Memantine Attenuates Cocaine and neuroHIV Neurotoxicity in the Medial Prefrontal Cortex

Abstract

Individuals with substance use disorder are at a higher risk of contracting HIV and progress more rapidly to AIDS as drugs of abuse, such as cocaine, potentiate the neurotoxic effects of HIV-associated proteins including, but not limited to, HIV-1 trans-activator of transcription (Tat) and the envelope protein Gp120. Neurotoxicity and neurodegeneration are hallmarks of HIV-1-associated neurocognitive disorders (HANDs), which are hypothesized to occur secondary to excitotoxicity from NMDA-induced neuronal calcium dysregulation, which could be targeted with NMDA antagonist drugs. Multiple studies have examined how Gp120 affects calcium influx and how cocaine potentiates this influx; however, they mostly focused on single cells and did not analyze effects in neuronal and vascular brain networks. Here, we utilize a custom multi-wavelength imaging platform to simultaneously study the neuronal activity (detected using genetically encoded Ca2+ indicator, GcaMP6f, expressed in neurons) and hemodynamic changes (measured by total hemoglobin and oxygenated hemoglobin within the tissue) in the prefrontal cortex (PFC) of HIV-1 Tg rats in response to cocaine and evaluate the effects of the selective NMDA antagonist drug memantine on cocaine and HIV neurotoxicity compared to those of non-HIV-1 Tg animals (controls). Our results show that memantine improved cocaine-induced deficit in cerebral blood volume while also attenuating an abnormal increase of the neuronal calcium influx and influx duration in both control rats and HIV-1 Tg rats. Cocaine-induced neuronal and hemodynamic dysregulations were significantly greater in HIV-1 Tg rats than in control rats. With memantine pretreatment, HIV-1 Tg rats showed attenuated cocaine’s effects on neuronal and hemodynamic responses, with responses similar to those observed in control rats. These imaging results document an enhancement of neuronal Ca2+ influx, hypoxemia, and ischemia with cocaine in the PFC of HIV-1 Tg rats that were attenuated by memantine pretreatment. Thus, the potential utility of memantine in the treatment of HAND and of cocaine-induced neurotoxicity deserves further investigation.

Hyperactivity of medial prefrontal cortex pyramidal neurons occurs in a mouse model of early-stage Alzheimer’s disease without β-amyloid accumulation

“…In addition, the present study also indicates that there was no increase in Ca 2+ influx via VGCCs in young mPFC pyramidal neurons in early-stage AD, likely due to the absence of Aβ plaques and lack of Aβ-formed Ca 2+ channels, in such early stage of AD. Based upon this finding, we predict that the hyperactivity and overexpression of L-channels, including those formed by Aβ, will occur at the late stage of AD, which will interplay with overactive NMDARs to exacerbate [Ca 2+ ] in dyshomeostasis in pyramidal neurons, thereby inducing neurotoxicity (Figure 7), as we observed in another neurodegenerative disease (Napier et al, 2014;Khodr et al, 2016;Du et al, 2022).…”

“…Therefore, a novel therapeutic approach is desperately needed to aim on reducing overactivation of both NMDARs and L-channels in hyperactive pyramidal neurons. Encouragingly, our previous studies show that combined, but not individual, antagonism of NMDAR and L-channel overactivation is more effective than memantine or L-channel blocker alone to diminish hyperactivity, excessive [Ca 2+ ] in , and neurotoxicity in pyramidal neurons ( Napier et al, 2014 ; Khodr et al, 2016 ; Du et al, 2021 ; 2022 ) in the context of neuroHIV, another neurodegenerative disease that could also lead to dementia; and therefore, may be more efficient to interfere the progression of AD during aging ( Figure 7 ).…”

Neurovascular effects of cocaine: relevance to addiction

“…The efficacy of NMDA antagonist for treatment of CUD has also been investigated. Cocaine naïve rodents pretreated with memantine (NDMA antagonist) prior to a cocaine challenge showed a shortened duration of calcium influx with improved cerebral hemodynamics as compared to controls ( Du et al, 2022 ). Taken together, these pre-clinical findings suggest that L-type calcium channels blockers and NMDA antagonists have potential as treatment to alleviate neuronal damage caused by increased calcium influx and chronic ischemia.…”

Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders

“…In this regard, cation channel blockers (Lamotrigine) and NMDA receptor antagonists (Acamprosate, Amantadine, Memantine, and MK-801) have gained much consideration in the development of therapeutic interventions, since they have been reported to protect neurons from excitotoxicity [ 88 , 97 , 98 , 99 ]. Among these, memantine and MK-801 have shown efficacy in reducing cocaine and alcohol craving and relapse in preclinical models by blocking excessive calcium influx through NMDA receptors [ 100 , 101 , 102 , 103 , 104 ]. However, the clinical evidence is conflicting and inconclusive [ 105 ].…”