Activation of NMDA receptors is required for the initiation and maintenance of walking-like activity in the mudpuppy (Necturus Maculatus)

2004 ◽  
Vol 82 (8-9) ◽  
pp. 637-644 ◽  
Author(s):  
Igor Lavrov ◽  
Jianguo Cheng
Keyword(s):  
Spinal Cord ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Rhythmic Activity ◽  
Nmda Receptor Antagonist ◽  
Glycine Site ◽  
Burst Frequency ◽  
Selective Antagonist ◽  
Dependent Inhibition ◽  
Dose Dependent

We hypothesized that blocking the activation of N-methyl-D-aspartate (NMDA) receptors prevents the initiation of walking-like activity and abolishes the ongoing rhythmic activity in the spinal cord - forelimb preparation from the mudpuppy. Robust walking-like movements of the limb and rhythmic alternating elbow flexor–extensor EMG pattern characteristic of walking were elicited when continuous perfusion of the spinal cord with solution containing D-glutamate. The frequency of the walking-like activity was dose-dependent on the concentration of D-glutamate in the bath over a range of 0.2 to 0.9 mmol/L. Elevation of potassium concentrations failed to induce walking-like activity. Application of the selective antagonist 2-amino-5-phosphonovalerate (AP-5) produced dose-dependent block of the initiation and maintenance of walking-like activity induced by D-glutamate. Complete block of the activity was achieved when the concentration of AP-5 reached 20 µmol/L. Furthermore, application of L-701,324 (a selective antagonist of the strychnine-insensitive glycine site of NMDA receptor) (1–10 µmol/L) also resulted in complete block of the walking-like activity. In contrast, application of the non-NMDA receptor antagonist 6-cyno-7-nitroquinoxaline-2,3-dione (CNQX) (1–50 µmol/L) induced a dose-dependent inhibition of the burst frequency but failed to result in a complete block. Only at concentration as high as 100 µmol/L, did CNQX cause complete block of the rhythmic activity, presumably through nonspecific action on the strychnine-insensitive glycine site of NMDA receptors. These results suggest that activation of NMDA receptors is required for the initiation and maintenance of walking-like activity. Operation of non-NMDA receptors plays a powerful role in the modulation of the walking-like activity in the mudpuppy.Key words: locomotion, central pattern generator, spinal cord, mudpuppy, glutamate, glycine, N-methyl-D-aspartate (NMDA)-receptor, 2-amino-5-phosphonovalerate (AP-5), 6-cyno-7-nitroquinoxaline-2,3-dione (CNQX).

scholarly journals Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors

2011 ◽  
Vol 301 (2) ◽  
pp. R448-R455 ◽  
Author(s):  
Jason Wright ◽  
Carlos Campos ◽  
Thiebaut Herzog ◽  
Mihai Covasa ◽  
Krzysztof Czaja ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Food Intake ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Fourth Ventricle ◽  
Nmda Receptor Antagonist ◽  
Behavioral Pattern ◽  
Vagal Afferents ◽  
Nmda Receptor Antagonists ◽  
The Brain

Intraperitoneal injection of CCK reduces food intake and triggers a behavioral pattern similar to natural satiation. Reduction of food intake by CCK is mediated by vagal afferents that innervate the stomach and small intestine. These afferents synapse in the hindbrain nucleus of the solitary tract (NTS) where gastrointestinal satiation signals are processed. Previously, we demonstrated that intraperitoneal (IP) administration of either competitive or noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists attenuates reduction of food intake by CCK. However, because vagal afferents themselves express NMDA receptors at both central and peripheral endings, our results did not speak to the question of whether NMDA receptors in the brain play an essential role in reduction of feeding by CCK. We hypothesized that activation of NMDA receptors in the NTS is necessary for reduction of food intake by CCK. To test this hypothesis, we measured food intake following IP CCK, subsequent to NMDA receptor antagonist injections into the fourth ventricle, directly into the NTS or subcutaneously. We found that either fourth-ventricle or NTS injection of the noncompetitive NMDA receptor antagonist MK-801 was sufficient to inhibit CCK-induced reduction of feeding, while the same antagonist doses injected subcutaneously did not. Similarly fourth ventricle injection of d-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (d-CPPene), a competitive NMDA receptor antagonist, also blocked reduction of food intake following IP CCK. Finally, d-CPPene injected into the fourth ventricle attenuated CCK-induced expression of nuclear c-Fos immunoreactivity in the dorsal vagal complex. We conclude that activation of NMDA receptors in the hindbrain is necessary for the reduction of food intake by CCK. Hindbrain NMDA receptors could comprise a critical avenue for control and modulation of satiation signals to influence food intake and energy balance.

NMDA receptor blockade in cat dorsal horn blunts reflex pressor response to muscle contraction and stretch

1996 ◽  
Vol 270 (2) ◽  
pp. H500-H508 ◽  
Author(s):  
G. A. Hand ◽  
A. F. Meintjes ◽  
A. W. Keister ◽  
A. Ally ◽  
L. B. Wilson
Keyword(s):  
Nmda Receptor ◽  
Muscle Contraction ◽  
Nmda Receptors ◽  
Dorsal Horn ◽  
Pressor Response ◽  
Cardiovascular Responses ◽  
Nmda Receptor Antagonist ◽  
Muscle Afferents ◽  
The Central Nervous System ◽  
Passive Stretch

The role of N-methyl-D-aspartate (NMDA) receptors in the reflex pressor response to static muscle contraction and passive stretch was examined by microdialyzing the NMDA receptor antagonist DL-2-amino-5-phosphonovalerate (AP-5) into the L7 or L6 and S1 levels of the dorsal horn of anesthetized cats. Contraction, elicited by electrical stimulation of the cut L7 and S1 ventral roots, increased mean arterial pressure (MAP) and heart rate (HR). Passive stretch at tensions similar to those generated by contraction also increased these variables. These cardiovascular changes were unaffected by dialyzing AP-5 (10 mM) into the dorsal horn at L7. Increasing the syringe concentration of AP-5 to 100 mM attenuated the pressor and HR responses from 62 +/- 8 to 31 +/- 6 mmHg and 18 +/- 4 to 12 +/- 4 beats/min, respectively. AP-5 blunted the increase in MAP (59 +/- 10 vs. 41 +/- 10 mmHg) evoked by muscle stretch. Simultaneously microdialyzing AP-5 (10 or 100 mM) into the dorsal horn at the L6 and S1 spinal levels also blunted the MAP and HR responses to contraction and stretch. These results suggest that NMDA receptors play a role in mediating the MAP and HR responses to static muscle contraction at the spinal level of the central nervous system. Furthermore, these data demonstrate that collaterals from muscle afferents partially mediate the reflex cardiovascular responses evoked by muscle contraction and stretch.

NMDA Receptor-Dependent Periodic Oscillations in Cultured Spinal Cord Networks

2001 ◽  
Vol 86 (6) ◽  
pp. 3030-3042 ◽  
Author(s):  
Edward W. Keefer ◽  
Alexandra Gramowski ◽  
Guenter W. Gross
Keyword(s):  
Spinal Cord ◽  
Nmda Receptor ◽  
Rhythmic Activity ◽  
Network Size ◽  
Observation Time ◽  
Network Activity ◽  
Early Postnatal Development ◽  
Bath Application ◽  
Coefficients Of Variation ◽  
Burst Patterns

Cultured spinal cord networks grown on microelectrode arrays display complex patterns of spontaneous burst and spike activity. During disinhibition with bicuculline and strychnine, synchronized burst patterns routinely emerge. However, the variability of both intra- and interculture burst periods and durations are typically large under these conditions. As a further step in simplification of synaptic interactions, we blocked excitatory AMPA synapses with 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzoquinoxaline-7-sulphonamide (NBQX), resulting in network activity mediated through the N-methyl-d-aspartate (NMDA) receptor (NMDAONLY). This activity was APV sensitive. The oscillation under NMDAONLY conditions at 37°C was characterized by a period of 2.9 ± 0.3 s (16 separate cultures). More than 98% of all neurons recorded participated in this highly rhythmic activity. The temporal coefficients of variation, reflecting the rhythmic nature of the oscillation, were 3.7, 4.7, and 4.9% for burst rate, burst duration, and interburst interval, respectively [mean coefficients of variation (CVs) for 16 cultures]. The oscillation persisted for at least 12 h without change (maximum observation time). Once established, it was not perturbed by agents that block mGlu receptors, GABABreceptors, cholinergic receptors, purinergic receptors, tachykinin receptors, serotonin (5-HT) receptors, dopamine receptors, electrical synapses, burst afterhyperpolarization, NMDA receptor desensitization, or the hyperpolarization-activated current. However, the oscillation was destroyed by bath application of NMDA (20–50 μM). These results suggest a presynaptic mechanism underlying this periodic rhythm that is solely dependent on the NMDA synapse. When the AMPA/kainate synapse was the sole driving force ( n = 6), the resulting burst patterns showed much higher variability and did not develop the highly periodic, synchronized nature of the NMDAONLYactivity. Network size or age did not appear to influence the reliability of expression of the NMDAONLYactivity pattern. For this reason, we suggest that the NMDAONLY condition unmasks a fundamental rhythmogenic mechanism of possible functional importance during periods of NMDA receptor-dominated activity, such as embryonic and early postnatal development.

Role of the medullary lateral tegmental field in reflex-mediated sympathoexcitation in cats

2004 ◽  
Vol 286 (3) ◽  
pp. R451-R464 ◽  
Author(s):  
Hakan S. Orer ◽  
Gerard L. Gebber ◽  
Shaun W. Phillips ◽  
Susan M. Barman
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Sympathetic Nerve Activity ◽  
Nmda Receptor Antagonist ◽  
Vagal Afferents ◽  
Reflex Pathways ◽  
Excitatory Responses ◽  
Stimulation Of

We tested the hypothesis that blockade of N-methyl-d-aspartate (NMDA) and non-NMDA receptors on medullary lateral tegmental field (LTF) neurons would reduce the sympathoexcitatory responses elicited by electrical stimulation of vagal, trigeminal, and sciatic afferents, posterior hypothalamus, and midbrain periaqueductal gray as well as by activation of arterial chemoreceptors with intravenous NaCN. Bilateral microinjection of a non-NMDA receptor antagonist into LTF of urethane-anesthetized cats significantly decreased vagal afferent-evoked excitatory responses in inferior cardiac and vertebral nerves to 29 ± 8 and 24 ± 6% of control ( n = 7), respectively. Likewise, blockade of non-NMDA receptors significantly reduced chemoreceptor reflex-induced increases in inferior cardiac (from 210 ± 22 to 129 ± 13% of control; n = 4) and vertebral nerves (from 253 ± 41 to 154 ± 20% of control; n = 7) and mean arterial pressure (from 39 ± 7 to 21 ± 5 mmHg; n = 8). Microinjection of muscimol, but not an NMDA receptor antagonist, caused similar attenuation of these excitatory responses. Sympathoexcitatory responses to the other stimuli were not attenuated by microinjection of a non-NMDA receptor antagonist or muscimol into LTF. In fact, excitatory responses elicited by stimulation of trigeminal, and in some cases sciatic, afferents were enhanced. These data reveal two new roles for the LTF in control of sympathetic nerve activity in cats. One, LTF neurons are involved in mediating sympathoexcitation elicited by activation of vagal afferents and arterial chemoreceptors, primarily via activation of non-NMDA receptors. Two, non-NMDA receptor-mediated activation of other LTF neurons tonically suppresses transmission in trigeminal-sympathetic and sciatic-sympathetic reflex pathways.

Interaction of Dopamine D1 and NMDA Receptors Mediates Acute Clozapine Potentiation of Glutamate EPSPs in Rat Prefrontal Cortex

2002 ◽  
Vol 87 (5) ◽  
pp. 2324-2336 ◽  
Author(s):  
Long Chen ◽  
Charles R. Yang
Keyword(s):  
Prefrontal Cortex ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Ampa Receptors ◽  
Nmda Receptor Antagonist ◽  
D1 Receptor ◽  
Resting Membrane Potential ◽  
Cellular Mechanisms ◽  
Cognitive Improvement

The atypical antipsychotic drug clozapine effectively alleviates both negative and positive symptoms of schizophrenia via unclear cellular mechanisms. Clozapine may modulate both glutamatergic and dopaminergic transmission in the prefrontal cortex (PFC) to achieve part of its therapeutic actions. Using whole cell patch-clamp techniques, current-clamp recordings in layers V–VI pyramidal neurons from rat PFC slices showed that stimulation of local afferents (in 2 μM bicuculline) evoked mixed [AMPA/kainate and N-methyl-d-aspartate (NMDA) receptors] glutamate receptor-mediated excitatory postsynaptic potentials (EPSPs). Clozapine (1 μM) potentiated polysynaptically mediated evoked EPSPs ( V Hold = −65 mV), or reversed EPSPs (rEPSP, V Hold = +20 mV) for >30 min. The potentiated EPSPs or rEPSPs were attenuated by elevating [Ca2+]O(7 mM), by application of NMDA receptor antagonist 2-amino5-phosphonovaleric acid (50 μM), or by pretreatment with dopamine D1/D5 receptor antagonist SCH23390 (1 μM) but could be further enhanced by a dopamine reuptake inhibitor bupropion (1 μM). Clozapine had no significant effect on pharmacologically isolated evoked NMDA-rEPSP or AMPA-rEPSPs but increased spontaneous EPSPs without changing the steady-state resting membrane potential. Under voltage clamp, clozapine (1 μM) enhanced the frequency, and the number of low-amplitude (5–10 pA) AMPA receptor-mediated spontaneous EPSCs, while there was no such changes with the mini-EPSCs (in 1 μM TTX). Taken together these data suggest that acute clozapine can increase spike-dependent presynaptic release of glutamate and dopamine. The glutamate stimulates distal dendritic AMPA receptors to increase spontaneous EPSCs and enabled a voltage-dependent activation of neuronal NMDA receptors. The dopamine released stimulates postsynaptic D1 receptor to modulate a lasting potentiation of the NMDA receptor component of the glutamatergic synaptic responses in the PFC neuronal network. This sequence of early synaptic events induced by acute clozapine may comprise part of the activity that leads to later cognitive improvement in schizophrenia.

Neural Pathways Between Sacrocaudal Afferents and Lumbar Pattern Generators in Neonatal Rats

2003 ◽  
Vol 89 (2) ◽  
pp. 773-784 ◽  
Author(s):  
I. Strauss ◽  
A. Lev-Tov
Keyword(s):  
Spinal Cord ◽  
Nmda Receptors ◽  
Neural Control ◽  
Nmda Receptor Antagonist ◽  
Neural Pathways ◽  
Synaptic Activation ◽  
Neonatal Rats ◽  
Artificial Cerebrospinal Fluid ◽  
Pattern Generators ◽  
Lumbar Cord

Projections of sacrocaudal afferents (SCA) onto lumbar pattern generators were studied in isolated spinal cords of neonatal rats. A locomotor-like pattern could be produced by SCA stimulation in the majority of the preparations. The SCA-induced lumbar rhythm was abolished after blocking synaptic transmission in the sacrococcygeal (SC) cord by bathing its segments in a low-calcium, high-magnesium artificial cerebrospinal fluid and restored when the synaptic block was alleviated by local application of calcium onto specific SC segments prior to SCA stimulation. Thus the SCA evoked lumbar rhythm involves synaptic activation of relay neurons in the SC cord. Functional activation of these relays depends on non– N-methyl-d-aspartate (NMDA) receptors because the lumbar rhythm was abolished when the non-NMDA receptor antagonist CNQX was added to the SC cord. By contrast, pharmacological block of the rhythmicity in the SC cord by specific antagonists of NMDA receptors and α1 and α2 adrenoceptors did not impair the SCA-induced lumbar rhythm. Midsagittal splitting experiments of parts of the SC and lumbar cord revealed that crossed and uncrossed ascending/propriospinal pathways are coactivated by SCA stimulation. We suggest that these pathways ascend onto the thoracolumbar cord through the lateral, ventrolateral, and ventral funiculi, because a complete block of the lumbar rhythm could only be obtained with a bilateral interruption of all of these funiculi. The relevance of our findings to the neural control of the rhythmogenic networks in the spinal cord is discussed.

Cholinergic modulation of the swimmeret motor system in crayfish

1993 ◽  
Vol 70 (6) ◽  
pp. 2391-2398 ◽  
Author(s):  
G. Braun ◽  
B. Mulloney
Keyword(s):  
Motor System ◽  
Motor Pattern ◽  
Rhythmic Activity ◽  
Muscarinic Agonist ◽  
Dependent Manner ◽  
Burst Frequency ◽  
Cholinergic Agonists ◽  
Cholinergic Interneurons ◽  
Dose Dependent ◽  
Esterase Inhibitor

1. The muscarinic agonist pilocarpine induced the swimmeret motor pattern in resting isolated preparations of the crayfish abdominal nerve cord and modulated the burst frequency in a dose-dependent manner. 2. Nicotine did not elicit rhythmic activity in resting isolated preparations but increased the burst frequency in active preparations. Nicotine produced higher burst frequencies than pilocarpine. 3. The acetylcholine (ACh) analogue carbachol combined the effects of pilocarpine and nicotine. It activated isolated resting preparations and increased the burst frequency as effectively as nicotine. The ACh-esterase inhibitor eserine also increased the burst frequency in active preparations. 4. Neither muscarinic nor nicotinic antagonists disrupted the proctolin-induced motor pattern, suggesting that proctolin and cholinergic agonists affect two different pathways for the activation of the swimmeret system. 5. We conclude that cholinergic interneurons participate in initiation of the swimmeret motor pattern and can modulate its burst frequency.

Intrathecal blockade of both NMDA and non-NMDA receptors attenuates the exercise pressor reflex in cats

1996 ◽  
Vol 80 (1) ◽  
pp. 315-322 ◽  
Author(s):  
C. M. Adreani ◽  
J. M. Hill ◽  
M. P. Kaufman
Keyword(s):  
Spinal Cord ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Initial Phase ◽  
Intrathecal Injection ◽  
Secondary Phase ◽  
Receptor Blockade ◽  
Lumbosacral Spinal Cord ◽  
Ventilatory Responses ◽  
Nmda Receptor Blockade

In decerebrate unanesthetized cats we tested the hypothesis that glutamatergic-receptor blockade in the lumbosacral spinal cord attenuated the reflex increases in mean arterial pressure, inspired minute ventilation, and renal sympathetic nerve activity (RSNA) evoked by static contraction of the triceps surae muscles. Blockade of N-methyl-D-aspartate (NMDA) receptors by intrathecal injection of DL-2-amino-5-phosphonovaleric acid had no effect on the initial phase of the pressor, ventilatory, and RSNA responses to contraction but did attenuate the secondary phase of these responses. Subsequent blockade of non-NMDA receptors in the lumbosacral spinal cord by intrathecal injection of 6-cyano-7-nitroquinoxaline-2,3-dione attenuated both the initial phase of the pressor, RSNA, and ventilatory responses to contraction and the secondary phase of these responses. In addition, NMDA-receptor blockade had no effect on the pressor or RSNA responses to tendon stretch, whereas non-NMDA-receptor blockade abolished these responses. We confirmed that our results were not related to the order of the antagonists injected by performing a series of experiments in which a non-NMDA-receptor antagonist was injected first. Our findings suggest that non-NMDA receptors mediate the spinal transmission of the initial and secondary phases of the pressor, RSNA, and ventilatory responses to contraction and tendon stretch. Therefore, non-NMDA receptors in the dorsal horn appear to be involved in the spinal processing of input from mechanoreceptors and metaboreceptors. Our findings also suggest that NMDA receptors mediate the spinal transmission of the secondary phase of the pressor, RSNA, and ventilatory responses to contraction but do not mediate the spinal transmission of the responses to tendon stretch. Therefore, NMDA receptors in the dorsal horn appear to be involved in the spinal processing of input from metaboreceptors.

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