Activation of AMPA Receptors in the Lateral Habenula Produces Anxiolytic Effects in a Rat Model of Parkinson’s Disease

Abstract

Background: Parkinson’s disease (PD) is commonly accompanied with anxiety disorder, however, the mechanisms underlying PD-mediated anxiety remain elusive. The lateral habenula (LHb) is a critical brain region that influences the activity of the monoaminergic system in the midbrain and consequently modulates anxiety. Most neurons in the LHb express AMPA receptors (AMPARs). The PD model for the pharmacological intervention of AMPA receptors was established by the unilateral lesion of the substantia nigra pars compacta (SNc) with 6-hydroxydopamine (6-OHDA).Methods: The AMPAR agonist (S)-AMPA and antagonist NBQX were microinjected into the LHb, respectively, to examine whether anxiety-like behaviors were altered in sham-operated and SNc-lesion rats, measured with the paradigms of the open-field test (OPT) and elevated plus maze (EPM). Furthermore, dopamine (DA) and 5-hydroxytryptamine (5-HT) levels in the basolateral amygdala (BLA) were measured using in vivo microdialysis immediately following the injections of (S)-AMPA and NBQX into the LHb.Results: Activation of LHb AMPA receptors by (S)-AMPA produced anxiolytic-like behaviors and enhanced the extracellular DA and 5-HT in the BLA. Conversely, NBQX induced anxiety-like effects and suppressed the extracellular DA and 5-HT in the BLA. In addition, the minimal doses inducing the effects in the SNc-lesion rats were lower than those in sham-operated rats.Conclusion: These findings suggest that the effects of AMPA receptors in the LHb on anxiety-like behaviors likely involve the extracellular levels of DA and 5-HT in the BLA. The present results may improve our understanding of the neuropathology and/or treatment of PD.

The initiator of neuroexcitotoxicity and ferroptosis in ischemic stroke: Glutamate accumulation

“…NO combines with superoxide radicals to produce large amounts of nitrite, which leads to protein oxidation, lipid peroxidation, and DNA damage (Lipton et al, 1993), as shown in the Figure 3. AMPAR is constructed from four subunits (GluR1-4; Hwang and Lupica, 2020;Zhang et al, 2022). Under resting conditions, the NMDAR channel pores are blocked by Mg 2+ ions and once sufficient membrane depolarization has been established, the Mg 2+ block is removed, allowing the influx of cations (Lin et al, 2008;Olive, 2009).…”

“…AMPAR is constructed from four subunits (GluR1-4; Hwang and Lupica, 2020 ; Zhang et al, 2022 ). Under resting conditions, the NMDAR channel pores are blocked by Mg 2+ ions and once sufficient membrane depolarization has been established, the Mg 2+ block is removed, allowing the influx of cations ( Lin et al, 2008 ; Olive, 2009 ).AMPAR activation increases Na + influx into neurons, depolarizes membranes, and activates voltage-dependent Ca 2+ channels and NMDARs ( Andriessen et al, 2010 ), the substitution of a positively-charged arginine residue for a neutrally-charged glutamine residue at the apex of the membrane reentrant pore loop (M2) changes the conductance properties of channels containing an edited GluR2 subunit ( Köhr et al, 1998 ; Hood and Emeson, 2012 ).…”

Neuronal regeneration after injury: a new perspective on gene therapy

“…This ultimately protects neurons from glutamateinduced damage. For example, the AMPA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline) has demonstrated reduced neuronal death, improved tissue preservation, and enhanced functional recovery in animal models of SCI (Schidlitzki et al, 2017;Zhang J. et al, 2022). To achieve effective dosing, it is crucial for nanoparticles carrying these therapeutic agents to accumulate at the injury site.…”

Glutamate Receptor Dysregulation and Platelet Glutamate Dynamics in Alzheimer’s and Parkinson’s Diseases: Insights into Current Medications

“…Anxiety in PD is modulated by AMPARs, which are found in the lateral habenula (LHb): a part of the brain that affects the monoaminergic system. Researchers investigated how neurotransmitter levels and anxiety-like behaviors in PD and control rats were affected by the AMPAR agonist (S)-AMPA and antagonist NBQX and it was found that in contrast to NBQX, (S)-AMPA had a calming effect while raising dopamine and serotonin levels in the basolateral amygdala [98].…”