scholarly journals Cortical and raphe GABAA, AMPA receptors and glial GLT-1 glutamate transporter contribute to the sustained antidepressant activity of ketamine

2020 ◽  
Author(s):  
Thu Ha Pham ◽  
Céline Defaix ◽  
Thi Mai Loan Nguyen ◽  
Indira Mendez-David ◽  
Laurent Tritschler ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Forced Swim Test ◽  
Glutamate Release ◽  
Glutamate Transporter ◽  
Antidepressant Activity ◽  
Gaba Release ◽  
Nmda Receptor Antagonist ◽  
Post Dose ◽  
Rapid Responses

ABSTRACTAt sub-anaesthetic doses, ketamine, a non competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated remarkable and rapid antidepressant (AD) efficacy in patients with treatment-resistant depression (TRD). However, its mechanism of action of ketamine is not fully understood. Since comorbid depression and anxiety disorders often occur, GABAergic/inhibitory and glutamatergic/excitatory drug treatments may be co-administered in these patients. Information regarding this combination is critical to establish efficacy or treatment restrictions to maximize translation from animal models to TRD patients, effectiveness and safety. To assess the specific role of excitatory/inhibitory neurotransmission in the medial prefrontal cortex-raphe nuclei (mPFC-DRN) circuit in the sustained antidepressant-like activity (AD) of ketamine (at t24h post dose), AMPA-R antagonist (intra-DRN) and GABAA-R agonist (intra-mPFC) were co-administered with ketamine (intra-mPFC). Twenty-four hours later, responses in the forced swim test (FST) and neurochemical consequences on extracellular mPFC glutamate, GABA and 5-HT levels were measured in BALB/cJ mice. Intra-DRN NBQX prevented the sustained AD-like activity of ketamine evidenced by decreases in FST swimming duration and blunted cortical 5-HText and Gluext. Intra-mPFC muscimol blocked ketamine AD-like activity and its effects on cortical 5-HText. Moreover, a selective glutamate transporter GLT-1 inhibitor, dihydrokainic acid (DHK) locally perfused into the mPFC produced an AD-like activity at t24h associated with robust increases in mPFC 5-HText, Gluext and GABAext. Thus, the sustained AD-like activity of ketamine is triggered by AMPA-R activation in the DRN and 5-HT - glutamate release in the mPFC, but limited by GABAA-R activation - GABA release in the mPFC. The local blockade of GLT-1 in the mPFC also mimics the rapid responses of ketamine, thus highlighting the role of neuronal-glial adaptation in these effects. These results also suggests the need to test for the concomitant prescription of ketamine and BZD to see whether its sustained antidepressant activity is maintained in TRD patients.

scholarly journals Alpha-1 Adrenergic Receptors Modulate Glutamate and GABA Neurotransmission onto Ventral Tegmental Dopamine Neurons during Cocaine Sensitization

2020 ◽  
Vol 21 (3) ◽  
pp. 790 ◽  
Author(s):  
Maria Carolina Velasquez-Martinez ◽  
Bermary Santos-Vera ◽  
Maria E. Velez-Hernandez ◽  
Rafael Vazquez-Torres ◽  
Carlos A. Jimenez-Rivera
Keyword(s):  
Glutamate Release ◽  
Cell Voltage ◽  
Gaba Release ◽  
Dopamine Neurons ◽  
Gamma Aminobutyric Acid ◽  
Gabaergic Neurotransmission ◽  
Cocaine Administration ◽  
Ventral Tegmental ◽  
Gaba Neurotransmission

The ventral tegmental area (VTA) plays an important role in the reward and motivational processes that facilitate the development of drug addiction. Presynaptic α1-AR activation modulates glutamate and Gamma-aminobutyric acid (GABA) release. This work elucidates the role of VTA presynaptic α1-ARs and their modulation on glutamatergic and GABAergic neurotransmission during cocaine sensitization. Excitatory and inhibitory currents (EPSCs and IPSCs) measured by a whole cell voltage clamp show that α1-ARs activation increases EPSCs amplitude after 1 day of cocaine treatment but not after 5 days of cocaine injections. The absence of a pharmacological response to an α1-ARs agonist highlights the desensitization of the receptor after repeated cocaine administration. The desensitization of α1-ARs persists after a 7-day withdrawal period. In contrast, the modulation of α1-ARs on GABA neurotransmission, shown by decreases in IPSCs’ amplitude, is not affected by acute or chronic cocaine injections. Taken together, these data suggest that α1-ARs may enhance DA neuronal excitability after repeated cocaine administration through the reduction of GABA inhibition onto VTA dopamine (DA) neurons even in the absence of α1-ARs’ function on glutamate release and protein kinase C (PKC) activation. α1-AR modulatory changes in cocaine sensitization increase our knowledge of the role of the noradrenergic system in cocaine addiction and may provide possible avenues for therapeutics.

scholarly journals Expression mechanisms underlying long-term potentiation: a postsynaptic view

2003 ◽  
Vol 358 (1432) ◽  
pp. 721-726 ◽  
Author(s):  
Roger A. Nicoll
Keyword(s):  
Nmda Receptor ◽  
Ampa Receptors ◽  
Glutamate Release ◽  
Glutamate Transporter ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Covalent Modification ◽  
Term Potentiation ◽  
Expression Mechanism

This review summarizes the various experiments that have been carried out to determine if the expression of long-term potentiation (LTP), in particular N -methyl-D-aspartate (NMDA) receptor-dependent LTP, is presynaptic or postsynaptic. Evidence for a presynaptic expression mechanism comes primarily from experiments reporting that glutamate overflow is increased during LTP and from experiments showing that the failure rate decreases during LTP. However, other experimental approaches, such as monitoring synaptic glutamate release by recording astrocytic glutamate transporter currents, have failed to detect any change in glutamate release during LTP. In addition, the discovery of silent synapses, in which LTP rapidly switches on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function at NMDA-receptor-only synapses, provides a postsynaptic mechanism for the decrease in failures during LTP. It is argued that the preponderance of evidence favours a postsynaptic expression mechanism, whereby NMDA receptor activation results in the rapid recruitment of AMPA receptors as well as a covalent modification of synaptic AMPA receptors.

scholarly journals Energy state alters regulation of proopiomelanocortin neurons by glutamatergic ventromedial hypothalamus neurons: pre- and post-synaptic mechanisms

2021 ◽  
Author(s):  
Andrew R. Rau ◽  
Shane T Hentges
Keyword(s):  
Food Intake ◽  
Ampa Receptors ◽  
Energy State ◽  
Glutamate Release ◽  
Glutamate Transporter ◽  
Ventromedial Hypothalamus ◽  
Information Encoding ◽  
Glutamatergic Neurons ◽  
Conditional Deletion ◽  
Inhibit Food Intake

To maintain metabolic homeostasis, motivated behaviors are driven by neuronal circuits that process information encoding the animal's energy state. Such circuits likely include ventromedial hypothalamus (VMH) glutamatergic neurons that project throughout the brain to drive food intake and energy expenditure. Targets of VMH glutamatergic neurons include proopiomelanocortin (POMC) neurons in the arcuate nucleus which, when activated, inhibit food intake. While an energy-state-sensitive, glutamate circuit between the VMH and POMC neurons has been previously indicated, the significance and details of this circuit have not been fully elucidated. This, the goal of the present work was to add to the understanding of this circuit. Using a knockout strategy, the data show that the VMH glutamateàPOMC neuron circuit is important for the inhibition of food intake. Conditional deletion of the vesicular glutamate transporter (VGLUT2) in the VMH results in increased bodyweight and increased food intake following a fast in both male and female mice. Additionally, the targeted blunting of glutamate release from the VMH resulted in an approximately 32% reduction in excitatory inputs to POMC cells suggesting that this circuit may respond to changes in energy state to affect POMC activity. Indeed, we found that glutamate release is increased at VMH-to-POMC synapses during feeding and POMC AMPA receptors switch from a calcium-permeable state to a calcium-impermeable state during fasting. Collectively, these data indicate that there is an energy-balance-sensitive VMH-to-POMC circuit conveying excitatory neuromodulation onto POMC cells at both pre- and post-synaptic levels, that may contribute to maintaining appropriate food intake and body mass.

scholarly journals Infralimbic cortical glutamate output is necessary for the neural and behavioral consequences of chronic stress

2020 ◽  
Author(s):  
Sebastian A. Pace ◽  
Connor Christensen ◽  
Morgan K. Schackmuth ◽  
Tyler Wallace ◽  
Jessica M. McKlveen ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Forced Swim Test ◽  
Glutamate Release ◽  
Cortical Cell ◽  
Early Gene ◽  
Male Rats ◽  
Infralimbic Cortex ◽  
Passive Coping ◽  
Avoidance Behaviors

AbstractExposure to prolonged stress is a major risk-factor for psychiatric disorders such as generalized anxiety and major depressive disorder (MDD). Human imaging studies have identified structural and functional abnormalities in the prefrontal cortex of MDD patients, particularly Brodmann’s area 25 (BA25). Further, deep brain stimulation of BA25 reduces symptoms of treatment-resistant depression. The rat homolog of BA25 is the infralimbic cortex (IL), which is critical for cognitive appraisal, executive function, and physiological stress reactivity. Previous studies indicate that the IL undergoes stress-induced changes in excitatory/inhibitory balance culminating in reduced activity of glutamate output neurons. However, the regulatory role of IL glutamate output in mood-related behaviors after chronic variable stress (CVS) is unknown. Here, we utilized a lentiviral-packaged small-interfering RNA to reduce translation of vesicular glutamate transporter 1 (vGluT1 siRNA), thereby constraining IL glutamate output. This viral-mediated gene transfer was used in conjunction with a quantitative anatomical analysis of cells expressing the stable immediate-early gene product ΔFosB, which accumulates in response to repeated neural activation. Through assessment of ΔFosB-expressing neurons across the frontal lobe in adult male rats, we mapped regions altered by chronic stress and determined the coordinating role of the IL in frontal cortical plasticity. Specifically, CVS-exposed rats had increased density of ΔFosB-expressing cells in the IL and decreased density in the anterior insula. The latter effect was dependent on IL glutamate output. Next, we examined the interaction of CVS and reduced IL glutamate output in behavioral assays examining coping, anxiety-like behavior, associative learning, and nociception. IL glutamate knockdown decreased immobility during the forced swim test compared to GFP controls, both in rats exposed to CVS as well as rats without previous stress exposure. Further, vGluT1 siRNA prevented CVS-induced avoidance behaviors, while also reducing risk aversion and passive coping. Ultimately, this study identifies the necessity of IL glutamatergic output for regulating frontal cortical neural activity and behavior following chronic stress. These findings also highlight how disruption of excitatory/inhibitory balance within specific frontal cortical cell populations may impact neurobehavioral adaptation and lead to stress-related disorders.HighlightsChronic stress increased ΔFosB in the infralimbic cortex and decreased insular ΔFosBDecreased insular ΔFosB was dependent on infralimbic glutamate outputKnockdown of infralimbic glutamate release reduced passive copingAvoidance behaviors after chronic stress were dependent on infralimbic glutamateInfralimbic projections innervated excitatory and inhibitory neurons in the insula

scholarly journals Cortical and raphe GABAA, AMPA receptors and glial GLT-1 glutamate transporter contribute to the sustained antidepressant activity of ketamine

2020 ◽  
Vol 192 ◽  
pp. 172913 ◽  
Author(s):  
Thu Ha Pham ◽  
Céline Defaix ◽  
Thi Mai Loan Nguyen ◽  
Indira Mendez-David ◽  
Laurent Tritschler ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Glutamate Transporter ◽  
Antidepressant Activity

Role of spinal NMDA and AMPA receptors in episodic hypertension in conscious spinal rats

1997 ◽  
Vol 273 (3) ◽  
pp. H1266-H1274 ◽  
Author(s):  
D. N. Maiorov ◽  
N. R. Krenz ◽  
A. V. Krassioukov ◽  
L. C. Weaver
Keyword(s):  
Receptor Antagonist ◽  
Ampa Receptors ◽  
Nmda Receptor Antagonist ◽  
Glutamatergic Transmission ◽  
Testing Effects ◽  
Pressor Responses ◽  
Cord Injury ◽  
Colon Distension ◽  
Sympathetic Reflexes

The neurotransmitters mediating the spinal sympathetic reflexes that initiate episodic hypertension after spinal cord injury are unknown. We examined the role of glutamatergic transmission in these reflexes by testing effects of the N-methyl-D-aspartate (NMDA)-receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) and of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzoquinone (NBQX) on the reflex hypertension caused by colon distension. Antagonists were administered intrathecally in conscious rats 1-2 days (acute, n = 10) or 15-16 days (chronic, n = 14) after cord transection at the fifth thoracic segment under barbiturate anesthesia. AP-5 blocked pressor responses to intrathecal NMDA but had no effect on responses to AMPA; similarly, NBQX blocked responses to AMPA but had no effect on responses to NMDA. Before antagonist injection, colon distension increased mean arterial pressure by 24 +/- 1 mmHg (from 100 +/- 3 mmHg) and by 37 +/- 2 mmHg (from 116 +/- 3 mmHg) in the acute and chronic groups, respectively. Pretreatment with AP-5 attenuated the pressor responses by 36 and 37% in these respective groups; pretreatment with NBQX attenuated them by 34 and 31%. These data suggest that both NMDA and AMPA receptors contribute to spinal viscerosympathetic transmission and initiation of episodic hypertension in conscious spinal rats.

Evidence for the Involvement of Monoaminergic Pathways in the Antidepressant-Like Activity of Cymbopogon citratus in Mice

Drug Research ◽  
2017 ◽  
Vol 67 (07) ◽  
pp. 419-424 ◽  
Author(s):  
Solomon Umukoro ◽  
Somtochukwu Ogboh ◽  
Osarume Omorogbe ◽  
Abdul-lateef Adekeye ◽  
Matthew Olatunde
Keyword(s):  
Forced Swim Test ◽  
Antidepressant Activity ◽  
Tail Suspension Test ◽  
Lethal Effect ◽  
Cymbopogon Citratus ◽  
Significant Stimulation ◽  
Monoaminergic System ◽  
Noradrenergic Pathway ◽  
Serotonin Biosynthesis

Abstract Objectives Depression is a complex neuropsychiatric disorder, which affects the quality of life of the sufferers and treatment approach is associated with serious adverse effects and sometimes therapeutic failures. Cymbopogon citratus leaf (CC) has been reported to exert anti-depressant effect but its mechanism of action is yet to be elucidated hence, the need for this study. Methods The anti-depressant-like effect of Cymbopogon citratus aqueous leaf was evaluated using forced swim test (FST), tail suspension test (TST) and yohimbine-induced lethality test (YLT) in aggregated mice. Interaction studies involving p-chlorophenylalanine (pCPA), an inhibitor of serotonin biosynthesis and yohimbine, α2-adrenergic receptor antagonist were carried out to evaluate the role of monoaminergic system in the anti-depressant-like effect of CC. The effect of CC on spontaneous motor activity (SMA) was also assessed using activity cage. Results Cymbopogon citratus (25 and 50 mg/kg, p.o.) demonstrated antidepressant-like activity devoid of significant stimulation of the SMA in mice. However, the antidepressant-like property of CC was significantly (p<0.05) attenuated by pretreatment with yohimbine suggesting involvement of noradrenergic pathway in the action of the extract. Also, pCPA reversed the anti-immobility effect of CC, indicating the role of serotonergic system in the mediation of its antidepressant activity. Moreover, CC (25 and 50 mg/kg) potentiated the lethal effect of yohimbine in aggregated mice, which further suggest the involvement of monoaminergic systems in its action. Conclusions The results of the study showed that C. citratus might be interacting with serotonergic and noradrenergic pathways to mediate its anti-depressant-like effect in mice.

Sign in / Sign up

Export Citation Format

Share Document