Non-competitive N-methyl-D-aspartate Receptor Research Articles

Excitotoxicity Plays a Role in the Death of Tyrosine Hydroxylase- Immunopositive Nigral Neurons Cultured in Serum-Free Medium

We studied the effects of different amino acid receptor antagonists and a calcium (Ca2+) channel blocker on the survival of embryonic tyrosine hydroxylase (TH)-immunopositive nigral neurons grown under serum-free culture conditions. Ventral mesencephalic neurons were cultivated for 2 or 7 days. Following serum withdrawal on day 2, some cultures were treated with different concentrations of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine hydrogen maleate (MK-801), the competitive NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid, the competitive kainate/quisqualate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione, and the Ca2+ channel blocker flunarizine. Treatment with MK-801 or flunarizine increased the survival of TH-positive neurons after serum deprivation. These findings suggest a possible role for excitotoxicity in dopaminergic cell death which can be prevented by blocking the NMDA receptor or by inhibiting Ca2+ entry through voltage-gated channels.

MK‐801 interaction with the 5‐HT transporter: a real‐time study in brain slices using fast cyclic voltammetry

The effects of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801) and a competitive NMDA antagonist, (±)-3–2-carboxypiperazin-4-yl-propyl-1-phosphonic acid (CPP) were compared in electrically evoked 5-HT release in the brain slices incorporating the substantia nigra pars reticulata (SNr) or the dorsal raphé nucleus (DRN) using fast cyclic voltammetry (FCV). Electrical stimulation of either the SNr or the DRN with 50 pulses at frequencies greater than 10 Hz generated signals that were indistinguishable from 5-HT. In the SNr, 0.6–60 μM MK-801 concentration dependently potentiated stimulated 5-HT release. CPP 20 μM or NMDA 100 μM had no effect on 5-HT release evoked by electrical stimulation. In the SNr, 1 μM fluvoxamine or 0.6–60 μM MK-801 potentiated electrically evoked release of 5-HT. Pre-exposure to 20 μM MK-801 inhibited the enhancing effects of 1 μM fluvoxamine on electrically evoked 5-HT release in the SNr. In the DRN, the presence of 1 μM fluvoxamine or 20 μM MK-801 weakly potentiated 5-HT release. In the presence of 1 μM methiothepin (a nonselective 5-HT1–2 antagonist), 1μM fluvoxamine or 20 μM MK-801 were equipotent in potentiating the concentration of 5-HT released in response to electrical stimulation. The T1/2 values for 5-HT release following MK-801 or fluvoxamine administration were significantly increased. Potentiation of 5-HT release by MK-801 in the SNr and the DRN and lack of effect of either CPP or NMDA on 5-HT release or uptake argues against a role for NMDA receptors in modulation of 5-HT release. Inhibition of fluvoxamine induced potentiation of 5-HT signal in the presence of MK-801 suggests that MK-801 and fluvoxamine may interact at the level of the 5-HT transporter. Synapse 32:212–224, 1999. © 1999 Wiley-Liss, Inc.

NMDA receptor antagonists inhibit apomorphine-induced climbing behavior not only in intact mice but also in reserpine-treated mice

The present study showed that the noncompetitive N-methyl- d-aspartate (NMDA) receptor antagonists, MK-801 {(+)-5-methyl-10,11-dihydroxy-5H-dibenzo-[a,d]-cyclohepten-5,10-imine hydrogen maleate}, ketamine, dextrorphan and dextromethorphan attenuated apomorphine-induced climbing behavior in reserpine-treated mice. In addition, the competitive NMDA receptor antagonists, d(−)-2-amino-5-phosphonopentanoic acid (AP-5) and d(−)-3-(2-carboxypipera-zine-4-yl)-propyl-1-phosphonic acid (CPP), also inhibited the apomorphine-induced climbing behavior in reserpine-treated mice as well as in intact mice. Previous work in our laboratory had shown that the noncompetitive NMDA receptor antagonists, MK-801, ketamine, dextrorphan and dextromethorphan cause a pronounced inhibition of apomorphine-induced cage climbing behavior in intact mice, suggesting the involvement of NMDA receptors in the glutamatergic modulation of dopaminergic function at the postsynaptic dopamine (DA) receptors. Therefore, the present results strongly support our previous conclusion that the NMDA receptors play important roles in the glutamatergic modulation of dopaminergic function at the postsynaptic DA receptors.

Nitric oxide (NO) release by glutamate and NMDA in the dorsal horn of the spinal cord: an in vivo electrochemical approach in the rat

Glutamate acts as a neurotransmitter of primary afferent messages in the spinal cord. Through glutamatergic mechanisms nitric oxide (NO) is also a potential intermediary in the transmission of sensory messages, particularly nociceptive, at the spinal level. The aim of the present study was, by using electrochemical monitoring of NO, to determine if the activation of glutamatergic transmission, particularly through NMDA receptors, could increase NO production within the dorsal horn of the lumbar spinal cord in the rat. 30 μm diameter treated carbon fiber electrodes coated with nickel–porphyrine and Nafion®, and associated with differential normal pulse voltammetry, have been used in vivo to monitor NO within the dorsal horn of the lumbar spinal cord of decerebrated–spinalized rats. A NO-dependent peak of oxidation current (650 mV vs. Ag–AgCl), remaining stable for up to 3 h (±5%) could be detected under basal conditions, which indicates that significant amounts of NO are produced continuously. The non-competitive N-methyl- d-aspartate (NMDA) channel blockers, Ketamine (100 mg kg −1 i.p.) and MK-801 (10 mg kg −1 i.p.), decreased the voltammograms to 70±5% and 69±2% of controls at 120 min, respectively. Glutamate (10 mM), when directly superfused upon the spinal cord (20 min at 50 μl min −1) induced a rapid and significant increase of the 650 mV peak, with a maximum at around 90 min (148±6% of control) followed by a slow decay (138±4% of control at 150 min). This increase could be totally reversed or blocked by i.p. injection of 100 mg kg −1 of Ketamine. NMDA (30 mg kg −1 i.p.) induced a long-lasting increase in the peaks (149±11% at 90 min and 162±20% at 120 min), which was also fully reversed by Ketamine or MK-801. These results provide in vivo direct evidence of a glutamate- and/or NMDA-induced release of NO at the spinal level, and is discussed in relation to the glutamatergic transmission of primary afferent messages.

Genetic differences in the antinociceptive effect of morphine and its potentiation by dextromethorphan in rats

The effect of the non-competitive N-methyl- d-aspartate (NMDA) receptor antagonist dextromethorphan on morphine-induced antinociception was studied with the hot plate test in Sprague–Dawley (SD), Wistar–Kyoto (WK), Spontaneously Hypertensive (SHR) and Dark-Agouti (DA) rats. Subcutaneous morphine at 5 mg/kg induced significant antinociception in all four rats strains. Subcutaneous dextromethorphan at 15 and 45 mg/kg, but not 5 mg/kg, significantly and dose-dependently potentiated morphine-induced antinociception in SDs, WKs and SHRs, but not in DAs. In SHRs and DAs the antinociceptive effect of morphine was followed by prolonged hyperalgesia, which was reduced (SHRs) or abolished (DAs) by dextromethorphan. These results suggest that there are significant differences among rat strains in their response to morphine and in the ability of dextromethorphan to potentiate morphine-induced antinociception. These differences are possibly of genetic origin. Moreover, these data show that morphine, at least in some strains of rats, induced a delayed and NMDA receptor-dependent hyperalgesic response, supporting the notion that administration of opiates may activate NMDA receptors, leading to reduced antinociceptive effect and the development of hyperalgesia

The non-competitive NMDA receptor blocker dizocilpine potentiates serotonergic function.

Forepaw treading induced in rats by the 5HT1A agonist 8-OH-DPAT, and head shakes caused by the administration of the 5HT2A receptor against DOI, and by the 5HT precursor (-)5HTP, were significantly increased by pretreatment with the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine. Dizocilpine administration also significantly increased the locomotor activity induced by the serotonin agonists. The competitive NMDA receptor antagonist CGP 43487 increased only the head shakes induced by DOI, but did not alter the behavior elicited by 8-OH-DPAT, or (-)5HTP, and did not modify locomotor responses to any of the agonists used. The dizocilpine-induced potentiation of head shakes elicited by DOI and (-)5HTP was inhibited by the 5HT2 agonist ketanserin, but was not modified by the selective dopamine D1 and D2 receptor blockers SCH 23390 and (-)sulpiride. The dopamine receptor antagonists did, however, counteract the dizocilpine facilitation of both forepaw treading induced by 8-OH-DPAT, and the locomotor response to all the serotonergic agonists. The results indicate that, unlike competitive NMDA receptor antagonists, the non-competitive antagonists enhanced the expression of serotonergic stimulation, and suggest that a glutamate deficiency could contribute to the pathogenesis of schizophrenia, not only through dopaminergic, but also through serotonergic, hyperactivity.

Arrhythmias induced by myocardial ischaemia-reperfusion are sensitive to ionotropic excitatory amino acid receptor antagonists

We have investigated the effects of (+)-5-methyl-10,11-dihydro-5H-dibenzo[ a, d]cyclohepten-5,10-imine hydrogen maleate (MK801), a non-competitive N-methyl- d-aspartate (NMDA) ionotropic excitatory amino acid receptor antagonist, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA ionotropic excitatory amino acid receptor antagonist, ketamine and memantine, NMDA receptor channel blockers, on ventricular arrhythmias induced by myocardial ischaemia and myocardial ischaemia-reperfusion. Coronary artery occlusion caused 100±2% ventricular tachycardia, in saline treated group, and 60±3% ventricular fibrillation. 66±6% of the animals recovered from ventricular fibrillation, while in 34±4% of animals the ventricular fibrillation caused mortality. The incidence of ventricular tachycardia, ventricular fibrillation and mortality was not modified by treatment of rats with MK801 (0.3 mg/kg i.v.), CNQX (1 mg/kg i.v.), ketamine (10 mg/kg) and memantine (1.5 mg/kg), injected 5 min prior to occlusion. Reperfusion caused severe arrhythmias which started within 5±2 s. For instance, in the saline treated group, the incidence of ventricular tachycardia was 100±5%, while ventricular fibrillation occurred in 87±3% of the animals and lasted 90±12 s. The mortality was 62±6%. The incidence of ventricular tachycardia, ventricular fibrillation and mortality induced by reperfusion was greatly ( P<0.01) reduced in animals treated with MK801 (0.3 mg/kg i.v.), CNQX (1 mg/kg i.v.), ketamine (10 mg/kg) and memantine (1.5 mg/kg), injected 5 min prior to occlusion. Therefore, reperfusion-induced arrhythmias, but not ischaemia-induced arrhythmias, are sensitive to NMDA/non-NMDA ionotropic excitatory amino acid receptor antagonists.

Effects of the non-competitive NMDA receptor antagonist ifenprodil on the morphine-induced place preference in mice

The effects of ifenprodil, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, on the morphine-induced place preference were examined in mice. Morphine (1–5 mg/kg, s.c.) produced a dose-related place preference in mice. In contrast, ifenprodil alone (5–20 mg/kg, i.p.) did not produce either preference or aversion for the drug-associated place. Pretreatment with ifenprodil (5–20 mg/kg, i.p.) suppressed the place preference produced by morphine in a dose-dependent manner. These results indicate that ifenprodil suppresses the rewarding effect produced by morphine.

Modifications of the behavioral profile of non-competitive NMDA receptor antagonists, memantine, amantadine and (+)MK-801 after chronic administration.

Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists show antiparkinsonian-like activity in animal models, and possess neuroprotective properties. However they also induce a number of behavioral side effects in rodents at higher doses; these include learning impairment, hyperlocomotion, and ataxia. The present study focused on the possible development of tolerance, or sensitization, to any of these effects after sustained administration, either by repeated injection or continuous infusion. When memantine or (+)MK-801 (20 and 0.31 mg/kg/day respectively) were either infused or repeatedly injected for 14 days, tolerance was observed to their learning impairing effect at high doses, in a passive avoidance test. Tolerance to their ataxic effect developed after repeated administration ((+)MK-801 and memantine), or after infusion (memantine). Sensitization to the locomotor stimulation was seen following repetitive injections of memantine for 14 days, but not seen with (+)MK-801. In animals with an unilateral 6-OHDA lesion of the nigrostriatal system, acute administration of memantine caused ipsilateral rotations, which were augmented following 14 days of infusion. The potency of amantadine to antagonize neuroleptic-induced catalepsy was unchanged following either infusion or repeated injections. The various acute effects of non-competitive NMDA receptor antagonists were modified differently by sustained treatment (i.e. tolerance to learning impairment and ataxia; sensitization to memantine's locomotor stimulation). The anti-cataleptic activity of amantadine remained unaltered. However, differences between drugs and the two treatment regimens (i.e. repetitive versus continuous treatments) were apparent.

Propofol inhibits ketamine-induced c-fos expression in the rat posterior cingulate cortex.

Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, has psychotomimetic activity. NMDA receptor antagonists cause morphological damage in the posterior cingulate cortex, which may be the brain region responsible for their psychotomimetic effects. Benzodiazepines are effective in preventing these effects through gamma-aminobutyric acid A (GABA(A)) receptor activation. We investigated the effect of propofol, which has both GABAA receptor-activating and NMDA receptor-suppressing activity, on ketamine-induced c-fos expression in the rat posterior cingulate cortex. Propofol or vehicle was continuously infused IV. Fifteen minutes later, 100 mg/kg ketamine or isotonic sodium chloride solution was injected intraperitoneally. Two hours later, brain sections were prepared, and c-fos expression was detected using immunohistochemical methods. Propofol significantly inhibited ketamine-induced c-fos expression in the posterior cingulate cortex. Propofol itself did not induce c-fos expression in this brain region. We conclude that propofol may be able to inhibit ketamine-induced psychotomimetic activity and neuronal damage. In the present study, we demonstrated that the clinically relevant dose of propofol significantly inhibited ketamine-induced c-fos expression in the rat posterior cingulate cortex. This finding implies that propofol may inhibit ketamine-induced psychotomimetic activity and neuronal damage.

Opioid analgesics as noncompetitive N-methyl- d-aspartate (NMDA) antagonists

Much evidence points to the involvement of N-methyl- d-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However, in order to obtain complete analgesia, a combination of an NMDA receptor antagonist and an opioid receptor agonist is needed. Recent in vitro data have demonstrated that methadone, ketobemidone, and dextropropoxyphene, in addition to being opioid receptor agonists, also are weak noncompetitive NMDA receptor antagonists. Clinical anecdotes suggest that the NMDA receptor antagonism of these opioids may play a significant role in the pharmacological action of these compounds; however, no clinical studies have been conducted to support this issue. In the present commentary, we discuss evidence for the NMDA receptor antagonism of these compounds and its relevance for clinical pain treatment; an overview of structure–activity relationships for the relevant opioids as noncompetitive NMDA receptor antagonists also is given. It is concluded that although the finding that some opioids are weak noncompetitive NMDA receptor antagonists in vitro has created much attention among clinicians, no clinical studies have been conducted to evaluate the applicability of these compounds in the treatment of neuropathic pain conditions.

Effect of MK-801 on Seizures Induced by Exposure to Hyperbaric Oxygen: Comparison with AP-7

The effect of the noncompetitiveN-methyl-d-aspartate (NMDA)-receptor antagonist MK-801 on seizures induced by hyperbaric oxygen in relation to changes in cerebral blood flow (CBF) was investigated. Rats were injected with MK-801 (0.005–8 mg/kg) 30 min before exposure to 100% O2at 5 atm (gauge pressure). MK-801 administration resulted in a biphasic response in seizure latency. Doses of 0.1–4 mg/kg significantly decreased time to EEG and motor seizures, while 8 mg/kg had no effect on seizure latency. MK-801 had no effect on seizure duration. In a dose range 0.1–8 mg/kg MK-801 increased CBF in awake animals, which might be responsible for the decreased seizure latency. The gradual increase in seizure latency with increasing MK-801 doses suggests involvement of an additional factor probably related to the drug's anticonvulsive effect. Unlike MK-801, a competitive NMDA receptor antagonist, AP-7, at a dose 250 mg/kg had no effect on latency to seizures or CBF.

Intrathecal administration of the mGluR compound, ( S)-4CPG, attenuates hyperalgesia and allodynia associated with sciatic nerve constriction injury in rats

The present study examined the effects of intrathecal (i.t.) treatment (twice-daily injections on post-operative (PO) days 0–8) with the metabotropic glutamate receptor (mGluR) compound, ( S)-4-carboxyphenylglycine (( S)-4CPG), or the non-competitive N-methyl- d-aspartate (NMDA) antagonist, dizocilipine maleate (MK-801), on mechanical allodynia and cold hyperalgesia associated with chronic constriction injury (CCI) of the sciatic nerve in rats. Also, the effects of early (twice-daily injections on days 0–3) or late (twice-daily injections on days 8–11) ( S)-4CPG treatment on the injury-related mechanical allodynia and cold hyperalgesia were assessed in CCI rats. Results demonstrated that 8-day ( S)-4CPG or MK-801 treatment attenuated mechanical allodynia (up to PO days 12 or 16, respectively) and cold hyperalgesia (up to PO days 8 or 16, respectively). Results also demonstrated that early ( S)-4CPG treatment significantly attenuated the development of mechanical allodynia (90 and 270 nmol) and cold hyperalgesia (270 nmol). However, late treatment with ( S)-4CPG did not reduce the nociceptive behaviours in either behavioural task. These data not only confirm that the NMDA receptor plays a role in chronic nociception, but also suggest that Group I mGluRs are more critically involved in the development, and not the maintenance, of mechanical allodynia and cold hyperalgesia associated with CCI in rats.

Neurochemical and Neuroendocrine Effects of Ibogaine in Rats: Comparison to MK-801.

Ibogaine (IBO) is a naturally-occurring indole compound that is being evaluated as a potential medication for substance use disorders. Although the precise mechanism of IBO action is unclear, recent in vitro data show this drug displays properties similar to the noncompetitive N-methyl-d-aspartate (NMDA) antagonist MK-801. The purpose of the present work was to compare In Vivo neurobiological effects of IBO and MK-801 in rats. Groups of male rats (n = 6-8/group) were decapitated 30 and 60 min after receiving intraperitoneal (i.p.) IBO (10 & 100 mg/kg), MK-801 (0.1 & 1.0 mg/kg) or vehicle. Trunk blood was collected for the analysis of plasma prolactin and corticosterone; brains were harvested and dissected for determination of dopamine (DA), serotonin (5-HT) and their metabolites. Both IBO and MK-801 increased corticosterone secretion, but only IBO elevated plasma prolactin. IBO produced dramatic reductions in tissue DA levels with concurrent increases in the metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This profile of IBO-induced changes in DA transmission was observed in the striatum, olfactory tubercle, and hypothalamus. The effects of MK-801 on DA metabolism did not mimic IBO, as MK-801 tended to increase DA and its metabolites. Neither drug appreciably affected 5-HT systems. Our results suggest that the effects of IBO on neuroendocrine function and DA transmission are not due to MK-801-like properties of IBO. Thus, the In Vivo mechanism of IBO action cannot be explained simply on the basis of antagonism at NMDA receptors.

Birth order and gender of heroin addicts: the role of siblings in the addict's “career” : V. Pomini, J. Liappas, V. Peppas, N. Papavasiliou, G. Christodoulou. Athens University Medical School Department of Psychiatry Vas. Sophias 72-1 1528 Athens, Greece

The anticonvulsants diazepam (1–10 mg/kg) and phenobarbital (30–100 mg/kg) protected against lethality without altering clonic convulsions induced by 75 mg/kg cocaine (CD100) in male Swiss Webster mice. In contrast, the non-competitive N-methyl-D-aspartate (NMDA) antagonists, MK-801 (dizocilpine) and phencyclidine, produced dose-dependent protection against cocaine convulsions. The competitive NMDA antagonists, CPP and NPC 12626, were also anti-convulsant, without producing the behavioral disturbances associated with non-competitive antagonists. Diazepam and phenobarbital protected against convulsions induced by 60 mg/kg cocaine (90% convulsions alone). Compounds that act at the strychnine-insensitive glycine receptor of the NMDA receptor comples, ACPC and 7-chlorokynurinic acid, also protected against convulsions induced by 60 mg/kg cocaine. In contrast, the non-opioid antitussive anticonvulsants (dextromethorphan, caramiphen, and carbetapentane) were not active against either dose of cocaine. The efficacy of compounds as antagonists of the convulsant effects of cocaine and NMDA appear related. These results suggest a potential role for the NMDA receptor complex in the convulsant actions of cocaine and new molecular targets for drug discovery in treating cocaine toxicity.

MK-801 Interferes with Nutrient-related Signals for Satiation

We previously reported that MK-801, a non-competitiveN-methyl-d-aspartate (NMDA) receptor antagonist, increased food intake by rats. Increased intake occurred only when deprivation or presentation of a highly preferred food had initiated feeding. MK-801 did not cause initiation of food intake. We hypothesized that MK-801 might increase food intake by interfering with nutrient-related feedback signals generated during ingestion (within meal). To test this hypothesis, we administered MK-801 at several times during the course of a deprivation-induced meal. We found that MK-801, administered early in the meal, increased food intake dramatically, but only slightly when given late in a meal. The antagonist was ineffective for increasing intake when given after the meal had ended. In a second experiment, we examined the effect of MK-801 on deprivation-induced intake of 0·2% saccharin as compared to that of 15% sucrose, or sucrose adulterated with bitter sucrose octa acetate (SOA). MK-801 increased intake of 15% sucrose or sucrose adulterated with SOA. It did not increase intake of the sweet, non-nutritive 0·2% saccharin solution. These results suggest that NMDA receptors participate in the process of satiation and that MK-801 delays satiation by interfering with feedback from nutritive components of a meal.

Glutamate Modulation of Dopamine Measured inVivo with Positron Emission Tomography (PET) and 11C-Raclopride in Normal Human Subjects

Subanesthetic doses of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist ketamine exacerbate psychosis in schizophrenic patients, and ketamine has significant abuse liability. These observations indicate that a secondary effect of ketamine may be to increase dopamine concentrations. The present study was undertaken using positron emission tomography (PET) and the dopamine (D2) radiotracer 11C-raclopride to determine whether ketamine would decrease D2 receptor availability, indicative of an increase in dopamine concentrations. Two scans were performed in seven male control subjects before and after administration of ketamine (0.5 mg/kg, IV infused over 20 min). Ketamine significantly increased cortisol levels and decreased dopamine receptor availability in the striatum (specific binding), but not in the cerebellum (nonspecific binding). In addition, the cerebellar binding subtracted from the striatal binding (to account for changes in nonspecific binding) was significantly decreased after ketamine administration. These results provide in vivo evidence for the ability of ketamine to increase striatal dopamine concentrations, consistent with the role of the NMDA receptor in modulating dopamine function.

Effect of systemic N-methyl-D-aspartate receptor antagonist (dextromethorphan) on primary and secondary hyperalgesia in humans

Dextromethorphan is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist known to inhibit wind-up and central hyperexcitability of dorsal horn neurones. We studied 24 healthy, unmedicated male volunteers, aged 21-28 yr, in a randomized, double-blind, placebo-controlled, crossover study. Burn injuries were produced on the medial surface of the dominant calf with a 25 x 50 mm rectangular thermode. On three separate days, at least 1 week apart, subjects were given oral dextromethorphan 60 mg, 120 mg or placebo. Dextromethorphan reduced the magnitude of secondary hyperalgesia to pinprick but not to stroke. Dextromethorphan had no influence on primary hyperalgesia, pain during prolonged noxious heat stimulation or heat pain detection thresholds in undamaged skin. Side effects were frequent but clinically acceptable. The effects of dextromethorphan were in agreement with experimental studies indicating that dextromethorphan is a NMDA receptor antagonist. The effects of dextromethorphan in the burn injury model were similar to those of ketamine and distinct from those of local anaesthetics and opioids.

Involvement of nitric oxide in development of tail-tremor induced by repeated nicotine administration in rats

Daily administration of nicotine (0.5 mg/kg/day s.c.) to rats caused a tremor that appeared only in the tail (tail-tremor) and which became more marked over 8 days. Nitric oxide (NO) synthase inhibitors, N w-nitro- l-arginine (10 mg/kg/day i.p.) or N w-nitro- l-arginine methyl ester (20 and 40 mg/kg/day i.p.), administered each day before nicotine attenuated the development of the tail-tremor. However, neither N w-nitro- l-arginine (2–10 mg/kg i.p.) nor N w-nitro- l-arginine methyl ester (10–40 mg/kg i.p.) affected the tail-tremor that developed after 14 days of repeated nicotine administration. The noncompetitive N-methyl- d-aspartate (NMDA) receptor antagonist, MK-801 ((+)-5-methyl-10,11,-dihydro-5 H-dibenzo[ a, b]cyclohepten-5,10-imine hydrogen maleate) at 0.2 mg/kg/day (i.p.), or competitive antagonist, CPP (3-[(±)-2-carboxypiperazin-4-yl] propyl-1-phosphonic acid) at 2 mg/kg/day (i.p.), administered each day before nicotine attenuated the development of the tail-tremor. MK-801 (0.01–0.2 mg/kg i.p.) but not CPP (0.5–4 mg/kg i.p.) suppressed the tail-tremor that developed after 14 days of repeated nicotine administration. These results suggest that NO formation mediated by NMDA receptors is involved in the mechanisms underlying the tail-tremor induced by the repeated administration of nicotine.

Dizocilpine (MK-801) increases not only dopamine but also serotonin and norepinephrine transmissions in the nucleus accumbens as measured by microdialysis in freely moving rats

The extracellular concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the nucleus accumbens (NACC) of freely moving rats were monitored simultaneously via intracerebral microdialysis. Local infusion of the non-competitive N-methyl- d-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) (5–250 μM) produced significant increases in extracellular levels of DA, NE and 5-HT in a concentration-dependent fashion. Perfusion with tetrodotoxin (TTX, 1 μM) blocked the ability of focal MK-801 (50 μM) to increase DA, NE and 5-HT in the dialysate. Systemic administration of MK-801 (0.3 mg/kg, i.p.) also produced small, but statistically significant, increases in extracellular concentrations of DA, NE and 5-HT in the NACC. Our microdialysis results are consistent with the hypothesis that, in addition to dopaminergic, serotonergic and noradrenergic neurotransmissions in the NACC are involved in the mechanism by which MK-801 alters behavior in rats. Also, the present study gives further support to the concept that NMDA receptors within the NACC do not regulate DA release through direct excitatory control.