Effects of tobacco smoke constituents, anabasine and anatabine, on memory and attention in female rats.

Nicotine has been well characterized to improve memory and attention. Nicotine is the primary, but not only neuroactive compound in tobacco. Other tobacco constituents such as anabasine and anatabine also have agonist actions on nicotinic receptors. The current study investigated the effects of anabasine and anatabine on memory and attention. Adult female Sprague-Dawley rats were trained on a win-shift spatial working and reference memory task in the 16-arm radial maze or a visual signal detection operant task to test attention. Acute dose-effect functions of anabasine and anatabine over two orders of magnitude were evaluated for both tasks. In the radial-arm maze memory test, anabasine but not anatabine significantly reduced the memory impairment caused by the NMDA antagonist dizocilpine (MK-801). In the signal detection attentional task, anatabine but not anabasine significantly attenuated the attentional impairment caused by dizocilpine. These studies show that non-nicotine nicotinic agonists in tobacco, similar to nicotine, can significantly improve memory and attentional function. Both anabasine and anatabine produced cognitive improvement, but their effectiveness differed with regard to memory and attention. Follow-up studies with anabasine and anatabine are called for to determine their efficacy as therapeutics for memory and attentional dysfunction.

MK-801 disrupts and nicotine augments 40 Hz auditory steady state responses in the auditory cortex of the urethane-anesthetized rat.

Patients with schizophrenia show marked deficits in processing sensory inputs including a reduction in the generation and synchronization of 40 Hz gamma oscillations in response to steady-state auditory stimulation. Such deficits are not readily demonstrable at other input frequencies. Acute administration of NMDA antagonists to healthy human subjects or laboratory animals is known to reproduce many sensory and cognitive deficits seen in schizophrenia patients. In the following study, we tested the hypothesis that the NMDA antagonist MK-801 would selectively disrupt steady-state gamma entrainment in the auditory cortex of urethane-anesthetized rat. Moreover, we further hypothesized that nicotinic receptor activation would alleviate this disruption. Auditory steady state responses were recorded in response to auditory stimuli delivered over a range of frequencies (10-80 Hz) and averaged over 50 trials. Evoked power was computed under baseline condition and after vehicle or MK-801 (0.03 mg/kg, iv). MK-801 produced a significant attenuation in response to 40 Hz auditory stimuli while entrainment to other frequencies was not affected. Time-frequency analysis revealed deficits in both power and phase-locking to 40 Hz. Nicotine (0.1 mg/kg, iv) administered after MK-801 reversed the attenuation of the 40 Hz response. Administered alone, nicotine augmented 40 Hz steady state power and phase-locking. Nicotine's effects were blocked by simultaneous administration of the α4ß2 antagonist DHßE. Thus we report for the first time, a rodent model that mimics a core neurophysiological deficit seen in patients with schizophrenia and a pharmacological approach to alleviate it.

Reversal of oxidative stress by histamine H3 receptor-ligands in experimental models of schizophrenia.

Schizophrenia (SCZ) is a debilitating disorder afflicting around 1% of the world population. Recent literature reveals oxidative injuries contribute enormously to the pathophysiology of SCZ alongside other psychopathological disturbances. Histamine H3R-antagonists have shown dual mechanism of action in experimental models of SCZ. Firstly it prevents oxidative stress and secondly alleviates schizophrenic symptoms, particularly the negative symptoms and cognitive deficits. In the present study, histamine H3R-antagonists used were ciproxifan (3.0 mg/kg, ip) and clobenpropit (15 mg/kg, ip) markedly controlled the elevated levels of various oxidative stress markers, for example, thiobarbituric acid reactive substance (TBARS), glutathione (GSH), superoxide dismutase, catalase, etc., as a result of augmented oxidative stress in the experimental models of SCZ such as amphetamine (0.5 mg/kg, sc) and dizocilpine (MK-801) (0.2 mg/kg, ip) induced locomotor hyperactivity, apomorphine (1.5 mg/kg, sc) induced climbing behavior and haloperidol (2.0 mg/kg, po) induced catalepsy. The results of the present study revealed that H3R-antagonists possess antioxidant activity and could serve with dual mechanism by supplementing antioxidant needs of SCZ and at the same time controlling symptoms of SCZ.

MK-801 alters Na+, K+-ATPase activity and oxidative status in zebrafish brain: reversal by antipsychotic drugs.

Schizophrenia is a debilitating mental disorder with a global prevalence of 1% and its etiology remains poorly understood. In the current study we investigated the influence of antipsychotic drugs on the effects of MK-801 administration, which is a drug that mimics biochemical changes observed in schizophrenia, on Na(+), K(+)-ATPase activity and some parameters of oxidative stress in zebrafish brain. Our results showed that MK-801 treatment significantly decreased Na(+), K(+)-ATPase activity, and all antipsychotics tested prevented such effects. Acute MK-801 treatment did not alter reactive oxygen/nitrogen species by 2'7'-dichlorofluorscein (H2DCF) oxidation assay, but increased the levels of thiobarbituric acid reactive substances (TBARS), when compared with controls. Some antipsychotics such as sulpiride, olanzapine, and haloperidol prevented the increase of TBARS caused by MK-801. These findings indicate oxidative damage might be a mechanism involved in the decrease of Na(+), K(+)-ATPase activity induced by MK-801. The parameters evaluated in this study had not yet been tested in this animal model using the MK-801, suggesting that zebrafish is an animal model that can contribute for providing information on potential treatments and disease characteristics.

Group II metabotropic glutamate receptor agonist ameliorates MK801-induced dysfunction of NMDA receptors via the Akt/GSK-3ß pathway in adult rat prefrontal cortex.

Pharmacological intervention targeting mGluRs has emerged as a potential treatment for schizophrenia, whereas the mechanisms involved remain elusive. We explored the antipsychotic effects of an mGluR2/3 agonist in the MK-801 model of schizophrenia in the rat prefrontal cortex. We found that the mGluR2/3 agonist LY379268 effectively recovered the disrupted expression of NMDA receptors induced by MK-801 administration. This effect was attributable to the direct regulatory action of LY379268 on NMDA receptors via activation of the Akt/GSK-3ß signaling pathway. As occurs with the antipsychotic drug clozapine, acute treatment with LY379268 significantly increased the expression and phosphorylation of NMDA receptors, as well as Akt and GSK-3ß. Physiologically, LY379268 significantly enhanced NMDA-induced current in prefrontal neurons and a GSK-3ß inhibitor occluded this effect. In contrast to the widely proposed mechanism of modulating presynaptic glutamate release, our results strongly argue that mGluR2/3 agonists modulate the function of NMDA receptors through postsynaptic actions and reverse the MK-801-induced NMDA dysfunction via the Akt/GSK-3ß pathway. This study provides novel evidence for postsynaptic mechanisms of mGluR2/3 in regulation of NMDA receptors and presents useful insights into the mechanistic actions of mGluR2/3 agonists as potential antipsychotic agents for treating schizophrenia.

Effects of neurosteroid actions at N-methyl-D-aspartate and GABA A receptors in the midbrain ventral tegmental area for anxiety-like and mating behavior of female rats.

RATIONALE: In the midbrain ventral tegmental area (VTA), actions of neurosteroids, such as the progesterone metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP), can facilitate mating and influence stress-related processes. Some actions of 3α,5α-THP may occur via positive modulation of GABA(A) receptors (GBRs), or negative modulation of N-methyl-D: -aspartate receptors (NMDARs), to influence anxiety-like behavior; but this is not known. OBJECTIVES: We aimed to assess the role that neurosteroids and stress factors play on intra-VTA NMDAR- and/or GBR-mediated anxiety-like and mating behavior. METHODS: Estradiol-primed, ovariectomized rats, which were partially or completely adrenalectomized (ADX), received infusions of vehicle, an NMDAR blocker (MK-801; 200 ng), or a GBR antagonist (bicuculline, 100 ng) to the VTA. Rats then received intra-VTA vehicle or a neurosteroidogenesis enhancer (N,N-Dihexyl-2-(4-fluorophenyl)indole-3-acetamide, FGIN 1-27, 5 µg) and anxiety-like and sexual behavior was assessed. RESULTS: Complete, compared to partial, ADX significantly reduced open arm exploration on an elevated plus maze, the proportion of females that engaged in mating, lordosis quotients, pacing of sexual contacts, and defensive aggression towards a sexually vigorous male. Intra-VTA MK-801 enhanced open arm investigation and the proportion of females that engaged in mating. Infusions of either, MK-801 or FGIN 1-27, enhanced lordosis and, when co-administered, FGIN 1-27 attenuated MK-801's lordosis-enhancing effects. Intra-VTA infusions of bicuculline, prior to FGIN 1-27, blocked FGIN 1-27's effects to enhance lordosis. CONCLUSIONS: Together, these data suggest that reduced NMDAR activity in the VTA may influence motivation to explore and engage in sexual behavior. These data suggest that neurosteroid actions at NMDARs and GBRs in the VTA are important for exploration and/or sexual behavior.

Nicotine and clozapine effects on attentional performance impaired by the NMDA antagonist dizocilpine in female rats.

Cognitive impairment is very prevalent in schizophrenia and is currently undertreated in most patients. Attentional deficit is one of the hallmark symptoms of schizophrenia. Antipsychotic drugs, which can be quite effective in combating hallucinations are often ineffective in reducing cognitive impairment and can potentiate cognitive impairment. Previously, we found that the antipsychotic drug clozapine impaired, while nicotine improved, the accuracy of rats performing a visual signal detection attentional task in normal rats. For the current study, in a model of cognitive impairment of schizophrenia with the NMDA antagonist dizocilpine (0.05 mg/kg), we examined the effects of clozapine and nicotine on significantly impaired attentional hit accuracy. This dizocilpine-induced impairment was significantly (p<0.05) reversed by either clozapine (1.25 mg/kg) or nicotine (0.025 mg/kg). Interestingly, when clozapine and nicotine were given together, they blocked each other's beneficial effects. When the effective doses of 1.25 mg/kg clozapine and 0.025 mg/kg nicotine were given together the combination no longer significantly reversed the dizocilpine-induced hit-accuracy impairment. Given that the great majority of people with schizophrenia smoke, the potential beneficial effects of clozapine on attentional function may be largely blocked by self-administered nicotine. In addition, there are promising results concerning the development of nicotinic treatments to reverse cognitive deficits including attentional impairment. This is supported in the current study by the reversal of the dizocilpine-induced attentional impairment by nicotine. However, in schizophrenia the efficacy of nicotinic treatments may be limited by co-treatment with antipsychotic drugs like clozapine. It will be important to determine which of the complex effects of clozapine and nicotine are key in reversing attentional impairment and how they block each other's effects for the development of therapy to combat the attentional impairment of schizophrenia.

Nicotine and clozapine actions on pre-pulse inhibition deficits caused by N-methyl-D-aspartate (NMDA) glutamatergic receptor blockade.

Pre-pulse inhibition (PPI) is a phenomenon of neurobehavioral plasticity in which the motor response to a startling stimulus is inhibited by a preceding stimulus of a lower intensity. Most often this is tested in the auditory mode. PPI is impaired in a variety of clinical states, most notably schizophrenia. PPI is easily modeled in experimental animals and serves as a useful basis for determining the neural bases for behavioral plasticity. In the current study we examined the interactions of N-methyl-D-aspartate (NMDA) glutamate and nicotinic cholinergic receptor systems in the expression of PPI. Female Sprague-Dawley rats were tested for auditory PPI after s.c. injections of the NMDA antagonist dizocilpine (also known as MK-801), the prototypic nicotinic agonist nicotine or both. Vehicle (saline) injections served as the control. Nicotine (0.2-0.8 mg/kg) by itself caused a modest but significant dose-related improvement in PPI. Dizocilpine (25-100 microg/kg) caused a dramatic dose-related impairment in PPI. Interestingly, the low to moderate doses of nicotine potentiated the PPI impairment by dizocilpine. In a second experiment nicotine and dizocilpine interactions with the atypical antipsychotic drug clozapine were assessed. As in the first experiment, nicotine potentiated the adverse effects of dizocilpine on PPI. The combination of nicotine with clozapine effectively attenuated the PPI impairment caused by dizocilpine when neither alone was effective. Inasmuch as PPI is impaired in schizophrenia, its reversal by the antipsychotic drug clozapine may depend on co-administration of nicotine by smoking in the patients. Development of nicotinic-based co-treatments for schizophrenia may achieve this benefit of nicotine without the hazards of smoking. Sensory modulation deficit, which is a syndrome of sensory over-responsiveness may also benefit from such combination therapy.

Erythropoietin protects the developing brain against N-methyl-D-aspartate receptor antagonist neurotoxicity.

Pharmacological blockade of NMDA receptor function induces apoptotic neurodegeneration in the developing rat brain. However, the use of NMDA receptor antagonists as anesthetics and sedatives represents a difficult-to-avoid clinical practice in pediatrics. This warrants the search for adjunctive neuroprotective measures that will prevent or ameliorate neurotoxicity of NMDA receptor antagonists. The NMDA receptor antagonist MK801 triggered apoptosis in the neonatal rat forebrain, most notably in cortex and thalamus. MK801 exposure reduced mRNA levels of erythropoietin (EPO) and the EPO receptor, suggesting that loss of endogenous EPO activity may contribute to MK801-induced apoptosis. Coadministration of recombinant EPO (rEPO) conferred 50% neuroprotection, partially restored MK801-induced reduction of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) mRNA, and prevented decreased phosphorylation levels of extracellular signal-regulated protein kinase-1/2 (ERK1/2) and Akt. These observations indicate that rEPO partly rescues newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways.

Chronic treatment with caffeine blunts the hyperlocomotor but not cognitive effects of the N-methyl-D-aspartate receptor antagonist MK-801 in mice.

RATIONALE: Administration of N-methyl- d-aspartate (NMDA) receptor antagonists produce hyperlocomotion and cognitive deficits in rodents. Activation of NMDA receptors promotes adenosine release, and adenosine agonists prevent central effects of NMDA receptor antagonists. We hypothesized that if NMDA receptor antagonists require adenosine to produce behavioral effects, mice tolerant to the adenosine receptor antagonist caffeine would have a diminished response to NMDA receptor antagonists. OBJECTIVES: To evaluate MK-801-induced hyperlocomotion and cognitive deficits after chronic caffeine treatment in mice. METHODS: Locomotor activity was analyzed in a computerized system, spontaneous alternation was assessed in the Y-maze and long-term memory was assessed with the inhibitory avoidance task in mice. RESULTS: Mice chronically treated with caffeine in drinking solution (1 mg/ml for 7 days) presented normal habituation and substantial tolerance to acute caffeine (30 mg/kg, i.p.) locomotor effects. MK-801 (0.25 mg/kg, i.p.) produced pronounced hyperlocomotion in water-treated mice, but this effect was abolished in caffeine-drinking mice. Chronic caffeine treatment had no influence on either normal or MK-801-induced deficits in spontaneous alternation and inhibitory avoidance tasks. CONCLUSION: Hyperlocomotion induced by MK-801 may be mediated by reduced adenosinergic activity. These results also suggest that locomotor and cognitive effects of MK-801 can be dissociated and are distinctly modulated. Finally, these findings agree with the adenosine hypofunction model of schizophrenia, since NMDA receptor antagonists are a pharmacological model for this disorder.

[Glutamate hypothesis of schizophrenia and targets for new antipsychotic drugs].

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) and ketamine have been known to cause schizophrenia-like psychosis (positive symptoms, negative symptoms, cognitive dysfunction) in humans. A dysfunction of glutamatergic neurotransmission may play an important role in the pathophysiology of schizophrenia. In this review, the glutamate hypothesis of schizophrenia, especially the mechanism of neurotoxicity of NMDA receptor antagonist in the posterior cingulate cortex and retrosplenial cortex of the brain, is summarized. Furthermore, the roles of the posterior cingulate cortex and the retrosplenial cortex in the pathophysiology of schizophrenia and Alzheimer's disease are also discussed. Moreover, the glycine site of the NMDA receptor, metabotropic glutamate receptor, AMPA receptor, and antioxidant glutathione as novel potential targets for the treatment of schizophrenia are discussed.

[NADPH-diaphorase activity and Fos expression in brainstem nuclei involved in cardiovascular regulation following intracarotid injection of capsaicin].

The present study was undertaken to define whether intracarotid injection of capsaicin induces Fos expression associated with the activation of NOS-containing neurons in brainstem nuclei by combining the immunocytochemical method for Fos with NADPH-d histochemical technique for NOS. The results obtained are as follows: (1) Intracarotid injection of capsaicin caused a significant increase of Fos-like immunoreactive neurons in area postrema (AP), nucleus tractus solitarius (NTS), paragigantocellularis lateralis (PGL) and locus coeruleus (LC), without influence upon the neurons of raphe nuclei (RN) and periaqueductal gray (PAG). (2) NO-containing neurons in PGL and NTS and the double-labeled neurons in PGL were also increased significantly following intracarotid injection of capsaicin. Small numbers of NO-containing neurons were found in LC, but there was no change in the number of NO-containing neurons in RN and PAG. No NADPH-d histochemical activity could be found in AP. (3) The above responses to capsaicin were significantly inhibited by pretreatment with either a capsaicin receptor antagonist ruthenium red or a NMDA receptor antagonist MK-801. The above results indicate that intracarotid injection of capsaicin may activate the neurons in brainstem nuclei involved in cardiovascular regulation, and that NO only plays an indirect role in the modulation of the responses of brainstem nuclei to capsaicin. These effects of capsaicin are mediated by capsaicin receptors with involvement of glutamate.

Characterization of MK-801-induced behavior as a putative rat model of psychosis.

The objective of this study was to characterize the behavior induced by the N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine maleate) in rats as a model of psychosis. The temporal profile, dose dependence, age, and sex differences of the behavior are described. A gas chromatographic method for the analysis of MK-801 in plasma and brain was developed. Female rats showed 4 to 10 times more MK-801-induced behavior and displayed around 25 times higher serum and brain concentrations of MK-801 than male rats. Twenty-one neuroactive compounds, including a number of excitatory amino acid-active substances, were tested for the effect on MK-801-induced behavior. Neuroleptics blocked MK-801-induced behavior in a dose-dependent manner that correlated to their antipsychotic potency in humans. Adenosine receptor agonists and an N-methyl-D-aspartate receptor-associated glycine site antagonist showed putative antipsychotic effects. In conclusion, MK-801-induced behavior represents a rat excitatory amino acid hypofunction model of psychosis that appears to be of clinical relevance and may be of value in the search for new antipsychotic agents.

Effects of 5-hydroxytryptamine2 receptor antagonism on the behavioral activation and immediate early gene expression induced by dizocilpine.

The noncompetitive N-methyl-D-aspartate (NMDA) antagonists dizocilpine and phencyclidine cause behavioral changes in animals that can be blocked by antipsychotic agents, implicating NMDA receptors in the expression of schizophrenic symptoms. In the present study, we examined the effects of dizocilpine (0.1-3.0 mg/kg s.c.) on locomotor activity and on the expression of c-fos and hsp-70 immediate-early genes (IEGs) in mice. Results indicate that dizocilpine increases locomotor activity and selectively increases the expression of c-fos and hsp-70 in the posterior cingulate cortex. Haloperidol (0.01-0.1 mg/kg) and clozapine (0.6-1.25 mg/kg) block both the locomotor response and the increased IEG immunoreactivity induced by dizocilpine (0.6 mg/kg). The 5-HT2 antagonists ritanserin (0.06-0.25 mg/kg), ketanserin (0.03-0.12 mg/kg) and amesergide (0. 3-1.25 mg/kg) also significantly attenuated the locomotor response to dizocilpine. Haloperidol and clozapine suppressed the head weaving induced by dizocilpine, but ritanserin, as previously reported did not. Although some attenuation of the c-fos and hsp-70 immunoreactivity was seen with the 5-HT2 antagonists it was less pronounced than that induced by haloperidol or clozapine. In conclusion, 5-HT2 antagonists as well as antipsychotic compounds attenuate the locomotor response to dizocilpine in mice. Haloperidol and clozapine appear to be more effective, however, in attenuating the expression of c-fos and hsp-70 in the posterior cingulate gyrus than 5-HT2 antagonists ritanserin, ketanserin or amesergide. We thus have seen a dissociation in the capacity of compounds to alter the effects on behavior and IEG expression after dizocilpine administration.

Both nicotine and mecamylamine block dizocilpine-induced explosive jumping behavior in mice: psychiatric implications.

Dizocilpine (MK-801) administration to an outbred strain of NIH Swiss mice elicits discrete episodes of explosive jumping behavior designated as "popping." This behavior may serve as a useful preclinical paradigm for the screening of potentially novel antipsychotic medications. Both nicotine and mecamylamine, a nicotinic antagonist, dose-dependently blocked dizocilpine-induced popping. The data suggest that nicotine may be of therapeutic benefit in the treatment of schizophrenia and that some of its effects may be mediated by non-nicotinic receptors.

Attenuating effect of bifemelane on an impairment of mealtime-associated activity rhythm in aged and MK-801-treated rats.

In the present experiment, we examined the attenuating effect of bifemelane hydrochloride (BF), 4-(o-benzyl phenoxy)-N-methylbutylamine hydrochloride, on the impairment of time perception caused by daily scheduled feeding using aged and MK-801-treated rats. When feeding was restricted to a single meal at a fixed time of day (1300-1700 h) for six successive days, young rats exhibited intense locomotor activity 1-3 h before feeding time. Intense locomotor activity was observed for 1200-1700 h even on the fasting day (day 7; mealtime-associated activity). Mealtime-associated activity was impaired in 24-mo-old rats and also in N-methyl-D-aspartate receptor antagonist, MK-801-treated rats. Daily injections of bifemelane at 1700 h for six successive days significantly attenuated the impairment of mealtime-associated activity on the seventh day in a dose-dependent manner in aged rats. In addition, cotreatment of MK-801 with bifemelane blocked the MK-801-induced impairment of mealtime-associated activity. The present study suggests that bifemelane has an enhancing effect on learning and memory performance, such as spatial and temporal perception.

Locomotor activation induced by MK-801 in the rat: postsynaptic interactions with dopamine receptors in the ventral striatum.

The effects of bilateral 6-hydroxydopamine-induced destruction of the dopamine nerve terminals in the ventral striatum (nucleus accumbens) or pharmacological blockade of dopamine receptors with haloperidol injected locally into this area were examined on the locomotor hyperactivity induced by systemic administration of the non-competitive NMDA receptor antagonist, MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d) cyclohepten-5,10-imine hydrogen maleate salt). The locomotor stimulation induced by two doses of MK-801 (0.15 and 0.3 mg/kg, i.p.) was not attenuated by 6-hydroxydopamine bilateral lesions to the ventral striatum, either 7 or 14 days after the operation. The same lesion however reduced the locomotor activation induced by 0.5 mg/kg d-amphetamine 14 days after surgery. Bilateral intra-accumbens injection of haloperidol at a dose (2.5 micrograms/side) that blocked d-amphetamine-induced hypermotility did not reduce the locomotor response to 0.3 mg/kg MK-801, while 5 micrograms/side haloperidol decreased the MK-801-induced locomotor stimulation. These results suggest that the locomotor response to MK-801 is dependent on an interaction between dopaminergic and excitatory amino acid transmission occurring postsynaptically rather than presynaptically in the ventral striatum.

Noncompetitive inhibition of N-methyl-D-aspartate by conantokin-G: evidence for an allosteric interaction at polyamine sites.

Conantokins T and G are polypeptide toxins present in snails of the genus Conus. These substances were recently reported to act as N-methyl-D-aspartate (NMDA) antagonists. In the present study, we examined the possible mechanisms producing this antagonism. Conantokin-G inhibited spermine- and spermidine-stimulated [3H]MK-801 binding to extensively washed rat forebrain membranes in a noncompetitive manner with IC50 values of approximately 507 and approximately 946 nM, respectively. In contrast, glutamate-enhanced [3H]MK-801 binding was unaffected by conantokin-G concentrations of less than or equal to 20 microM. At concentrations greater than or equal to 5 microM, conantokin-G effected a modest, noncompetitive inhibition of glycine-stimulated [3H]MK-801 binding and also produced a small enhancement of basal [3H]MK-801 binding. Conantokin-G reduced (IC50 approximately 1.08 microM) the NMDA-stimulated accumulation of cyclic GMP in cerebellar granule cell cultures to basal values, but did not affect kainate-mediated increases in cyclic GMP. These findings indicate that conantokin-G acts as a noncompetitive NMDA antagonist through an allosteric inhibition of polyamine responses. The neurochemical profile of this polypeptide is distinct from previously described noncompetitive NMDA antagonists.