Competitive and noncompetitive NMDA antagonist effects in rats trained to discriminate lever-press counts

The glutamate activated N-methyl-D-aspartate (NMDA) receptor may play a role in short-term memory processing. Among the evidence for this is that NMDA antagonists can impair accuracy in fixed consecutive number (FCN) tasks. This study was designed to further characterize this effect by examining NMDA antagonists differing in their cellular mechanisms of action. Rats were trained to respond under an FCN operant schedule, which required eight presses on one lever (counting lever) before one press at an alternate lever (reinforcement lever) would produce food reinforcement. The effects of three noncompetitive [MK-801 (0.01-0.56 mg/kg); phencyclidine (0.3-3.0 mg/kg); memantine (1-10 mg/kg)] and two competitive [SDZ EAA 494 (0.3-3.0 mg/kg) and NPC 17742 (2.0-16 mg/kg)] NMDA antagonists were analyzed. MK-801 and phencyclidine decreased accuracy at doses not reducing response rates. Memantine, and both of the competitive antagonists, also reduced accuracy, but did so only at doses that markedly reduced response rates. These results suggest that both the affinity and the site bound on the NMDA glutamate receptor by antagonists can determine their effects on FCN performance. Subsequent studies investigated whether SCH 23390, a dopamine D1 receptor antagonist, and NMDA could modulate the effects by phencyclidine and SDZ EAA 494, respectively, on FCN performance.     

Dizocilpine improves beneficial effects of cholinergic antagonists in anticholinesterase-treated mice.

Mice were administered anticholinesterase pesticides dichlorvos (DDVP) or methomyl (MET). Both DDVP and MET induced dose-dependent seizures and lethality in mice. The muscarinic antagonist atropine (ATR, 1.8 mg/kg) did not prevent seizures but diminished the lethality induced by DDVP or MET. The nicotinic antagonist mecamylamine (MEC, 1 mg/kg) affected neither DDVP-induced seizures nor DDVP- and MET-induced lethality, but diminished MET-induced seizures. At a higher dose (10 mg/kg), MEC attenuated seizures produced by MET, but not DDVP, and decreased lethality of both anticholinesterases. The N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801, 1 mg/kg) prevented DDVP-, but not MET-induced seizures. MK-801 did not affect DDVP- or MET-induced lethality. Concurrent administration of ATR and MK-801 prevented the occurrence of DDVP- but not MET-induced seizures. MK-801 coadministered with ATR enhanced its protective effect against DDVP- or MET-induced lethality in mice. Coinjection of MEC (at both doses studied) and MK-801 completely prevented seizures produced by both acetylcholinesterase (AChE) inhibitors. Coadministration of MEC (1 mg/kg) and MK-801 protected mice against DDVP or MET lethality. MK-801 administered along with MEC at 10 mg/kg enhanced antilethal effects of the nicotinic antagonist in DDVP- or MET-treated mice. With respect to the mechanism underlying anticholinesterase-induced neurotoxicity, muscarinic and nicotinic, as well as NMDA receptors, seem to play major roles. The results suggest that combined treatment with cholinergic and NMDA antagonists might be beneficial in anticholinesterase-induced poisonings.     

Effects of dopamine D1 and D2 receptor blockade on MK-801-induced hyperlocomotion in rats

Blocking glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptor complex with MK-801 (0.15–0.5 mg/kg, IP) was found to induce a robust, dose-dependent increase in locomotor activity. This behavioural activation was similar in intensity to that observed afterd-amphetamine (1 mg/kg, SC). The locomotor stimulation induced by MK-801 at 0.3 mg/kg was significantly inhibited by the D₂ dopamine receptor antagonist raclopride (0.1–0.3 mg/kg, SC) and by the D₁ receptor antagonist SCH 23390 (0.04 mg/kg, SC). The locomotor activity induced by a higher dose of MK-801 (0.5 mg/kg) was reduced by higher doses of raclopride or SCH 23390 administered alone (0.3 and 0.08 mg/kg, respectively), and was inhibited by simultaneous administration of ineffective doses. Raclopride significantly reducedd-amphetamine-induced locomotor activity at a dose (0.2 mg/kg) that also blocked the effects of a low dose of MK-801. In contrast, SCH 23390 blocked the effects ofd-amphetamine at a dose (i.e. 0.01 mg/kg) lower than that needed to block MK-801. These results suggest that the dopaminergic system may in part mediate the locomotor effects induced by the NMDA antagonist, MK-801, in rats. However, the locomotor activity induced by MK-801 appears to be less sensitive to dopaminergic receptor blockade than that induced byd-amphetamine, suggesting that the underlying mechanisms, although similar, are not identical.     

The discriminative stimulus effects of MK-801 in pigeons

The discriminative stimulus effects of MK-801 [(+)-5-methyl-10, 11-dihydroxy-5H-dibenzo (a,d) cyclohepten-5, 10-imine], a proposed noncompetitive N-methyl-D-aspartate (NMDA) antagonist, were studied in pigeons discriminating MK-801 from saline, responding being maintained by food. Compounds with noncompetitive NMDA antagonist effects in other preparations (PCP [0.18-5.6mg/kg], dextrorphan [1-32mg/kg], ketamine [1-32mg/kg] and dexoxadrol [1-10mg/kg]) produced MK-801-appropriate responding dose-dependently. The potency order for this effect, and for response rate decreasing effects, closely mirrored the potency order for these compounds in causing catalepsy, an effect believed to be mediated by antagonism at the NMDA receptor complex. NMDA (0.32-5.6mg/kg), morphine (1-10mg/kg) and pentobarbital (1-17.8mg/kg) produced almost no MK-801-appropriate responding. There were no consistent potency differences among the (+)-isomer (1-32mg/kg), the (-)-isomer (1-17.8mg/kg) and the racemate (1-17.8mg/kg) of SKF 10,047 in producing MK-801-appropriate responding. The competitive NMDA antagonist CGS 19755 (1-10mg/kg) produced partial MK-801-appropriate responding (maximum value = 77.8%) up to 8h after administration. The homogeneity of the discriminative stimulus effects among compounds with noncompetitive NMDA antagonist effects in vitro, as well as the partial substitution for MK-801 by CGS 19755, suggest that the MK-801 discriminative stimulus in pigeons is due to noncompetitive NMDA antagonism.     

Are glycineB sites involved in the development of morphine tolerance?

Numerous data have indicated that competitive and non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists attenuate the development of tolerance to the analgesic effect of morphine. This study extends these findings on the effects of glycine(B) site antagonist, L-701.324. Tolerance to the analgesic effect of morphine was measured in hot-plate test in Wistar rats. For 9 days, animals were first injected with vehicle or glycine(B) receptor antagonist, L-701.324 (2.5 and 5 mg/kg, po). The non-competitive NMDA receptor antagonist, MK-801 (0.05 or 0.1 mg/kg, ip) was used as a reference compound. The injection of L-701.324, MK-801 or saline was followed, 20 min later, by the injection of morphine (10 mg/kg, sc). Hot-plate latencies were determined 20 min after the second injection on odd-numbered days. The results indicated that chronic administration of glycine(B) site antagonist, L-701.324 decreased the analgesic effect of morphine and they may suggest that this substance at both used doses increased the development of morphine tolerance, whereas non-competitive NMDA antagonist, MK-801 at the dose of 0.1 mg/kg potentiated the analgesic effect of morphine and attenuated the development of morphine tolerance.     

Effects of NMDA receptor antagonists on acute mu-opioid analgesia in the rat

Mixed research findings have led to a debate regarding the effect of N-methyl-D-aspartate (NMDA) receptor antagonists on opiate analgesia. NMDA antagonists have been found in various studies to enhance, to inhibit, or to have no effect on opiate analgesia. The present research used a single protocol to explore the effects of six NMDA receptor antagonists on acute morphine (3.0 mg/kg s.c.) and fentanyl (0.05 mg/kg s.c.) analgesia in adult male Sprague-Dawley rats. NMDA receptor antagonists were selected based on their abilities to block various sites on the NMDA receptor complex, including the noncompetitive antagonists MK-801 (0.1 and 0.3 mg/kg i.p.), dextromethorphan (10.0 and 30.0 mg/kg i.p.), and memantine (3.0 and 10.0 mg/kg i.p.), a glycine site antagonist, (+)-HA-966 (10.0 and 30.0 mg/kg i.p.), a competitive antagonist, LY235959 (1.0 and 3.0 mg/kg i.p.), and a polyamine site antagonist, ifenprodil (1.0 and 3.0 mg/kg i.p.). Analgesia was assessed using the tail-flick test. A single dose of each opiate was used. The low doses of the antagonists, which are known to produce significant neural and behavioral actions at NMDA receptors, had no effect on morphine or fentanyl analgesia. At the higher doses, morphine analgesia was significantly enhanced by LY235959 (3.0 mg/kg), and fentanyl analgesia was significantly enhanced by LY235959 (3.0 mg/kg), dextromethorphan (30.0 mg/kg), and (+)-HA-966 (30.0 mg/kg). Enhancement of analgesia occurred without any apparent adverse side effects. None of the NMDA antagonists affected tail-flick responses on their own, except the higher dose of LY235959 (3.0 mg/kg), which produced a mild analgesic effect. Because no consistent effects were observed, the data suggest that NMDA receptors are not involved in acute mu-opioid analgesia. The mechanisms underlying the enhancement of opiate analgesia by selected NMDA antagonists, such as LY235959, dextromethorphan, and (+)-HA-966, remain to be determined.     

Anticataleptic effects of the N-methyl-D-aspartate antagonist MK-801 in rats

The N-methyl-D-aspartate (NMDA) antagonist MK-801 was administered to rats in three doses (0.08, 0.16, 0.33 mg/kg) in order to examine its effects on catalepsy that was induced by haloperidol (0.5 mg/kg). The degree of catalepsy was assessed 30 and 60 min after application of drugs by placing the rat on a horizontal bar, on a podium and on a vertical grid. Animals having received saline and haloperidol showed a higher degree of catalepsy than animals having received MK-801 and haloperidol (except for the lowest dose of MK-801). These findings may suggest a therapeutic potential of MK-801 and possibly of other NMDA antagonists in the treatment of Parkinson's disease.     

The effects of -cycloserine and MK-801 on the performance of rats in two spatial learning and memory tasks

The present study was undertaken to investigate the effects of modulation of the (NMDA) receptor on learning and memory. Thus, the performance of rats treated with -cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor complex, and MK-801, a noncompetitive NMDA receptor antagonist, either alone or concurrently were assessed in radial arm maze and water maze tasks. Administration of MK-801 (0.1 mg/kg, i.p.) impaired acquisition in the water maze (increased escape latency and distance) and working memory in the radial arm maze (increased re-entries) in rats. Moreover, in the radial arm maze, MK-801 disrupted locomotion (increased latencies and decreased arm entries per minute) and impaired the acquisition of reference memory (increased number of errors) performance of rats. -Cycloserine (0.03, 0.3, 1.0, 3.0, 10 mg/kg, i.p.) had no effects on acquisition or memory performance of control or MK-801-treated rats in either of these tasks. However, -cycloserine (0.03, 0.3, 3.0 mg/kg) reversed the MK-801-induced disruption in locomotion. Furthermore, 3.0 mg/kg -cycloserine increased behavioral activity and also decreased the time needed to complete the task in control animals. To conclude, our results suggest that the consequences of NMDA receptor modulation on learning and memory processes and sensorimotor functions may be functionally different or have distinct anatomical locations.     

Ethological analysis of the effects of MK-801 upon aggressive male mice: similarity to chlordiazepoxide

Previous studies have demonstrated benzodiazepine-like effects of competitive and noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) type of excitatory amino acid receptor. The present experiment compared the effects of the benzodiazepine chlordiazepoxide and the NMDA noncompetitive antagonist MK-801 upon the behavior of aggressive male mice in dyadic interactions using ethological analysis. OF-1 male mice housed with females were administered either chlordiazepoxide (Vehicle, 3.0, 10.0 and 30.0 mg/kg IP) or MK-801 (Vehicle, 0.1, 0.3 and 0.3 mg/kg, IP) in a randomised order thirty minutes prior to pairing with unfamiliar male opponents in an unfamiliar environment. It was found that both compounds tended to increase aggressiveness and social behavior and reduce ambivalent activity consistent with approach-avoidance conflict. The increases in aggressiveness and decreases in ambivalent activity were induced by MK-801 at doses lower than those resulting in gross motor effects. These data confirm that noncompetitive antagonists of NMDA may generate a benzodiazepine-like behavioral profile.     

D1/D2 dopamine and N-methyl-d-aspartate (NMDA) receptor participation in experimental catalepsy in rats

Mixed D₁/D₂ dopamine (DA) antagonists, perphenazine (5 mg/kg) and haloperidol (2 mg/kg) induced catalepsy in rats. SCH 23390 (1 mg/kg), a D₁ DA antagonist, also produced catalepsy. Co-administration of perphenazine (0.5 mg/kg) and SCH 23390 (0.1 mg/kg), at low doses, produced a marked increase in cataleptic response. B-HT 920, a D₂ agonist, reversed the cataleptogenic effects of perphenazine, haloperidol and SCH 23390. SKF 38893 (5 mg/kg) reduced the cataleptogenic effect of SCH 23390 but failed to reverse haloperidol- or perphenazine-induced catalepsy. SKF 38393 (10 mg/kg), however, protected the animals against perphenazine- induced catalepsy. Combined administration of B-HT 920 (0.1 mg/kg) and SKF 38393 (5 mg/kg) enhanced the protective effect of B-HT 920 in SCH 23390-treated animals but not in animals treated with haloperidol or perphenazine. MK-801 (0.025–0.5 mg/kg), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reduced the cataleptogenic effects of perphenazine, haloperidol as well as SCH 23390. The anticataleptic action of MK-801 was enhanced by scopolamine (0.1 mg/kg) but not by bromocriptine (1 mg/kg) or clonidine (0.05 mg/kg) in perphenazine-treated rats. Unlike B-HT 920 (0.1 mg/kg), SKF 38393 (5 mg/kg) potentiated the anticataleptic effect of MK-801 (0.01 mg/kg) against SCH 23390-induced catalepsy. The above data suggests D₁/D₂ interdependence in catalepsy and a modulatory role of D₁ and D₂ DA receptor stimulation on the anticataleptic effect of MK-801.     

Effect of NMDA receptor antagonists on behavioral impairment induced by chronic treatment with dexamethasone

Severe and prolonged stress but also long-term treatment with glucocorticoids (GCs) have been described to cause brain damage (especially hippocampal and striatal neurons) in humans as well as in animals. GCs potentiate stress or ischemia-induced accumulation of excitatory amino acids (EAA) in the extracellular space of the hippocampus. It was shown that EAA play a major role in various neurologic disorders with cognitive dysfunction. Many authors suggested the neuroprotective effect of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists in some acute or chronic neurodegenerative diseases. On the other hand, many NMDAreceptor antagonists produce highly undesirable side-effects at the doses within their putative therapeutic range. The aim of the present study was to evaluate the behavioral effects (memory performance, motor coordination, lethality and body weight) of MK-801 or memantine (MEMAN, non-competitive NMDAreceptor antagonists) (at the doses of 25 and 50 microg/kg/day or 2.5 and 5.0 mg/kg/day, respectively) on neurotoxicity induced by dexamethasone (DEX) administered chronically at the doses of 40 or 80 mg/kg/day in mice. It was shown that prolonged treatment (for 10 days) with DEX at the dose of 80 mg/kg/day (but not at 40 mg/kg/day) significantly decreased the retention time in the memory task in mice and impaired the motor coordination in "chimney" test. Neither MK-801 nor MEMAN (at the both doses used) were able to counteract the behavioral impairment induced by DEX administration. Moreover, the potentiation of the body weight reduction and lethality induced by DEX were noted in mice co-treated with MK-801 or MEMAN. The above findings suggest that MK-801 or MEMAN at the doses used have no neuroprotective effect. On the contrary, both NMDA receptor antagonists potentiate the toxicity of DEX given chronically.     

The effects of d-cycloserine and MK-801 on the performance of rats in two spatial learning and memory tasks

The present study was undertaken to investigate the effects of modulation of the (NMDA) receptor on learning and memory. Thus, the performance of rats treated with d-cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor complex, and MK-801, a noncompetitive NMDA receptor antagonist, either alone or concurrently were assessed in radial arm maze and water maze tasks. Administration of MK-801 (0.1 mg/kg, i.p.) impaired acquisition in the water maze (increased escape latency and distance) and working memory in the radial arm maze (increased re-entries) in rats. Moreover, in the radial arm maze, MK-801 disrupted locomotion (increased latencies and decreased arm entries per minute) and impaired the acquisition of reference memory (increased number of errors) performance of rats. d-Cycloserine (0.03, 0.3, 1.0, 3.0, 10 mg/kg, i.p.) had no effects on acquisition or memory performance of control or MK-801-treated rats in either of these tasks. However, d-cycloserine (0.03, 0.3, 3.0 mg/kg) reversed the MK-801-induced disruption in locomotion. Furthermore, 3.0 mg/kg d-cycloserine increased behavioral activity and also decreased the time needed to complete the task in control animals. To conclude, our results suggest that the consequences of NMDA receptor modulation on learning and memory processes and sensorimotor functions may be functionally different or have distinct anatomical locations.     

Effects of dizocilpine (MK-801) on flash-evoked potentials, body temperature, and locomotor activity of hooded rats

The present study examined the effects of Dizocilpine (MK-801; a noncompetitive N-methyl-D-aspartate receptor antagonist) on flash-evoked potentials recorded from both the visual cortex (VC) and superior colliculus (SC) of chronically implanted hooded rats. The potentials were recorded at 5, 20, and 35 min following i.p. injections of saline, and of 0.1, 0.3, and 1.0 mg/kg MK-801 on separate days. The amplitude of VC component P1 was unaltered following drug treatment. N1 was increased in amplitude by the 0.1-, 0.3-, and 1.0-mg/kg doses, while two other negative peaks in the VC emerged, beginning with the 0.1-mg/kg dose, to complicate the waveform. One negative peak developed between N1 and P2, while the other effectively split peak P2 (forming P2A and P2B). P2A was depressed at all doses, while P2B was depressed at 0.1 mg/kg but augmented at the 1.0-mg/kg dose. N2 was elevated by the 0.3- and 1.0-mg/kg doses, while P3 was increased in amplitude by all doses. N3 was transiently enhanced by the 0.3-mg/kg dose. SC amplitudes were less affected, with P3 and N4 reduced in amplitude by the 0.3- and 1.0-mg/ kg doses. The latencies of most components in both structures were decreased, often with all doses, but generally at the later recording times. A second experiment demonstrated significant MK-801-induced hyperthermia at all of the above doses, although a higher dose of 3.0 mg/kg MK-801 caused hypothermia. The reduction in component latencies may, therefore, result at least in part from a drug-induced hyperthermia. A third experiment demonstrated MK-801-induced changes in locomotor activity in rats in an open field. The effects were both dose and time dependent. The 0.3-mg/kg dose of MK-801 produced significant increases in the number of line crossings from 20-60 min in comparison to the saline condition. Increases in the number of line crossings with the 1.0-mg/kg dose peaked at 15 min, and then gradually declined. It is unlikely, however, that these changes in movement can account for the effects of MK-801 on evoked potentials. In conclusion, the results show that blockade of the ion channel associated with the NMDA receptor produces profound changes in the activity of the neural pathways that are reflected in the middle components of the flash-evoked potential recorded from the VC.     

Effects of repeated MK-801 on ambulation in mice and in sensitization following methamphetamine

The noncompetitive NMDA receptor antagonist MK-801, (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine, increased ambulatory activity in the mouse at doses over 0.1 mg/kg (IP). The effect was enhanced when 0.3 mg/kg MK-801 was repeatedly administered at intervals of 3–4 days. In contrast, a reduction of the effect was induced with repeated doses of 0.1 and 1 mg/kg. The mice that had repeatedly experienced 1 mg/kg MK-801 exhibited a decrease in the sensitivity to methamphetamine (2 mg/kg SC). In addition, the repeated co-administration of 1 mg/kg MK-801 with methamphetamine induced a decrease in the sensitivity to methamphetamine. No modification of methamphetamine sensitivity was elicited by 0.1 and 0.3 mg/kg MK-801 in both the single and co-administration schedules. On the other hand, established sensitization to methamphetamine was hardly affected by repeated treatment with 0.1–1 mg/kg MK-801. These results indicate that the mechanism of the inhibitory action of MK-801 on the development of methamphetamine sensitization is different from that of dopamine D₂ antagonists, which may act to decrease the effective unit dose of methamphetamine and reduce ambulation-increasing effect of methamphetamine.     

The H3 antagonist, ciproxifan, alleviates the memory impairment but enhances the motor effects of MK-801 (dizocilpine) in rats

Antagonists of H₃-type histamine receptors exhibit cognitive-enhancing properties in various memory paradigms as well as evidence of antipsychotic activity in normal animals. The present study determined if a prototypical H₃ antagonist, ciproxifan, could reverse the behavioral effects of MK-801, a drug used in animals to mimic the hypoglutamatergic state suspected to exist in schizophrenia. Four behaviors were chosen for study, locomotor activity, ataxia, prepulse inhibition (PPI), and delayed spatial alternation, since their modification by dizocilpine (MK-801) has been well characterized. Adult male Long-Evans rats were tested after receiving a subcutaneous injection of ciproxifan or vehicle followed 20 min later by a subcutaneous injection of MK-801 or vehicle. Three doses of MK-801 (0.05, 0.1, & 0.3 mg/kg) increased locomotor activity. Each dose of ciproxifan (1.0 & 3.0 mg/kg) enhanced the effect of the moderate dose of MK-801, but suppressed the effect of the high dose. Ciproxifan (3.0 mg/kg) enhanced the effects of MK-801 (0.1 & 0.3 mg/kg) on fine movements and ataxia. Deficits in PPI were observed after treatment with MK-801 (0.05 & 0.1 mg/kg), but ciproxifan did not alter these effects. Delayed spatial alternation was significantly impaired by MK-801 (0.1 mg/kg) at a longer delay, and ciproxifan (3.0 mg/kg) alleviated this impairment. These results indicate that some H₃ antagonists can alleviate the impact of NMDA receptor hypofunction on some forms of memory, but may exacerbate its effect on other behaviors.     

Lowered brain stimulation reward thresholds in rats treated with a combination of caffeine and N-methyl-D-aspartate but not alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate or metabotropic glutamate receptor-5 receptor antagonists

Previous studies suggested that adenosine A1 and A2A receptor agonists counteract behavioral effects of N-methyl-D-aspartate (NMDA) receptor antagonists while adenosine receptor antagonists may produce opposite effects enhancing the actions of NMDA receptor antagonists. To further evaluate the effects of combined administration of adenosine receptor antagonist caffeine and various NMDA and non-NMDA glutamate receptor antagonists on brain stimulation reward (discrete-trial threshold current intensity titration procedure), rats with electrodes implanted into the ventral tegmental area were tested after pretreatment with NMDA receptor channel blocker MK-801 (0.01-0.3 mg/kg), competitive antagonist D-CPPene (0.3-5.6 mg/kg), glycine site antagonist L-701,324 (1.25-5 mg/kg), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist GYKI-53655 (1-10 mg/kg), metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP (1-10 mg/kg) alone and in combination with caffeine (1-30 mg/kg). MK-801 (0.056 and 0.1 mg/kg) was the only tested glutamate antagonist that lowered self-stimulation thresholds, while D-CPPene (5.6 mg/kg) and MPEP (5.6 and 10 mg/kg) had the opposite effects. Threshold-increasing effects of D-CPPene, but not of MPEP, however, were associated with marked impairment of operant performance, reflected by longer latencies to respond and higher rates of responding during the inter-trial intervals. Operant performance was also disrupted by the highest dose of MK-801 (0.3 mg/kg). For subsequent experiments, caffeine (1-30 mg/kg) was combined with the highest doses of NMDA receptor antagonists that did not lower the brain stimulation reward thresholds and did not impair operant performance. Caffeine had no appreciable effects on self-stimulation behavior when given alone. A low dose of caffeine (3 mg/kg) significantly lowered self-stimulation thresholds only when given together with MK-801 (0.03 mg/kg) or D-CPPene (3 mg/kg). Combined with the same antagonist drugs, higher doses of caffeine (10 and 30 mg/kg) facilitated time-out responding. These results indicate that, within a limited dose range, caffeine in combination with an NMDA receptor channel blocker and a competitive antagonist significantly lowers brain stimulation reward thresholds in rats.     

Increased expression of neuronal Src and tyrosine phosphorylation of NMDA receptors in rat brain after systemic treatment with MK-801

We have observed that systemic treatment with the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 increases Src expression and NMDA receptor phosphorylation in rat brain. A partial cDNA encoding rat neuronal Src was isolated and its sequence was used to design specific oligonucleotide probes. Systemically administered MK-801 (5 mg/kg for 4 h) increased by 28+/-4% mRNA expression of neuronal Src in the superficial layers of the parietal cortex. This effect was observed at doses as low as 0.2 mg/kg. A similar, although more modest, induction was observed 6 h after phencyclidine (15 mg/kg) administration, but not after high doses of memantine and ketamine. The MK-801-induced effect was not blocked by pretreatment with clozapine. Consistent with the increase in mRNA levels, cortical Src protein was increased to 186 +/- 24% of control 24 h after MK-801 treatment. Total cellular Src activity was also increased in parietal cortex homogenates 4 h after MK-801 (5 mg/kg). Moreover, MK-801 treatment (0.5 mg/kg and 5 mg/kg for 4 h) increased tyrosine phosphorylation, but not protein levels, of the NMDA receptor subunit NR2A. These results provide evidence for a contribution of Src and tyrosine phosphorylation of NMDA receptors in the pharmacological actions of uncompetitive NMDA receptor antagonists.     

NMDA antagonist modulation of morphine antinociception in female vs. male rats

NMDA antagonists may be useful for their potential to increase or prolong opioid analgesia while attenuating the development of opioid tolerance and dependence. The purpose of this study was to determine whether there are sex differences in NMDA antagonist modulation of morphine antinociception. Adult female and male Sprague–Dawley rats were injected s.c. with saline or one dose of MK-801 (0.005, 0.01, 0.02, or 0.04 mg/kg), dextromethorphan (5, 10, or 20 mg/kg), or LY235959 (0.5, 1.0, or 2.0 mg/kg) in combination with saline or one dose of morphine (1.8, 3.2, or 5.6 mg/kg), and tested on the 50 °C hotplate and tail withdrawal assays 15–120 min post-injection. At the doses examined, only LY235959 produced any antinociception when administered alone. MK-801 attenuated morphine antinociception on both assays, but only at sporadic (inconsistent) dose-combinations. Dextromethorphan increased morphine antinociception on the hotplate but not tail withdrawal assay, at all three morphine doses in males, but only the higher morphine doses in females. In contrast, LY235959 modulated morphine antinociception on both assays; the lowest dose attenuated, and higher doses enhanced morphine antinociception, but the particular morphine doses and assay in which these effects occurred depended on the sex of the subject. Thus, all three NMDA antagonists modulated morphine antinociception in female and male rats, but the direction of this modulation depended on the particular antagonist examined, the nociceptive test, the dose of antagonist and of morphine, and time post-injection.     

Attenuation of morphine dependence and withdrawal by glycine B site antagonists in rats

Numerous data indicate that noncompetitive and competitive N-methyl-D-aspartate (NMDA) receptor antagonists inhibit the development of physical dependence on opioids when these substances are administered together, and NMDA receptor antagonists are used at lower range of doses. Higher doses of these antagonists can enhance some opioid-induced effects. The present study extends these findings to the effects of NMDA/glycine (glycine(B)) site antagonists. Wistar rats were rendered dependent on morphine by implantation of morphine pellets. Both of the glycine(B) site antagonists used, 7-chloro-4-hydroxy-3-(3-phenoxy)-phenyl-2(H)-quinolone (L-701,324; 2.5 and 5.0 mg/kg) and 5,7-dichlorokynurenic acid (5,7-DCKA; 25, 50, and 100 mg/kg), suppressed the expression of morphine withdrawal syndrome estimated as wet dog shakes. Furthermore, L-701,324 (2.5 and 5 mg/kg), given twice a day during the development of morphine dependence, attenuated the development of morphine dependence, and the results were comparable to those obtained after administration of noncompetitive NMDA receptor antagonist - MK801 (0.1 mg/kg). Our data suggest that glycine(B) site antagonists may attenuate wet dog shakes (withdrawal) and the development of dependence, both being induced by chronic morphine administration in rats.     

Sex-related differences in the enhancement of morphine antinociception by NMDA receptor antagonists in rats

The effect of the N-methyl-D-aspartate (NMDA) receptor antagonists dextromethorphan (DEX), ketamine (KET), and MK-801 on morphine (MOR)-induced antinociception has been investigated in male and female rats. DEX (7.5, 15, and 30 mg/kg), KET (0.75, 1.5, and 3 mg/kg), and MK-801 (0.075, 0.15, and 0.3 mg/kg) dose-dependently enhanced MOR-induced (3 mg/kg) analgesia in female rats. DEX and KET enhanced the peak effect, whereas MK-801 increased both magnitude and duration of analgesia. DEX also enhanced MOR-induced analgesia in male rats. However, the interaction was of less magnitude in male compared with female rats. The effects of KET and MK-801 on MOR-induced analgesia were negligible in male rats. A 3-mg/kg dose of MOR given alone produced greater analgesia in male than in female rats, but in the presence of NMDA antagonists, MOR elicited similar analgesic responses in both sexes.