scholarly journals Opioid withdrawal abruptly disrupts amygdala circuit function by reducing peptide actions

2021 ◽  
Author(s):  
Gabrielle C Gregoriou ◽  
Sahil D Patel ◽  
Sebastian Pyne ◽  
Bryony L Winters ◽  
Elena E Bagley
Keyword(s):  
Drug Use ◽  
Synaptic Transmission ◽  
Basolateral Amygdala ◽  
Glutamate Release ◽  
Brain Slices ◽  
Opioid Withdrawal ◽  
Endogenous Opioids ◽  
Endogenous Opioid ◽  
Patch Clamp Electrophysiology ◽  
Dependent Learning

Opioid withdrawal drives relapse and contributes to compulsive drug use through disruption of endogenous opioid dependent learning circuits in the amygdala. Normally, endogenous opioids control these circuits by inhibiting glutamate release from basolateral amygdala principal neurons onto GABAergic intercalated cells. Using patch-clamp electrophysiology in rat brain slices, we reveal that opioid withdrawal dials down this endogenous opioid inhibition of synaptic transmission. Peptide activity is dialled down due to a protein kinase A dependent increase in the activity of the peptidase, neprilysin. This disrupts peptidergic control of both GABAergic and glutamatergic transmission through multiple amygdala circuits, including reward-related outputs to the nucleus accumbens. This likely disrupts peptide-dependent learning processes in the amygdala during withdrawal. and may direct behaviour towards compulsive drug use. Restoration of endogenous peptide activity during withdrawal may be a viable option to normalise synaptic transmission in the amygdala and restore normal reward learning.

Glutamatergic Synaptic Plasticity in the Periaqueductal Gray Governs Fear-induced Depression-like Behavior in Rats

2017 ◽  
Vol 41 (S1) ◽  
pp. S633-S633 ◽  
Author(s):  
Y.C. Ho ◽  
M.C. Hsieh ◽  
C.Y. Lai ◽  
H.Y. Peng
Keyword(s):  
Synaptic Transmission ◽  
Learned Helplessness ◽  
Depressive Disorders ◽  
Glutamate Release ◽  
Brain Slices ◽  
Periaqueductal Gray ◽  
Control Group ◽  
Patch Clamp Recording ◽  
Whole Cell Patch Clamp ◽  
Competing Interest

IntroductionMajor depressive disorder affecting more than 110 million people worldwide every year is a heterogeneous illness influenced by a variety of factors, including repeated stressful factors. Despite widely research during the past several decades, the pathophysiology and neurobiological mechanisms of depressive disorders remain unclear. Ventrolateral periaqueductal gray (vlPAG), a midbrain nucleus, has been considered as an important part of the circuitry that involves in stress-induced depression-like behaviors. Dysregulation of glutamatergic neurotransmission in depressed patients suggests that glutamate-mediated excitatory system is critical involved in the depressive disorders.ObjectivesIt is still unclear that whether vlPAG involves in fear condition-elicited depression-like behavior.AimsWe investigated the synaptic transmission in the vlPAG to examine whether vlPAG participates in fear-induced depression-like behavior in rats.MethodsDepression-like behaviors, in the rats, were induced by learned helplessness procedure. The synaptic transmission was conducted by whole-cell patch-clamp recording in the rat brain slices containing periaqueductal gray.ResultsRats receiving learned helplessness procedure displayed high failure rate in the escapable foot-shock test compared to control group. Both amplitude and frequency of miniature excitatory postsynaptic currents were significant reduced compared to control group, suggesting reduced presynaptic glutamate release and postsynaptic responses were involved in the learned helplessness procedure-induced depression behavior in rats.ConclusionsReduced glutamatergic transmission in the vlPAG contributes to learned helplessness procedure-induced depression-like behavior in rats through pre – and post-synaptic mechanisms.Disclosure of interestThe authors have not supplied their declaration of competing interest.

CB1 Cannabinoid Receptor Inhibits Synaptic Release of Glutamate in Rat Dorsolateral Striatum

2001 ◽  
Vol 85 (1) ◽  
pp. 468-471 ◽  
Author(s):  
Gregory Gerdeman ◽  
David M. Lovinger
Keyword(s):  
Basal Ganglia ◽  
Synaptic Transmission ◽  
Neurotransmitter Release ◽  
Cannabinoid Receptors ◽  
Glutamate Release ◽  
Brain Slices ◽  
Cb1 Receptor ◽  
Motor Deficits ◽  
Dependent Manner ◽  
Dorsolateral Striatum

CB1 cannabinoid receptors in the neostriatum mediate profound motor deficits induced when cannabinoid drugs are administered to rodents. Because the CB1 receptor has been shown to inhibit neurotransmitter release in various brain areas, we investigated the effects of CB1 activation on glutamatergic synaptic transmission in the dorsolateral striatum of the rat where the CB1 receptor is highly expressed. We performed whole cell voltage-clamp experiments in striatal brain slices and applied the CB1 agonists HU-210 or WIN 55,212–2 during measurement of synaptic transmission. Excitatory postsynaptic currents (EPSCs), evoked by electrical stimulation of afferent fibers, were significantly reduced in a dose-dependent manner by CB1 agonist application. EPSC inhibition was accompanied by an increase in two separate indices of presynaptic release, the paired-pulse response ratio and the coefficient of variation, suggesting a decrease in neurotransmitter release. These effects were prevented by application of the CB1 antagonist SR141716A. When Sr2+ was substituted for Ca2+ in the extracellular solution, application of HU-210 (1 μM) significantly reduced the frequency, but not amplitude, of evoked, asynchronous quantal release events. Spontaneous release events were similarly decreased in frequency with no change in amplitude. These findings further support the interpretation that CB1 activation leads to a decrease of glutamate release from afferent terminals in the striatum. These results reveal a novel potential role for cannabinoids in regulating striatal function and thus basal ganglia output and may suggest CB1-targeted drugs as potential therapeutic agents in the treatment of Parkinson's disease and other basal ganglia disorders.

scholarly journals Presynaptic and Postsynaptic NMDA Receptors Mediate Distinct Effects of Brain-Derived Neurotrophic Factor on Synaptic Transmission

2008 ◽  
Vol 100 (6) ◽  
pp. 3175-3184 ◽  
Author(s):  
Joseph C. Madara ◽  
Eric S. Levine
Keyword(s):  
Synaptic Transmission ◽  
Nmda Receptors ◽  
Neurotrophic Factor ◽  
Developmental Plasticity ◽  
Granule Cells ◽  
Slow Component ◽  
Glutamate Release ◽  
Brain Slices ◽  
Brain Derived Neurotrophic Factor ◽  
Cellular Mechanisms

In addition to its effects on neuronal survival and differentiation, brain-derived neurotrophic factor (BDNF) plays an important role in modulating synaptic transmission and plasticity in many brain areas, most notably the neocortex and hippocampus. These effects may underlie a role for BDNF in learning and memory as well as developmental plasticity. Consistent with localization of the tropomyosin-related kinase B receptor to both sides of the synapse, BDNF appears to have pre- and postsynaptic effects, but the underlying cellular mechanisms are unclear and it is not known whether pre- and postsynaptic modulations by BDNF occur simultaneously. To address these issues, we recorded dual-component (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and N-methyl-d-aspartate [NMDA]) miniature excitatory postsynaptic currents (mEPSCs) from cortical and hippocampal pyramidal neurons and dentate gyrus granule cells from acute brain slices. BDNF had no effect on the fast component of mEPSC decay or on the peak amplitude, suggesting that BDNF did not modulate postsynaptic AMPA receptors, although BDNF rapidly modulated NMDA receptors, as seen by an enhancement of the slow component of mEPSC decay that was prevented by blocking postsynaptic NMDA receptors. At the same time, BDNF acted presynaptically to enhance mEPSC frequency. Surprisingly, the effect on frequency was also NMDA receptor dependent, but required activation of presynaptic, not postsynaptic, NMDA receptors. BDNF also enhanced action potential–dependent glutamate release via presynaptic NMDA receptors, an effect that was unmasked when voltage-gated calcium channels were partially inhibited. Our results indicate that BDNF acutely modulates presynaptic release and postsynaptic responsiveness through simultaneous effects on pre- and postsynaptic NMDA receptors.

Modulation of Synaptic Transmission in the Rat Nucleus of the Solitary Tract by Endomorphin-1

2005 ◽  
Vol 93 (5) ◽  
pp. 2530-2540 ◽  
Author(s):  
Nicholas R. Glatzer ◽  
Bret N. Smith
Keyword(s):  
Synaptic Transmission ◽  
Opioid Receptors ◽  
Nucleus Tractus Solitarius ◽  
Integration Site ◽  
Brain Slices ◽  
Inhibitory Neurons ◽  
Solitary Tract ◽  
Endogenous Opioid ◽  
Opioid Agonist ◽  
Postsynaptic Currents

Activation of opioid receptors in the periphery and centrally in the brain results in inhibition of gastric and other vagally mediated functions. The aim of this study was to examine the role of the endogenous opioid agonist endomorphin 1 (EM-1) in regulating synaptic transmission within the nucleus tractus solitarius (NTS), an integration site for autonomic functions. We performed whole cell patch-clamp recordings from coronal brain slices of the rat medulla. A subset of the neurons studied was prelabeled with a stomach injection of the transsynaptic retrograde virus expressing EGFP, PRV-152. Solitary tract stimulation resulted in constant latency excitatory postsynaptic currents (EPSCs) that were decreased in amplitude by EM-1 (0.01–10 μM). The paired-pulse ratio was increased with little change in input resistance, suggesting a presynaptic mechanism. Spontaneous EPSCs were decreased in both frequency and amplitude by EM-1, and miniature EPSCs were reduced in frequency but not amplitude, suggesting a presynaptic mechanism for the effect. Spontaneous inhibitory postsynaptic currents (IPSCs) were also reduced in frequency by EM-1, but the effect was blocked by TTX, suggesting activity at receptors on the somata of local inhibitory neurons. Synaptic input arising from local NTS neurons, which were activated by focal photolysis of caged glutamate, was inhibited by EM-1. The actions of EM-1 were similar to those of d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) and were blocked by naltrexone, d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), or d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP). These results suggest that EM-1 acts at μ-opioid receptors to modulate viscerosensory input and specific components of local synaptic circuitry in the NTS.

Direct Actions of Cannabinoids on Synaptic Transmission in the Nucleus Accumbens: A Comparison With Opioids

2001 ◽  
Vol 85 (1) ◽  
pp. 72-83 ◽  
Author(s):  
Alexander F. Hoffman ◽  
Carl R. Lupica
Keyword(s):  
Nucleus Accumbens ◽  
Synaptic Transmission ◽  
Drugs Of Abuse ◽  
Glutamate Release ◽  
Brain Slices ◽  
Resting Membrane Potential ◽  
Projection Neurons ◽  
Whole Cell ◽  
Postsynaptic Currents ◽  
Abused Drugs

The nucleus accumbens (NAc) represents a critical site for the rewarding and addictive properties of several classes of abused drugs. The medium spiny GABAergic projection neurons (MSNs) in the NAc receive innervation from intrinsic GABAergic interneurons and glutamatergic innervation from extrinsic sources. Both GABA and glutamate release onto MSNs are inhibited by drugs of abuse, suggesting that this action may contribute to their rewarding properties. To investigate the actions of cannabinoids in the NAc, we performed whole cell recordings from MSNs located in the shell region in rat brain slices. The cannabinoid agonist WIN 55,212-2 (1 μM) had no effect on the resting membrane potential, input resistance, or whole cell conductance, suggesting no direct postsynaptic effects. Evoked glutamatergic excitatory postsynaptic currents (EPSCs) were inhibited to a much greater extent by [Tyr-d-Ala2, N-CH3-Phe4, Gly-ol-enkephalin] (DAMGO, ∼35%) than by WIN 55,212-2 (<20%), and an analysis of miniature EPSCs suggested that the effects of DAMGO were presynaptic, whereas those of WIN 55,212-2 were postsynaptic. However, electrically evoked GABAergic inhibitory postsynaptic currents (evIPSCs), were reduced by WIN 55,212-2 in every neuron tested (EC50 = 123 nM; 60% maximal inhibition), and the inhibition of IPSCs by WIN 55,212-2 was completely antagonized by the CB1 receptor antagonist SR141716A (1 μM). In contrast evIPSCs were inhibited in ∼50% of MSNs by the μ/δ opioid agonistd-Ala2-methionine2-enkephalinamide and were completely unaffected by a selective μ-opioid receptor agonist (DAMGO). WIN 55,212-2 also increased paired-pulse facilitation of the evIPSCs and did not alter the amplitudes of tetrodotoxin-resistant miniature IPSCs, suggesting a presynaptic action. Taken together, these data suggest that cannabinoids and opioids differentially modulate inhibitory and excitatory synaptic transmission in the NAc and that the abuse liability of marijuana may be related to the direct actions of cannabinoids in this structure.

scholarly journals GPI-1046 Increases Presenilin-1 Expression and Restores NMDA Channel Activity

2010 ◽  
Vol 37 (4) ◽  
pp. 457-467 ◽  
Author(s):  
Joseph P. Steiner ◽  
Kathryn B. Payne ◽  
Christopher Drummond Main ◽  
Sabrina D'Alfonso ◽  
Kirsten X. Jacobsen ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Synaptic Transmission ◽  
Brain Slices ◽  
Synaptic Activity ◽  
Presenilin 1 ◽  
Receptor Function ◽  
Channel Function ◽  
Nmda Channel ◽  
Nmda Receptor Function ◽  
6 Hydroxydopamine

Background:Previously we showed that 6-hydroxydopamine lesions of the substantia nigra eliminate corticostriatal LTP and that the neuroimmunolophilin ligand (NIL), GPI-1046, restores LTP.Methods:We used cDNA microarrays to determine what mRNAs may be over- or under-expressed in response to lesioning and/or GPI-1046 treatment. Patch clamp recordings were performed to investigate changes in NMDA channel function before and after treatments.Results:We found that 51 gene products were differentially expressed. Among these we found that GPI-1046 treatment up-regulated presenilin-1 (PS-1) mRNA abundance. This finding was confirmed using QPCR. PS-1 protein was also shown to be over-expressed in the striatum of lesioned/GPI-1046-treated rats. As PS-1 has been implicated in controlling NMDA-receptor function and LTP is reduced by lesioning we assayed NMDA mediated synaptic activity in striatal brain slices. The lesion-induced reduction of dopaminergic innervation was accompanied by the near complete loss of NDMA receptor-mediated synaptic transmission between the cortex and striatum. GPI-1046 treatment of the lesioned rats restored NMDA-mediated synaptic transmission but not the dopaminergic innervation. Restoration of NDMA channel function was apparently specific as the sodium channel current density was also reduced due to lesioning but GPI-1046 did not reverse this effect. We also found that restoration of NMDA receptor function was also not associated with either an increase in NMDA receptor mRNA or protein expression.Conclusion:As it has been previously shown that PS-1 is critical for normal NMDA receptor function, our data suggest that the improvement of excitatory neurotransmission occurs through the GPI-1046-induced up-regulation of PS-1.

Activation of Presynaptic Group III Metabotropic Receptors Enhances Glutamate Release in Rat Entorhinal Cortex

2000 ◽  
Vol 83 (5) ◽  
pp. 2519-2525 ◽  
Author(s):  
D. Ieuan Evans ◽  
Roland S. G. Jones ◽  
Gavin Woodhall
Keyword(s):  
Synaptic Transmission ◽  
Entorhinal Cortex ◽  
Metabotropic Glutamate Receptors ◽  
Glutamate Release ◽  
Facilitatory Effect ◽  
Metabotropic Receptors ◽  
Patch Clamp Technique ◽  
Group Iii ◽  
Bath Application ◽  
Layer V

The role of group III metabotropic glutamate receptors (mGluRs) in modulating excitatory synaptic transmission was investigated in the rat entorhinal cortex (EC) in vitro. AMPA receptor-mediated excitatory postsynaptic currents (EPSCs) were recorded in the whole cell configuration of the patch-clamp technique from visually identified neurons in layers V and II. In layer V, bath application of the specific group III mGluR agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4, 500 μM) resulted in a marked facilitation of both spontaneous and activity-independent “miniature” (s/mEPSC) event frequency. The facilitatory effect of L-AP4 (100 μM) on sEPSC frequency prevailed in the presence ofdl−2-amino-5-phosphonopentanoic acid (100 μM) but was abolished by the group III antagonist (RS)-cyclopropyl-4-phosphonophenylglycine (20 μM). These data confirmed that group III mGluRs, and not N-methyl-d-aspartate (NMDA) receptors were involved in the response to L-AP4. Bath application of the specific mGluR4a agonist (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid (20 μM) also had a facilitatory effect on sEPSC frequency, suggesting involvement of mGluR4a. In layer II neurons, L-AP4 caused a reduction in sEPSC frequency but did not affect mEPSCs recorded in the presence of tetrodotoxin. These findings suggest that a group III mGluR with mGluR4a-like pharmacology is involved in modulating synaptic transmission in layer V cells of the EC. The effect on mEPSCs suggests that this receptor is located presynaptically and that its activation results in a direct facilitation of glutamate release. This novel facilitatory effect is specific to layer V and, to our knowledge, is the first report of a direct facilitatory action of group III mGluRs on synaptic transmission. In layer II, L-AP4 had an inhibitory effect on glutamate release similar to that reported in other brain regions.

Presynaptic Modulation of Synaptic Transmission by Pregnenolone Sulfate as Studied by Optical Recordings

2005 ◽  
Vol 94 (6) ◽  
pp. 4131-4144 ◽  
Author(s):  
Ling Chen ◽  
Masahiro Sokabe
Keyword(s):  
Synaptic Transmission ◽  
Glutamate Release ◽  
Hippocampal Slices ◽  
Receptor Activation ◽  
Optical Recording ◽  
Perforant Path ◽  
Dependent Manner ◽  
Pregnenolone Sulfate ◽  
Voltage Sensitive Dyes ◽  
Dose Dependent

The effects of pregnenolone sulfate (PREGS), a putative neurosteroid, on the transmission of perforant path–granule cell synapses were investigated with an optical recording technique in rat hippocampal slices stained with voltage-sensitive dyes. Application of PREGS to the bath solution resulted in an acute augmentation of EPSP in a dose-dependent manner. The PREGS effect was dependent on the extracellular Ca2+ concentration ([Ca2+]o), but independent of NMDA receptor activation. PREGS caused a decrease in paired-pulse facilitation, which implies that PREGS positively modulates presynaptic neurotransmitter releases. Firmer support for this mechanism was that PREGS augmented the synaptically induced glial depolarization (SIGD) that reflects the activity of electrogenic glutamate transporters in glial cells during the uptake of released glutamate. The selective α7nAChR antagonist α-BGT or MLA prevented the SIGD increase by PREGS. Furthermore DMXB, a selective α7nAChR agonist, mimicked the PREGS effect on SIGD and antagonized the effect of PREGS. The presynaptic effect of PREGS was partially attenuated by the L-type Ca2+ channel (VGCC) blocker nifedipine. Based on these findings, we proposed a novel mechanism underlying the facilitated synaptic transmission by PREGS: this neurosteroid sensitizes presynaptic α7nAChR that is followed by an activation of L-type VGCC to increase the presynaptic glutamate release.

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