Evidence that MK-801 stimulates intraoral intake by acting on hepatic afferents

Satiety signals from the gastrointestinal tract travel via vagal afferents to the nucleus of the solitary tract (NTS) in the brain stem, the first central relay in a neural network which controls food intake. The non-competitive NMDA antagonist MK-801 facilitates food intake in rats by acting on the NTS. Here we report that hepatic portal vein infusion of MK-801 (25 or 50 microg/kg) increases intake of an intraorally infused 1 M solution of sucrose (by 113 +/- 9 and 132 +/- 11%, respectively) and that this effect is prevented by hepatic vagotomy. By contrast, jugular vein infusion of MK-801 fails to increase sucrose intake but induces forward locomotion, indicating activation of a central mechanism. These data suggest that MK-801 can stimulate food intake by acting peripherally on hepatic vagal afferents.     

Delay in meal termination follows blockade of N-methyl- -aspartate receptors in the dorsal hindbrain

We have reported that rats increased their intake of food, but not water, following an intraperitoneal injection of MK-801, a non-competitive antagonist of N-methyl- -aspartate (NMDA)-activated ion channels. The antagonist appears to specifically interfere with signals that participate in meal termination (satiety), thereby prolonging the meal and increasing its size. The anatomical site at which MK-801 acts to increase food intake is not known. However, vagal sensory neurons are known to participate in satiation for food. Furthermore, NMDA receptor immunoreactivity is present in the caudal nucleus of the solitary tract (NTS) where vagal sensory fibers terminate. Therefore, we hypothesized that MK-801 might increase food intake by blocking NMDA receptors in the NTS. To test this hypothesis, we microinjected MK-801 directly into the hindbrain, immediately prior to a deprivation-induced meal of 15% sucrose. We found that sucrose intake was significantly increased following injection of MK-801 (2 μg/3 μl) into the fourth ventricle. When MK-801 was injected directly into the caudomedial NTS, intake was increased significantly by doses as small as 198 ng/30 nl, while equivalent injections into other hindbrain areas or the fourth ventricle did not increase food intake. These data are consistent with control of food intake by endogenous glutamate and NMDA-type glutamate receptors located in the caudomedial NTS.     

Delayed onset of enhanced MK-801-induced motor hyperactivity after neonatal lesions of the rat ventral hippocampus.

BACKGROUND: Abnormalities in the glutamatergic system, glutamate/dopamine/gamma-aminobutyric acid interactions, and cortical development are implicated in schizophrenia. Moreover, patients with schizophrenia show symptom exacerbation in response to N-methyl-D-aspartate (NMDA) antagonist drugs. Using an animal model of schizophrenia, we compared the impact of neonatal and adult hippocampal lesions on behavioral responses to MK-801, a noncompetitive NMDA antagonist. METHODS: Neonatal rats were lesioned on postnatal day 7. Their motor activity in response to MK-801 was tested at a juvenile age, in adolescence, and in adulthood. We also measured binding of [(3)H]MK-801 and the expression of NR1 messenger RNA (mRNA) in the medial prefrontal cortex and nucleus accumbens. Adult rats received similar lesions and were tested 4 and 8 weeks after the lesion. RESULTS: As juveniles, neonatally lesioned rats did not differ from control rats in responsiveness to MK-801, whereas in adolescence and adulthood they showed more pronounced hyperactivity than control rats. The adult lesion did not alter behaviors elicited by MK-801. Neonatally lesioned rats showed no apparent changes in [(3)H]MK-801 binding or expression of the NR1 mRNA. CONCLUSIONS: These results suggest that an early lesion of the ventral hippocampus affects development of neural systems involved in MK-801 action without changes at the NMDA receptor level, and they show that the behavioral changes manifest first in early adulthood.     

Effects of MK-801 on rat primary afferent neurons and fibers

Recent evidence suggests that glutamate and its N-methyl-D-aspartate (NMDA) receptor may participate in regulating neurite morphology and peptide expression. A previous study from this laboratory showed that treatment with the NMDA receptor antagonist, MK-801, induced an apparent increase in the density of calcitonin gene-related peptide (CGRP)-immunoreactive primary afferent fibers in the dorsal spinal cord of the rat. The present study was undertaken to extend this work by: 1) quantifying the MK-801-induced increase in CGRP immunostaining in the dorsal grey commissure/medial dorsal horn region and 2) examining the effect of MK-801 on the number of CGRP-immunoreactive primary afferent cell bodies in lumbar dorsal root ganglia. Following 7 days of MK-801 treatment, a significant increase (p less than 0.001) in CGRP immunostaining was observed in the dorsal grey commissure/medial dorsal horn. However, after MK-801 treatment, no significant difference was noted in the numbers of CGRP-immunoreactive primary afferent cell bodies in dorsal root ganglia. These data suggest that MK-801 produces significant alterations in the intraspinal projection of CGRP-immunoreactive fibers without inducing immunocytochemically detectable CGRP within a new population of primary afferent neurons.     

Competitive (AP7) and non-competitive (MK-801) NMDA receptor antagonists differentially alter glucose utilization in rat cortex.

The effects of D,L-2-amino-7-phosphonoheptanoic acid (AP7), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, and MK-801, a non-competitive NMDA receptor antagonist, on regional brain metabolism were studied in unanesthetized, freely moving rats by using the quantitative [14C]2-deoxyglucose autoradiographic procedure. AP7 (338 or 901 mg/kg) produced a dose-dependent decrease of metabolic activity throughout most of the regions studied including sensory, motor, and limbic cortices. In contrast, MK-801 (0.1 or 1.0 mg/kg) resulted in a dose-dependent decrease of metabolic activity in sensory cortices, and an increase in limbic regions such as the hippocampal stratum lacunosum moleculare and entorhinal cortex. MK-801 also produced a biphasic response in agranular motor cortex, whereby the low dose increased while the high dose decreased labeling. In addition, MK-801 produced heterogeneous effects on regional cerebral metabolism in sensory cortices. Metabolic activity decreased in layer IV relative to layer Va following MK-801 treatment in primary somatosensory (SI) and visual (VI) cortices, suggesting a shift in activity from afferent fibers innervating layer IV to those innervating layer Va. MK-801 administration also decreased metabolic activity in granular SI relative to dysgranular SI, and in VI relative to secondary visual cortex (VII), thus providing a relative sparing of activity in dysgranular SI and VII. Thus, the non-competitive NMDA receptor antagonist suppressed activity from extrinsic neocortical sources, enhancing relative intracortical activity and stimulating limbic regions, while the competitive NMDA antagonist depressed metabolic activity in all cortical regions.(ABSTRACT TRUNCATED AT 250 WORDS)     

多巴胺D1和谷氨酸NMDA受体参与调控异动症大鼠纹状体△FosB蛋白的表达

目的研究多巴胺D1和D2受体以及谷氨酸NMDA受体对△FosB蛋白表达水平的影响,由此探讨它们在左旋多巴诱导的异动症(Levodopa-induced Dyskinesia,LID)发病机制中的作用。方法对单侧黑质纹状体6-羟多巴胺(6-OHDA)损毁致帕金森病(PD)大鼠给予左旋多巴治疗28d制作LID模型,将大鼠分为7组:正常对照组、PD组、LID组、SCH23390治疗组、MK-801治疗组、raclopride治疗组和非LID组,分别观察各组行为学改变并进行异常不自主运动(abnormal involuntary movement,AI M)评分,用免疫组化和免疫印迹方法测定各组△FosB蛋白表达水平。结果多巴胺D1受体阻断剂SCH23390和谷氨酸NMDA受体阻断剂MK-801明显减轻LID大鼠行为学异常,而多巴胺D2受体阻断剂raclopride对异常不自主运动无明显影响;LID大鼠损毁侧纹状体△FosB蛋白表达较PD大鼠和非LID大鼠明显增加;与LID大鼠相比,MK-801和SCH23390均使△FosB蛋白表达显著下降,而raclopride没有这种效应;各组大鼠健侧纹状体△FosB蛋白表达水平没有显著差异。结论多巴胺D1受体和谷氨酸NMDA受体均通过参与调控纹状体△FosB蛋白的表达而影响大鼠LID的发生。     

Periventricular anteroventral third ventricle lesions diminish the pressor response produced by systemic injection of the N-methyl-D-aspartate receptor antagonist MK-801.

This study examined whether electrolytic ablation of the periventricular anteroventral third ventricle (AV3V) would affect the increases in mean arterial blood pressure (MAP) and heart rate (HR) in conscious rats produced by systemic injection of the centrally acting N-methyl-D-aspartate (NMDA) receptor ion-channel blocker, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine (MK-801; 250 microgram/kg, i.v.). MK-801 produced a smaller increase in MAP in rats with AV3V lesions than in sham-lesion rats (+36+/-2% vs. +52+/-5%, respectively, P<0.05). In contrast, MK-801 produced similar increases in HR in the AV3V- and sham-lesion rats (+28+/-3% vs. +22+/-4%, respectively, P>0.05). These findings demonstrate that the MK-801-induced pressor response is dependent upon the integrity of the AV3V region, whereas the MK-801-induced tachycardia is not.     

NMDA receptor antagonism modifies the synergistic regulation of striatal tachykinin gene expression induced by dopamine D(1) and serotonin(2) receptor stimulation following neonatal dopamine depletion

Co-application of SKF-38393 (dopamine D(1) agonist; 1 mg/kg) and DOI (serotonin(2) agonist; 1 mg/kg) induced a synergistic increase in striatal preprotachykinin (PPT) mRNA levels in adult rats 60 days after neonatal intracerebroventricular injection of 6-hydroxydopamine. This magnitude of response was not observed in intact (vehicle-injected) rats and was restricted to the dorsomedial (DM, 333+/-25% of lesion) subregion of the anterior striatum, with smaller increases observed in the dorsolateral striatum (DL, 206+/-26% of lesion). A single i.p. injection of MK-801 (NMDA antagonist; 0.1 mg/kg) administered prior to dopamine D(1) (D(1)) and serotonin(2) (5-HT(2)) receptor co-stimulation suppressed the synergistic regulation of PPT mRNA expression in the DM striatum, but also produced a large increase in PPT message levels within the DL striatum (321+/-17% of lesion). These data suggest that the synergistic regulation of PPT mRNA within the DM striatum induced by D(1)/5-HT(2) receptor co-stimulation in the dopamine lesioned rat is dependent on NMDA receptor activity. However, MK-801 may simultaneously potentiate striatal PPT mRNA expression by a separate mechanism due to the changed environment of the dopamine-depleted basal ganglia.     

Intranigral but not intrastriatal microinjection of the NMDA antagonist MK-801 induces contralateral circling in the 6-OHDA rat model

When systemically administered to unilaterally 6-OHDA lesioned rats, the non-competitive antagonists of (NMDA) receptors MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) produces a marked rotation response toward the lesioned side. In addition, the same type of injection in non-denervated rats increases locomotor activity without direction predominance. These findings suggest that MK-801 interacts with the dopaminergic pathway to induce motor activity. However, intracerebral injection of MK-801 (5 μg/0.5 μl) in the substantia nigra pars reticula a (SNr), either on the lesioned side or the intact side, induces a significant circling response, contraversive to the injection side. A similar injection of MK-801 (5 μg/1.0 μl) in the striatum causes no rotation response. These results show that the non-competitive NMDA antagonist can induce motor activity in the presence or in the absence of the dopaminergic pathway and that in the latter case its actions is exerted predominantly at the level of the substantia nigra, perhaps through suppression of the excitatory subthalamic drive.     

Central and peripheral vagal transport of cholecystokinin binding sites occurs in afferent fibers

The effects of various vagal lesions on cholecystokinin (CCK) binding sites in the nucleus tractus solitarii (NTS) and area postrema (AP) and the peripheral transport of CCK binding sites in the cervical vagus were examined in rats by in vitro autoradiography with [125I]CCK-8. Unilateral supraganglionic, but not subdiaphragmatic vagotomy significantly reduced CCK binding in the ipsilateral NTS. Specific unilateral afferent, but not efferent, vagal rootlet transections also significantly reduced NTS CCK binding ipsilateral to the transections. None of the vagal lesions altered CCK binding in the AP. Infraganglionic but not supraganglionic vagotomy eliminated the peripheral transport of vagal CCK binding sites. Together these results demonstrate that CCK receptors in the NTS are located on vagal afferent terminals, that CCK receptors in the AP are likely postsynaptic to a vagal afferent input and that the peripheral and central transport of vagal CCK binding sites occurs in afferent fibers.     

Ontogeny of glycine-enhanced [3H]MK-801 binding to N-methyl-D-aspartate receptor-coupled ion channels.

The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is thought to play a critical role in neuronal development, differentiation and plasticity. A number of studies have shown an enhanced sensitivity to NMDA receptor ligands in neonatal animals. This study examined the ontogenetic changes in the glycinergic modulation of NMDA-coupled cation channels in the developing central nervous system of rat pups. The nonequilibrium binding of the specific channel ligand [3H]MK-801 was used as a measure of NMDA channel access. Glycine (10(-5) M) enhancement of [3H]MK-801 binding at 2 h in forebrain membranes from adult rats was significantly greater than that observed in tissues from 8- to 28-day-old rat pups. This difference was due to changes in the efficacy, but not potency of glycine. The observed ontogenetic changes in the efficacy of glycine-enhanced [3H]MK-801 binding were attributable to developmental changes in receptor site density, as determined by equilibrium [3H]MK-801 saturation isotherms. Kinetic studies revealed that glycine increased the association rate constants of [3H]MK-801 in 8-day and adult membranes by a similar magnitude (0.111 +/- 0.021 vs 0.094 +/- 0.009 nM-1 h-1, respectively). Similarly, the fractional amount of [3H]MK-801 bound (i.e., amount bound at time t normalized to amount bound at equilibrium) in the presence of glycine was relatively constant throughout neonatal development. These findings suggest that the allosteric modulation of the NMDA ionophore by glycine is similar in postnatal and adult rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

A within-subjects microdialysis/behavioural study of the role of striatal acetylcholine in D1-dependent turning.

In rats lesioned with 6-hydroxydopamine (6-OHDA) the effect of the noncompetitive N-methyl D-aspartate (NMDA) receptor antagonist, MK-801, the dopamine (DA) D2 receptor agonist quinpirole and the A2A adenosine antagonist SCH 58261 was studied on acetylcholine (ACh) release in the lesioned striatum and contralateral turning behaviour stimulated by the administration of the DA D1 receptor agonist CY 208-243. Administration of CY 208-243 (75, 100 and 200 microg/kg) to 6-OHDA-lesioned rats dose-dependently stimulated ACh release and induced contralateral turning. MK-801 (50 and 100 microg/kg) reduced basal ACh release (max 22%) and did not elicit any turning. MK-801 (50 and 100 microg/kg) potentiated the contralateral turning, but failed to modify the stimulation of ACh release elicited by 100 and 200 microg/kg of CY 208-243. MK-801 (100 microg/kg) prevented the increase in striatal ACh release evoked by the lower dose of CY 208-243 (75 microg/kg) but contralateral turning was not observed. The D2 receptor agonist quinpirole (30 and 60 microg/kg) elicited low-intensity contralateral turning and decreased basal ACh release. Quinpirole potentiated the D1-mediated contralateral turning behaviour elicited by CY 208-243 (100 microg/kg), but failed to affect the increase in ACh release elicited by the D1 agonist. The adenosine A2A receptor antagonist SCH 58261 (1 microg/kg i.v.) failed per se to elicit contralateral turning behaviour. SCH 58261 potentiated the contraversive turning induced by CY 208-243 but failed to affect the increase of ACh release. The results of the present study indicate that blockade of NMDA receptors by MK-801. stimulation of DA D2 receptors by quinpirole and blockade of adenosine A2A receptors by SCH 58261 potentiate the D1-mediated contralateral turning behaviour in DA denervated rats without affecting the action of the D1 agonist on ACh release. These observations do not support the hypothesis that the potentiation of D1-dependent contralateral turning by MK-801, quinpirole or SCH 58261 is mediated by changes in D1-stimulated release of ACh in the striatum.     

The effect of glutamate receptor blockade on anoxic depolarization and cortical spreading depression.

We examined the effect of blockade of N-methyl-D-aspartate (NMDA) and non-NMDA subtype glutamate receptors on anoxic depolarization (AD) and cortical spreading depression (CSD). [K+]e and the direct current (DC) potential were measured with microelectrodes in the cerebral cortex of barbiturate-anesthetized rats. NMDA blockade was achieved by injection of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate [MK-801; 3 and 10 mg/kg] or amino-7-phosphonoheptanoate (APH; 4.5 and 10 mg/kg). Non-NMDA receptor blockade was achieved by injection of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX; 10 and 20 mg/kg). MK-801 and APH blocked CSD, while NBQX did not. In control rats, the latency from circulatory arrest to AD was 2.1 +/- 0.1 min, while the amplitude of the DC shift was 21 +/- 1 mV, and [K+]e increased to 50 +/- 6 mM. All variables remained unchanged in animals treated with MK-801, APH, or NBQX. Finally, MK-801 (14 mg/kg) and NBQX (40 mg/kg) were given in combination to examine the effect of total glutamate receptor blockade on AD. This combination slightly accelerated the onset of AD, probably owing to circulatory failure. In conclusion, AD was unaffected by glutamate receptor blockade. In contrast, NMDA receptors play a crucial role for CSD.     

Post-lesion administration of the NMDA receptor antagonist MK-801 does not impair motor recovery after unilateral sensorimotor cortex injury in the rat

Although treatment with N-methyl-D-aspartate (NMDA) receptor antagonists reduce neuronal loss after cerebral infarction and brain trauma in laboratory animals, there is little data concerning the effects of these drugs on behavioral recovery. Because NMDA receptor antagonists impede certain kinds of learning, and because motor recovery after sensorimotor cortex injury in the rat is dependent on post-lesion experience, we hypothesized that treatment with MK-801 after focal brain injury would be detrimental. Groups of rats were first trained to traverse a narrow elevated beam and then subjected a right sensorimotor cortex suction-ablation lesion. In the first experiment, 24 h later, each rat received a single dose of either saline or the NMDA receptor antagonist MK-801 (0.5, 1.0, or 2.0 mg/kg). Beam-walking recovery was measured over the next 12 days. In a second experiment, rats were given 3 doses of MK-801 (0.5 mg/kg) at 24 h intervals beginning 24 h after cortex injury. In a third experiment, lesioned and sham-operated rats were allowed to recover for 12 days and then given MK-801 (0.5 mg/kg). Despite obvious behavioral effects of the drug, there was no overall difference in beam-walking performances among the treatment groups in any of the experiments. If 're-learning' is involved in motor recovery after cortex injury, the present results suggest that the process is not susceptible to permanent disruption by the early or late administration of an NMDA receptor antagonist.     

Quantitative autoradiography of angiotensin II receptors in the rat solitary-vagal area: effects of nodose ganglionectomy or sinoaortic denervation

The experiments reported here were designed to examine whether angiotensin II (AII) receptors in the rat solitary-vagal area (SVA) are associated with the neuronal components of the baroreceptor reflex. AII receptors were characterized both in membrane preparations from the rat brainstem and by in vitro autoradiography using the radiolabeled AII antagonist [125I]Sar1,Ile8-AII([ 125I]SI-AII). Saturation analysis of [125I]SI-AII binding to membrane preparations from rat brainstem indicated binding to two high affinity sites (Kd1 0.32 nM and Bmax1 5.10 fmol/mg protein, Kd2 0.99 nM and Bmax2 7.94 fmol/mg protein). The rank order competition by unlabeled angiotensin peptides (SI-AII greater than AII greater than AIII greater than AI) in both membrane preparations and by quantitative autoradiography was consistent with the labeling of the brain AII receptor. Autoradiography of the [125I]SI-AII binding in sections through the SVA revealed that the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMV) were heavily labeled. Bilateral sinoartic denervation, which disrupts primary baroreceptor afferents, resulted in a small decrease in [125I]SI-AII binding in the rostral and intermediate NTS and DMV. Unilateral nodose ganglionectomy, which disrupts completely the vagal afferent input to the NTS and produces retrograde degeneration of the vagal efferent neurons in the DMV, resulted in a marked decrease in [125I]SI-AII binding at all levels of the ipsilateral NTS and 56% decrease within the ipsilateral DMV. These results indicate that AII receptors within the SVA are distributed heterogeneously, with a large portion associated with vagal afferent fibers in the NTS and vagal efferent neurons of the DMV, and a small but significant portion associated with baroreceptor afferents. The majority of AII receptors in the NTS, however, were not affected by these surgical interventions and therefore appear to be located on intrinsic interneurons or non-vagal afferents in the NTS.     

Anteroventral third ventricular N-methyl-D-aspartate receptors, but not metabotropic glutamate receptors are involved in hemorrhagic AVP secretion

This study aimed to investigate the roles of glutamate (Glu) receptors in the anteroventral third ventricular region (AV3V), a pivotal area for water, cardiovascular and neuroendocrine regulations, in causing vasopressin (AVP) secretion and other phenomena in response to bleeding. The effects of intracerebral infusions of MK-801 [a N-methyl-D-aspartate (NMDA) receptor antagonist] or a metabotropic Glu receptor antagonist (MCPG) on plasma levels of AVP, electrolytes, osmolality and glucose, heart rate and arterial pressure following AV3V administration with NMDA or bleeding stimuli were analyzed in conscious rats. NMDA provoked prominent rises of plasma AVP, osmolality, glucose and arterial pressure, without changing plasma electrolytes or heart rate significantly. All the effects of NMDA were blocked by pre-administration of MK-801 into the same loci. Removal through a femoral arterial line of 10 ml blood per kg body weight did not affect arterial pressure or other variables significantly, although plasma AVP and angiotensin II (ANG II) tended to increase. When bleeding was repeated after 10 min (B2), arterial pressure dropped promptly, and plasma AVP, ANG II, osmolality and glucose augmented remarkably. MK-801 applied 35 min preceding B2, to loci such as the median preoptic nucleus, periventricular nucleus and medial preoptic area inhibited the response of plasma AVP significantly, without exerting any effects on other variables. When MK-801 was administered intracerebroventricularly, or when MCPG was infused into the AV3V, significant alterations did not occur in B2-evoked responses of plasma AVP nor in those of the other variables. In rats given sham bleeding after AV3V infusions of MK-801 or MCPG or intracerebroventricular applications of MK-801, all monitored variables roughly remained at stable levels throughout the experiments. We conclude that NMDA receptors in AV3V, but not metabotropic Glu receptors, may facilitate AVP secretion in hypotensive hypovolemia.     

Anteroventral third ventricular N-methyl-d-aspartate receptors, but not metabotropic glutamate receptors are involved in hemorrhagic AVP secretion

This study aimed to investigate the roles of glutamate (Glu) receptors in the anteroventral third ventricular region (AV3V), a pivotal area for water, cardiovascular and neuroendocrine regulations, in causing vasopressin (AVP) secretion and other phenomena in response to bleeding. The effects of intracerebral infusions of MK-801 [a N-methyl-D-aspartate (NMDA) receptor antagonist] or a metabotropic Glu receptor antagonist (MCPG) on plasma levels of AVP, electrolytes, osmolality and glucose, heart rate and arterial pressure following AV3V administration with NMDA or bleeding stimuli were analyzed in conscious rats. NMDA provoked prominent rises of plasma AVP, osmolality, glucose and arterial pressure, without changing plasma electrolytes or heart rate significantly. All the effects of NMDA were blocked by pre-administration of MK-801 into the same loci. Removal through a femoral arterial line of 10 ml blood per kg body weight did not affect arterial pressure or other variables significantly, although plasma AVP and angiotensin II (ANG II) tended to increase. When bleeding was repeated after 10 min (B2), arterial pressure dropped promptly, and plasma AVP, ANG II, osmolality and glucose augmented remarkably. MK-801 applied 35 min preceding B2, to loci such as the median preoptic nucleus, periventricular nucleus and medial preoptic area inhibited the response of plasma AVP significantly, without exerting any effects on other variables. When MK-801 was administered intracerebroventricularly, or when MCPG was infused into the AV3V, significant alterations did not occur in B2-evoked responses of plasma AVP nor in those of the other variables. In rats given sham bleeding after AV3V infusions of MK-801 or MCPG or intracerebroventricular applications of MK-801, all monitored variables roughly remained at stable levels throughout the experiments. We conclude that NMDA receptors in AV3V, but not metabotropic Glu receptors, may facilitate AVP secretion in hypotensive hypovolemia.     

Inhibition of rat nucleus tractus solitarius neurones by activation of 5-HT2C receptors

In vivo, nucleus tractus solitarius (NTS) neurones receiving monosynaptic vagal input and inactive intermediate neurones were inhibited by both DOI and a selective 5-HT2C receptor agonist, MK-212. Cells receiving a more polysynaptic input were excited by DOI and although MK-212 also excited a few of these cells, the majority of cells in these groups were unaffected by MK-212. The inhibitory, but not the excitatory actions of both MK-212 and DOI were prevented by a selective 5-HT2C receptor antagonist, RS-102221. In contrast, most dorsal vagal preganglionic neurones were unaffected by application of either DOI or MK-212, the few remaining cells being excited by both agonists. These data demonstrate that DOI-evoked inhibition of NTS cells activated by vagal afferent input and DOI-evoked excitation of vagal preganglionic neurones is mediated by 5-HT2C receptors.     

Effects of chronic administration of MK-801 upon local cerebral glucose utilisation and ligand binding to the NMDA receptor complex

Although clinical use of N-methyl-D-aspartate (NMDA) receptor antagonists will involve prolonged drug administration, knowledge of the functional consequences of chronic NMDA receptor blockade is limited. Local cerebral glucose utilisation was measured in conscious rats in 74 discrete brain regions after chronic administration of (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine (MK-801) (0.5 mg/kg i.p.). Chronic treatment with MK-801 caused small, significant changes in glucose use in 4 of the 74 brain areas; parietal cortex (-13%), frontal cortex (-10%), subthalamic nucleus (-14%) and nucleus accumbens (-17%). These focal alterations in glucose use were not associated with changes in ligand binding to various sites within the NMDA receptor complex (i.e. agonist recognition site, glycine site, ion channel site) which were assessed autoradiographically. The acute effects of MK-801 on glucose utilisation were significantly enhanced after chronic MK-801 in 7 brain regions (e.g. frontal and parietal cortices) and attenuated in 6 brain regions (e.g. nucleus accumbens, hippocampus, posterior cingulate cortex). Neither local enhancement nor attenuation of the acute response to MK-801 was due to alterations in ligand binding to sites within the NMDA receptor complex. The data clearly indicate that the functional consequences of NMDA blockade are altered after chronic MK-801 treatment in an anatomically organised, though complex manner. These adaptive functional changes after chronic MK-801 treatment cannot be attributed readily to alterations in the NMDA receptor complex in affected regions.     

NMDA glutamate receptor stimulation is required for the expression of D2 dopamine mediated responses in apomorphine primed 6-hydroxydopamine lesioned rats

Three priming injections with the D1/D2 dopamine agonist apomorphine permits a challenge with the D2 agonist quinpirole to elicit robust contralateral rotation and ipsilateral striatal Fos expression in 6-hydroxydopamine lesioned rats. Pretreatment with NMDA glutamate antagonists MK-801 or CPP dose-dependently attenuates these quinpirole-mediated responses. These findings suggest that concomitant NMDA receptor stimulation is required for the expression of D2-mediated responses in apomorphine primed dopamine-depleted rats.