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![| Neuronal Δ[Ca 2+ ] i and brain hemodynamic responses to memantine between control and HIV-1 Tg rats. Memantine increased (A) neuronal Δ[Ca 2+ ] i activity but did not change (B) blood volume (Δ[HbT]) nor (C) oxygenated hemoglobin (Δ[HbO 2 ]) in PFC, and these responses did not differ between controls and HIV-1 Tg rats.](publication/360845214/figure/fig1/AS:1159629975359491@1653488739752/Neuronal-DCa-2-i-and-brain-hemodynamic-responses-to-memantine-between-control-and.png)
| Neuronal Δ[Ca 2+ ] i and brain hemodynamic responses to memantine between control and HIV-1 Tg rats. Memantine increased (A) neuronal Δ[Ca 2+ ] i activity but did not change (B) blood volume (Δ[HbT]) nor (C) oxygenated hemoglobin (Δ[HbO 2 ]) in PFC, and these responses did not differ between controls and HIV-1 Tg rats.
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![FIGURE 2 | Neuronal Δ[Ca 2+ ] i and brain hemodynamic responses to...](publication/360845214/figure/fig1/AS:1159629975359491@1653488739752/Neuronal-DCa-2-i-and-brain-hemodynamic-responses-to-memantine-between-control-and_Q320.jpg)
![FIGURE 4 | Memantine attenuates cocaine-induced Δ[HbT] decrease in the...](publication/360845214/figure/fig3/AS:1159629975367683@1653488739857/Memantine-attenuates-cocaine-induced-DHbT-decrease-in-the-PFC-of-control-animals-A_Q320.jpg)
![FIGURE 5 | Reduction of Δ[HbO 2 ] in the PFC of control animals induced...](publication/360845214/figure/fig4/AS:1159629975359492@1653488739985/Reduction-of-DHbO-2-in-the-PFC-of-control-animals-induced-by-cocaine-is-attenuated_Q320.jpg)
![FIGURE 6 | Attenuated neuronal Δ[Ca 2+ ] i response to cocaine with...](publication/360845214/figure/fig5/AS:1159629979561984@1653488740070/Attenuated-neuronal-DCa-2-i-response-to-cocaine-with-memantine-pretreatment-in_Q320.jpg)
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 neurodegenera...
Contexts in source publication
Context 1
... Control rats (n = 3) with memantine administration (10 mg/kg, s.c.); b. HIV-1 Tg rats (n = 4) with memantine administration (10 mg/kg, s.c.) Figure 2 Expt 2: Imaged PFC response to cocaine with or without memantine in control rats (n = 5). ...
Context 2
... quantify changes in Ca 2+ and hemodynamics in response to cocaine challenge, we selected five regions of interest (ROI) for each animal (as illustrated in Figure 3: yellow circles). From full-field images, we selected the hemisphere in which GCaMP6f was injected and expressed ( Supplementary Figures S2, S3). ROIs were then positioned in regions along the periphery of the GCaMP6f expression and were placed to avoid vasculature, as described in our previous publications (Allen et al., 2019;Du et al., 2020;Du et al., 2021;Park et al., 2022 ...
Citations
... 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]. ...
... Non-selective NMDA receptor antagonist ASD [39,40] SUD [100,102] MK-801 (Dizocilpine) NMDA receptor antagonist SUD [101,104] N-acetyl-L-cysteine mGluR2/3 agonist ASD [45,46] Nitrous oxide NMDA receptor antagonist MDD [181] Pomaglumetad mGluR2/3 agonist Schizophrenia [132,147] Psilocybin 5-HT1A, 5-HT2A and 5-HT2C activator MDD [182] Reviewed in [183] SUD [184] Riluzole [97,99] NMDA: N-methyl-D-aspartate, TRPV1: transient receptor potential cation channel subfamily V member 1, CB1: cannabinoid receptor 1, CB2: cannabinoid receptor 2, 5-HT1A: 5-hydroxytryptamine receptor subtype 1A, ASD: autism spectrum disorder, MDD: major depressive disorder, SUD: substance use disorder, SERT: serotonin transporter, NET: norepinephrine transporter, AMPA: α-amino-3-hydroxy-5-methyl-a-isoxazolepropionate, PTSD: post-traumatic stress disorder, GlyT1: Glycine transporter type-1, TRD: treatment-resistant depression, LSD: lysergic acid diethylamide, D2: dopamine receptor 2, D3: dopamine receptor 3, MDMA: 3,4-Methylenedioxymethamphetamine, SSRI: selective serotonin reuptake inhibitor, SNRI: serotonin and norepinephrine reuptake inhibitor, TCA: tricyclic antidepressant. ...
These authors contributed equally to this work. Abstract: Glutamate is the main excitatory neurotransmitter in the brain wherein it controls cognitive functional domains and mood. Indeed, brain areas involved in memory formation and consolidation as well as in fear and emotional processing, such as the hippocampus, prefrontal cortex, and amygdala, are predominantly glutamatergic. To ensure the physiological activity of the brain, gluta-matergic transmission is finely tuned at synaptic sites. Disruption of the mechanisms responsible for glutamate homeostasis may result in the accumulation of excessive glutamate levels, which in turn leads to increased calcium levels, mitochondrial abnormalities, oxidative stress, and eventually cell atrophy and death. This condition is known as glutamate-induced excitotoxicity and is considered as a pathogenic mechanism in several diseases of the central nervous system, including neurodevelopmental, substance abuse, and psychiatric disorders. On the other hand, these disorders share neuroplasticity impairments in glutamatergic brain areas, which are accompanied by structural remodeling of glutamatergic neurons. In the current narrative review, we will summarize the role of glutamate-induced excitotoxicity in both the pathophysiology and therapeutic interventions of neurodevelopmental and adult mental diseases with a focus on autism spectrum disorders, substance abuse, and psychiatric disorders. Indeed, glutamatergic drugs are under preclinical and clinical development for the treatment of different mental diseases that share glutamatergic neuroplasticity dysfunctions. Although clinical evidence is still limited and more studies are required, the regulation of glutamate homeostasis is attracting attention as a potential crucial target for the control of brain diseases.
Cocaine is a highly addictive drug, and its use is associated with adverse medical consequences such as cerebrovascular accidents that result in debilitating neurological complications. Indeed, brain imaging studies have reported severe reductions in cerebral blood flow (CBF) in cocaine misusers when compared to the brains of healthy non-drug using controls. Such CBF deficits are likely to disrupt neuro-vascular interaction and contribute to changes in brain function. This review aims to provide an overview of cocaine-induced CBF changes and its implication to brain function and to cocaine addiction, including its effects on tissue metabolism and neuronal activity. Finally, we discuss implications for future research, including targeted pharmacological interventions and neuromodulation to limit cocaine use and mitigate the negative impacts.
Background
With improved survival among People Living with HIV (PLHIV), many are confronted with age associated comorbidities and geriatric syndromes. Neurocognitive impairment is one of the three most frequent conditions that affects quality of life of PLHIV despite achieving viral suppression. Healthcare providers face challenges in early identification of neurocognitive impairment, performing comprehensive assessment and managing older PLHIV.
Objectives
This paper aims to review available evidence regarding aetiology and management of older PLHIV who develop neurocognitive impairment, suggest improvements on current management and postulate future study direction.
Methods
A PubMed search for original articles and Clinical Guidelines was conducted from September 2021 to August 2022 using a combination of keywords related to neurocognitive impairment in PLHIV. The citations from all selected articles were reviewed for additional studies.
Results
Older PLHIV tend to be frailer than their uninfected counterparts, are plagued with multi-morbidity and are at increased risk of cognitive impairment. The aetiologies for neurocognitive impairment are multifactorial, multi-dimensional and complex. The management of neurocognitive impairment in older PLHIV involves identifying and optimizing predisposing factors, physical function, social and psychological health with appropriate care navigation.
Conclusion
Identification and management of neurocognitive impairment in older PLHIV through interdisciplinary collaboration among stakeholders is important. This exemplifies an integrated model of care for older PLHIV and promotes the notion of living well beyond viral suppression.
The normal function of the medial prefrontal cortex (mPFC) is essential for regulating neurocognition, but it is disrupted in the early stages of Alzheimer’s disease (AD) before the accumulation of Aβ and the appearance of symptoms. Despite this, little is known about how the functional activity of medial prefrontal cortex pyramidal neurons changes as Alzheimer’s disease progresses during aging. We used electrophysiological techniques (patch-clamping) to assess the functional activity of medial prefrontal cortex pyramidal neurons in the brain of 3xTg-Alzheimer’s disease mice modeling early-stage Alzheimer’s disease without Aβ accumulation. Our results indicate that firing rate and the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) were significantly increased in medial prefrontal cortex neurons from young Alzheimer’s disease mice (4–5-month, equivalent of <30-year-old humans) compared to agematched control mice. Blocking ionotropic glutamatergic NMDA receptors, which regulate neuronal excitability and Ca2+ homeostasis, abolished this neuronal hyperactivity. There were no changes in Ca2+ influx through the voltage-gated Ca2+ channels (VGCCs) or inhibitory postsynaptic activity in medial prefrontal cortex neurons from young Alzheimer’s disease mice compared to controls. Additionally, acute exposure to Aβ42 potentiated medial prefrontal cortex neuronal hyperactivity in young Alzheimer’s disease mice but hadnoeffects oncontrols. These findings indicate that the hyperactivity of medial prefrontal cortex pyramidal neurons at early-stage Alzheimer’s disease is induced byanabnormalincreaseinpresynapticglutamate releaseandpostsynaptic NMDA receptor activity, which initiates neuronal Ca2+ dyshomeostasis. Additionally, because accumulated Aβ forms unconventional but functional Ca2+ channels in medialprefrontal cortex neuronsinthelatestageofAlzheimer’sdisease,ourstudy also suggests an exacerbated Ca2+ dyshomeostasis in medial prefrontal cortex pyramidal neurons following overactivation of such VGCCs.
The detrimental physical, mental, and socioeconomic effects of substance use disorders (SUDs) have been apparent to the medical community for decades. However, it has become increasingly urgent in recent years to develop novel pharmacotherapies to treat SUDs. Currently, practitioners typically rely on monotherapy. Monotherapy has been shown to be superior to no treatment at all for most substance classes. However, many randomized controlled trials (RCTs) have revealed that monotherapy leads to poorer outcomes when compared with combination treatment in all specialties of medicine. The results of RCTs suggest that monotherapy frequently fails since multiple dysregulated pathways, enzymes, neurotransmitters, and receptors are involved in the pathophysiology of SUDs. As such, research is urgently needed to determine how various neurobiological mechanisms can be targeted by novel combination treatments to create increasingly specific yet exceedingly comprehensive approaches to SUD treatment. This article aims to review the neurobiology that integrates many pathophysiologic mechanisms and discuss integrative pharmacology developments that may ultimately improve clinical outcomes for patients with SUDs. Many neurobiological mechanisms are known to be involved in SUDs. These include dopaminergic, nicotinic, N-methyl-D-aspartate (NMDA), and kynurenic acid (KYNA) mechanisms, for example. Emerging evidence indicates that KYNA, a tryptophan metabolite, modulates all these major pathophysiologic mechanisms. Therefore, achieving KYNA homeostasis by harmonizing integrative pathophysiology and pharmacology could prove to be a better therapeutic approach for SUDs. We propose KYNA-NMDA-α7nAChRcentric pathophysiology, the “conductor of the orchestra,” as a novel approach to treat many SUDs concurrently. KYNA-NMDA-7nAChR pathophysiology may be the “command center” of neuropsychiatry. To date, extant RCTs have shown equivocal findings across comparison conditions, possibly because investigators targeted single pathophysiologic mechanisms, hit wrong targets in underlying pathophysiologic mechanisms, and tested inadequate monotherapy treatment. We provide examples of potential combination treatments that simultaneously target multiple pathophysiologic mechanisms in addition to KYNA. Kynurenine pathway metabolism demonstrates the greatest potential as a target for neuropsychiatric diseases. The investigational medications with the most evidence include memantine, galantamine, and N-acetylcysteine. Future RCTs are warranted with novel combination treatments for SUDs. Multicenter RCTs with integrative pharmacology offer a promising, potentially fruitful avenue to develop novel therapeutics for the treatment of SUDs.
