day withdrawal.

We found that both Meth and neuroHIV suppressed the activity of astrocytic K⁺ channels, regardless of subtypes. The maximum reduction occurred in response to combined Meth/neuroHIV, showing exacerbated astrocyte dysfunction. Blocking the trace amine-associated receptor 1 (TAAR1)/G protein-coupled signaling pathway abolished Meth-induced, but not neuroHIV-induced, suppression of K_2P, K_v, and K_ir channel activity.

Collectively, these findings demonstrate that Meth and neuroHIV inhibit astrocyte function, which could exacerbate mPFC neuronal dysfunction in MUD and/or neuroHIV. They also suggest that Meth- and neuroHIV-induced astrocytic K⁺ channel function was mediated by TAAR1-and/or chemokine receptor-coupled signaling pathways.