Glycine and <Emphasis Type="SmallCaps">d</Emphasis>-serine,but not <Emphasis Type="SmallCaps">d</Emphasis>-cycloserine,attenuate prepulse inhibition deficits induced by NMDA receptor antagonist MK-801

RATIONALE: Several agents that stimulate the glycine site of N-methyl-D: -aspartate (NMDA) receptors have been reported to moderately improve both negative symptoms and cognitive dysfunctions in patients with schizophrenia. However, differences in efficacy have also been reported, and further comparative pharmacological studies are still needed. OBJECTIVES: We aimed to explore the effects of two glycine site agonists of the NMDA receptor, glycine and D: -serine, and a partial agonist, D: -cycloserine, on prepulse inhibition (PPI) deficits induced by a NMDA receptor antagonist, MK-801, in mice. Furthermore, we performed in vivo microdialysis and additional PPI measurements using a selective glycine site antagonist to verify if the beneficial effects observed after the systemic administration of glycine were due to glycine itself via its activity at the glycine site. RESULTS: High doses of glycine (1.6 g/kg) and D: -serine (1.8 and 2.7 g/kg) significantly attenuated MK-801-induced PPI deficits. In contrast, D: -cycloserine did not show any amelioration of MK-801-induced PPI deficits at doses ranging from 7.5 mg/kg to 60 mg/kg. The selective glycine site antagonist, L-701,324 (10 mg/kg), antagonized the effect of glycine on MK-801-induced PPI deficits. Furthermore, in vivo microdialysis demonstrated that intraperitoneal injection of glycine significantly increased glycine and L: -serine levels, but decreased D: -serine levels in the prefrontal cortex. CONCLUSIONS: The findings of the present study suggest that glycine and D: -serine but not D: -cycloserine could attenuate PPI deficits associated with NMDA receptor hypofunction via NMDA glycine sites in the brain.     

The effect of zotepine, risperidone, clozapine and olanzapine on MK-801-disrupted sensorimotor gating

Dizocilpine (MK-801; 0.3 mg/kg i.p.)-induced disruption in prepulse inhibition of the acoustic startle response (PPI) can be preferentially restored by “atypical” antipsychotics. In contrast, some findings indicate that not all of the “atypical” antipsychotics, such as clozapine and risperidone, are effective in restoring the NMDA antagonist-induced deficits in PPI.

In our study, we evaluated the effect of four different “atypical” antipsychotic drugs on deficits in PPI induced by MK-801. Zotepine and risperidone have high affinities to D2-like and 5-HT_2A receptors, while clozapine and olanzapine have multipharmacological profiles with the highest affinities to serotonin 5-HT_1A,2A/2C receptors and muscarinic receptors.

Results have shown that MK-801 disrupted PPI and increased the ASR in rats. Our results showed no effect of zotepine (1 and 2 mg/kg) and risperidone (0.1 and 1 mg/kg) on disrupted PPI by MK-801. Administration of clozapine (5 and 10 mg/kg) and olanzapine (2.5 and 5 mg/kg) restored the deficits in PPI induced by MK-801. Additionally, we found a decrease of approximately 46% in PPI after administration of clozapine (5 mg/kg) and olanzapine (2.5 and 5 mg/kg) without MK-801 treatment.

In summary, the four “atypical” antipsychotics had different efficacies to restore the disrupted PPI by MK-801. Only clozapine and olanzapin restored the MK-801-induced deficits in PPI.     

Abnormally persistent latent inhibition induced by MK801 is reversed by risperidone and by positive modulators of NMDA receptor function: differential efficacy depending on the stage of the task at which they are administered

Rationale Latent inhibition (LI) is the poorer conditioning to a stimulus resulting from its nonreinforced preexposure. LI indexes the ability to ignore irrelevant stimuli and is used extensively to model attentional impairments in schizophrenia (SZ). We showed that rats and mice treated with the N-methyl-d-aspartic acid (NMDA) receptor antagonist MK801 expressed LI under conditions preventing LI expression in controls. This abnormally persistent LI was reversed by the atypical antipsychotic drug (APD) clozapine and by compounds enhancing NMDA transmission via the glycineB site, but not by the typical APD haloperidol, lending the MK801 LI model predictive validity for negative/cognitive symptoms. Objective To test additional representatives from the two classes of drugs and show that the model can dissociate between atypical APDs and glycinergic drugs are the objectives of the study. Materials and methods LI was measured in a conditional emotional response procedure. Atypical APD risperidone, selective 5HT2A antagonist M100907, and three glycinergic drugs were administered in preexposure or conditioning. Results Rats treated with MK801 (0.05 mg/kg) exhibited LI under conditions that disrupted LI in controls. This abnormality was reversed by risperidone (0.25 and 0.067 mg/kg) and M100907 (1 mg/kg) given in preexposure. Glycine (0.8 g/kg), d-cycloserine (DCS;15 and 30 mg/kg), and glycyldodecylamide (GDA; 0.05 and 0.1 g/kg.) counteracted MK801-induced LI persistence when given in conditioning. Conclusions These results support the validity of MK801-induced persistent LI as a model of negative/cognitive symptoms in SZ and indicate that this model may have a unique capacity to discriminate between typical APDs, atypical APDs, and glycinergic compounds, and thus, foster the identification of novel treatments for SZ.     

Effects of the H<Subscript>3</Subscript> antagonist,thioperamide, on behavioral alterations induced by systemic MK-801 administration in rats

Rationale  Recent studies have raised the possibility that antagonists of H₃ histamine receptors possess cognitive-enhancing and antipsychotic properties. However, little work has assessed these compounds in classic animal models of schizophrenia. Objectives  The purpose of this study was to determine if a prototypical H₃ antagonist, thioperamide, could alter behavioral deficits caused by the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, in adult male rats. MK-801 was chosen to be studied since it produces a state of NMDA receptor hypofunction in rats that may be analogous to the one hypothesized to occur in schizophrenia. Methods  The interaction between thioperamide and MK-801 was measured in three behavioral tests: locomotor activity, prepulse inhibition (PPI), and delayed spatial alternation. In each test, rats received a subcutaneous injection of saline or thioperamide (3.0 and 10 mg/kg) followed 20 min later by a subcutaneous injection of saline or MK-801 (0.05, 0.10, and 0.30 mg/kg). Results  Locomotor activity was significantly elevated by MK-801 in a dose-dependent manner. Thioperamide pretreatment alone did not alter locomotor activity; however, its impact on MK-801 was dose-dependent. Each thioperamide dose enhanced the effects of two lower doses of MK-801 but reduced the effect of a higher MK-801 dose. Clear deficits in PPI and delayed spatial alternation were produced by MK-801 treatment, but neither impairment was significantly modified by thioperamide pretreatment. Conclusions  H₃ receptors modulate responses to NMDA antagonists in behaviorally specific and dose-dependent ways.     

Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia

RATIONALE: Schizophrenic patients demonstrate prominent negative and cognitive symptoms that are poorly responsive to antipsychotic treatment. Abnormal glutamatergic neurotransmission may contribute to these pathophysiological dimensions of schizophrenia. OBJECTIVE: We examined the involvement of the glycine coagonist site on the N-methyl-D: -aspartate receptor (NMDAR) glycine coagonist site in the modulation of negative and cognitive endophenotypes in mice. MATERIALS AND METHODS: Behavioral phenotypes relevant to schizophrenia were assessed in Grin1(D481N) mice that have reduced NMDAR glycine affinity. RESULTS: Grin1(D481N) mutant mice showed abnormally persistent latent inhibition (LI) that was reversed by two agents that enhance NMDAR glycine site function, D: -serine (600 mg/kg) and ALX-5407 (1 mg/kg), and by the classical atypical antipsychotic clozapine (3 mg/kg). Similarly, blockade of the NMDAR glycine site with the antagonist L-701,324 (5 mg/kg) induced persistent LI in C57BL6/J mice. In a social affiliations task, Grin1(D481N) mutant animals showed reduced social approach behaviors that were normalized by D: -serine (600 mg/kg). During a nonassociative spatial object recognition task, mutant mice demonstrated impaired reactivity to a spatial change that was reversible by D: -serine (300 and 600 mg/kg) and clozapine (0.75 mg/kg). In contrast, responses to social novelty and nonspatial change remained unaffected, indicating that the Grin1(D481N) mutation induces selective deficits in sociability and spatial discrimination, while leaving intact the ability to react to novelty. CONCLUSIONS: Genetic and pharmacologically induced deficiencies in glycine binding appear to model the impairments in behavioral flexibility, sociability, and spatial recognition related to the negative and cognitive symptoms of schizophrenia. Antipsychotics that target the NMDAR glycine site may be beneficial in treating such psychiatric symptoms.     

Systemic administration of MK-801 produces an abnormally persistent latent inhibition which is reversed by clozapine but not haloperidol

Abstract Rationale. Latent inhibition (LI) refers to retarded conditioning to a stimulus as a consequence of its inconsequential pre-exposure, and disrupted LI in the rat is considered to model an attentional deficit in schizophrenia. Blockade of NMDA receptor transmission, which produces behavioral effects potentially relevant to schizophrenic symptomatology in several animal models, has been reported to spare LI. Objectives. To show that systemic administration of the non-competitive NMDA antagonist MK-801 will lead to an abnormally persistent LI which will emerge under conditions that disrupt LI in controls, and that this will be reversed by the atypical neuroleptic clozapine but not by the typical neuroleptic haloperidol, as found for other NMDA antagonist-induced models. Methods. LI was measured in a thirst-motivated conditioned emotional response (CER) procedure by comparing suppression of drinking in response to a tone in rats which previously received 0 (non-pre-exposed) or 40 tone exposures (pre-exposed) followed by two (experiment 1) or five (experiments 2–5) tone – foot shock pairings. Results. MK-801 at doses of 0.1 and 0.2 mg/kg reduced conditioned suppression while no effect on suppression was seen at the 0.05 mg/kg dose. At the latter dose, intact LI was seen with parameters that produced LI in controls (40 pre-exposures and two conditioning trials). Raising the number of conditioning trials to five disrupted LI in control rats, but MK-801-treated rats continued to show LI, and this abnormally persistent LI was due to the action of MK-801 in the conditioning stage. MK-801-induced LI perseveration was unaffected by both haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) administered in conditioning, and was reversed by clozapine but not by haloperidol administered in pre-exposure. Conclusion. MK-801-induced perseveration of LI is consistent with other reports of perseverative behaviors, suggested to be particularly relevant to negative symptoms of schizophrenia, following NMDA receptor blockade. We suggest that LI perseveration may model impaired attentional set shifting associated with negative symptoms of schizophrenia. Moreover, the finding that the action of MK-801 on LI and the action of clozapine are exerted in different stages of the LI procedure suggests that the MK-801-based LI model may provide a unique screening tool for the identification of novel antipsychotic compounds, whereby the schizophrenia-mimicking LI abnormality is drug-induced, but the detection of the antipsychotic action is not dependent on the mechanism of action of the pro-psychotic drug. Electronic Publication     

The effects of haloperidol and clozapine on the disruption of sensorimotor gating induced by the noncompetitive glutamate antagonist MK-801

The amplitude of the acoustic startle response in rats is decreased if the startle stimulus is preceded by a nonstartle-eliciting auditory stimulus. This sensory gating phenomenon, known as prepulse inhibition, is diminished in schizophrenic individuals. In rats, the noncompetitive glutamate antagonist MK-801 disrupts prepulse inhibition. The present study examined whether the disruption by MK-801 is reversible in rats pretreated with the classical antipsychotic haloperidol or the atypical antipsychotic clozapine. Male Sprague-Dawley rats were placed into a startle chamber and presented with auditory stimuli consisting of either 95 or 105 dB tones presented alone or preceded by a 70 dB tone. Rats treated with 0.1 mg/kg MK-801 demonstrated a significant disruption of prepulse inhibition. Haloperidol (0.1 and 0.5 mg/kg) and clozapine (1.0 and 5.0 mg/kg) each consistently failed to antagonize the MK-801-induced blockade of prepulse inhibition. The effects of haloperidol and clozapine on prepulse inhibition were also examined in saline-treated rats. Clozapine and, to some extent, haloperidol produced a dose-related facilitation of prepulse inhibition. Although preliminary, this finding raises the possibility that the enhancement of prepulse inhibition by antipsychotics might provide a useful rodent model for screening potential antipsychotic drugs.     

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.     

Effects of haloperidol, clozapine, and quetiapine on sensorimotor gating in a genetic model of reduced NMDA receptor function

Rationale Reduced N-methyl d-aspartate (NMDA) receptor function is hypothesized to contribute to the pathophysiology of schizophrenia. In order to model chronic and developmental NMDA receptor hypofunction, a mouse line was developed that expresses low levels of the NMDA R1 (NR1) subunit of the NMDA receptor. These mice show increased acoustic startle reactivity and deficits in prepulse inhibition (PPI) of acoustic startle. Objectives The present study tested the hypothesis that these altered acoustic startle responses in the NR1 hypomorphic (NR1−/−) mice would be affected by antipsychotic drug treatment. Methods Mice were injected with drugs 30 min before assessment of acoustic startle responses with and without prepulse stimuli. Results Haloperidol (0.5 or 1.0 mg/kg) did not reduce the increased startle reactivity in the NR1−/− mice, but did increase PPI in both the mutant and wild type mice. Clozapine (3 mg/kg) and quetiapine (20 mg/kg) reduced startle magnitude and increased PPI in both the wild type and mutant mice. The antidepressant drug imipramine (10 and 20 mg/kg) had minimal effects on startle amplitude in NR1−/− or wild type mice. However, for the 20-mg/kg dose of imipramine, a significant increase in PPI was observed in the wild type animals, but not in the mutant mice. Conclusions The results demonstrate that PPI can be increased in a mouse model of chronic NMDA receptor hypofunction by typical and atypical antipsychotic drugs. The similar effects of typical and atypical antipsychotic drugs to increase PPI in the wild type and mutant mice indicates that the assessment of behavior of the NR1 hypomorphic mice in the PPI paradigm offers no advantage over the wild type controls for identifying new clozapine-like drugs.     

Reversal of phencyclidine-induced prepulse inhibition deficits by clozapine in monkeys

Rationale Prepulse inhibition (PPI) of the acoustic startle reflex is a measure of sensorimotor gating, which occurs across species and is deficient in severe neuropsychiatric disorders such as schizophrenia. In monkeys, as in rodents, phencyclidine (PCP) induces schizophrenia-like deficits in PPI. In rodents, in general, typical antipsychotics (e.g. haloperidol) reverse PPI deficits induced by dopamine (DA) agonists (e.g. apomorphine), but not those induced by N-methyl-d-aspartate (NMDA) receptor antagonists [e.g. phencyclidine (PCP)], whereas atypical antipsychotics (e.g. clozapine) reverse PPI deficits induced by DA agonists and NMDA antagonists. However, some discrepancies exist with some compounds and strains of rodents.Objectives This study investigated whether a typical (haloperidol, 0.035 mg/kg) and an atypical (clozapine, 2.5 mg/kg) antipsychotic could be distinguished in their ability to reverse PCP-induced deficits in PPI in eight monkeys (Cebus apella).Methods First, haloperidol dose was determined by its ability to attenuate apomorphine-induced deficits in PPI. Then, haloperidol and clozapine were tested in eight monkeys with PCP-induced deficits of PPI. Experimental parameters were similar to standard human PPI procedures, with 115 dB white noise startle pulses, either alone or preceded by 120 ms with a prepulse 16 dB above the 70 dB background noise.Results Clozapine reversed PCP-induced PPI deficits. In contrast, haloperidol did not significantly attenuate PCP-induced PPI deficits even at doses that significantly attenuated apomorphine effects.Conclusions In this primate model, clozapine was distinguishable from haloperidol by its ability to attenuate PCP-induced deficits in PPI. The results provide further evidence that PPI in nonhuman primates may provide an important animal model for the development of novel anti-schizophrenia medications.     

A two-hit model: behavioural investigation of the effect of combined neonatal MK-801 administration and isolation rearing in the rat

This study combined two neurodevelopmental manipulations, neonatal MK-801 treatment and isolation rearing, to produce a 'two-hit' model and determine whether two hits induce a more robust behavioural phenotype of an animal model of aspects of schizophrenia compared with individual manipulations alone. The effect of clozapine was also assessed. Male Sprague-Dawley rats received 0.2 mg/kg MK-801 or saline intraperitoneally (i.p.) once daily on postnatal days (PNDs) 7-10 and were assigned to group or isolation rearing at weaning (PND 21). From PND 77, they received a vehicle or 5 mg/kg clozapine (i.p.) treatment regimen and were subjected to three prepulse inhibition (PPI) tests, a locomotor activity assessment and a novel object recognition task. MK-801-treated rats reared in isolation displayed robust PPI disruptions which were consistently manifested in all three tests. PPI deficits were also detected in saline-treated rats reared in isolation but not in all tests. Only the two-hit rats demonstrated hyperlocomotion and impaired object recognition memory. Clozapine restored PPI anomalies in the two-hit rats. The two-hit model showed greater psychotic-like effects than either neonatal MK-801 or isolation rearing alone. The preliminary predictive validity shown with clozapine suggests this model may be useful for predicting the efficacy of putative antipsychotics.     

mGluR5, but not mGluR1, antagonist modifies MK-801-induced locomotor activity and deficit of prepulse inhibition

Hypoglutamatergic theory of schizophrenia is substantiated by observation that high affinity uncompetitive antagonists of NMDA receptors such as PCP can induce psychotic symptoms in humans. Recently, metabotropic glutamate receptors of the mGluR5 type have also been discussed as possible players in this disease. However, less is known about the potential contribution of mGluR1 in schizophrenia. Therefore, the aim of the present study was to compare the effect of selective mGluR1 antagonist EMQMCM, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) and mGluR5 antagonist (MTEP ([(2-methyl-1, 3-thiazol-4-yl) ethynyl] pyridine) either alone or in combination with (+)MK-801 in a prepulse inhibition (PPI) model and locomotor activity tests. Additionally, the effect of both mGluR1 and mGluR5 antagonists on (+)MK-801-evoked ataxia was tested. In contrast to (+)MK-801, which induced disruption of PPI, neither MTEP (1.25-5 mg/kg) nor EMQMCM (0.5-4 mg/kg) altered the PPI. However, MTEP, but not EMQMCM, enhanced disruption of PPI induced by (+)MK-801. Although neither mGluR1 nor mGluR5 antagonists given alone changed locomotor activity of rats, MTEP at 5 mg/kg potentiated the effect of (+)MK-801 while EMQMCM (up to 4 mg/kg) turned out to be ineffective. On the other hand, EMQMCM, but not MTEP, enhanced ataxia evoked by MK-801. The present results demonstrate that blockade of mGluR1 and mGluR5 evokes different effects on behavior induced by NMDA receptor antagonists.     

Cannabidiol reverses MK-801-induced disruption of prepulse inhibition in mice.

Cannabidiol, a nonpsychoactive constituent of the Cannabis sativa plant, has been reported to act as an agonist of the vanilloid 1 channel in the transient receptor potential family (TRPV1) and also to inhibit the hydrolysis and cellular uptake of the endogenous cannabinoid anandamide. Cannabidiol has also been reported to have potential as an antipsychotic. We investigated the effect of cannabidiol on sensorimotor gating deficits in mice induced by the noncompetitive NMDA receptor antagonist, MK-801. Sensorimotor gating is deficient in psychotic disorders such as schizophrenia and may be reliably measured by prepulse inhibition (PPI) of the startle response in rodents and humans. MK-801 (0.3-1 mg/kg i.p.) dose dependently disrupted PPI while cannabidiol (1-15 mg/kg i.p.), when administered with vehicle, had no effect on PPI. Cannabidiol (5 mg/kg i.p.) successfully reversed disruptions in PPI induced by MK-801 (1 mg/kg i.p.), as did the atypical antipsychotic clozapine (4 mg/kg i.p.). Pretreatment with capsazepine (20 mg/kg i.p.) prevented the reversal of MK-801-induced disruption of PPI by cannabidiol, providing preliminary evidence that TRPV1 receptors are involved in the reversal of MK-801-induced sensorimotor gating deficits by cannabidiol.     

Antipsychotic agents antagonize non-competitiveN-methyl-d-aspartate antagonist-induced behaviors

Antipsychotic agents were tested for their ability to antagonize both dopaminergic-induced and non-competitiveN-methyl-d-aspartate (NMDA) antagonist-induced behaviors. All of the agents dose-dependently antagonized the apomorphine-induced climbing mouse assay (CMA) and dizocilpine (MK-801)-induced locomotion and falling assay (MK-801-LF) with a CMA/MK-801-LF ratio of less than or equal to 1.6. However, clozapine and its structural analog olanzapine more potently antagonized MK-801-LF (1.1 and 0.05 mg/kg) than the CMA (12.3 and 0.45 mg/kg) and as a result had a CMA/MK-801-LF ratio of 11.2 and 9, respectively. Furthermore, phencyclidine (PCP) (2 mg/kg) can selectively induce social withdrawal in naive rats that were housed in pairs (familiar) for 10 days prior to testing without affecting motor activity. SCH 23390, raclopride, haloperidol, chlorpromazine and risperidone failed to reverse the social withdrawal induced by PCP up to doses which produced significant motor impairment. However, clozapine (2.5 and 5.0 mg/kg) and olanzapine (0.25 and 0.5 mg/kg) significantly reversed this social withdrawal in rats. Therefore, the non-competitive NMDA antagonists PCP and MK-801 can induce behaviors in Rodents which are selectively antagonized by clozapine and olanzapine. Furthermore, assessment of the effects of antipsychotic agents in the CMA, MK-801-LF and PCP-induced social withdrawal assays may provide a preclinical approach to identify novel agents for negative symptoms and treatment resistant schizophrenia.     

Habituation of acoustic startle is disrupted by psychotomimetic drugs: differential dependence on dopaminergic and nitric oxide modulatory mechanisms

Rationale A deficit in attention and information processing has been considered a central feature in schizophrenia, which might lead to stimulus overload and cognitive fragmentation. It has been shown that patients with schizophrenia display a relative inability to gate incoming stimuli. Thus, patients repeatedly subjected to acoustic startle-eliciting stimuli habituate less to these stimuli than controls. Furthermore, schizophrenia-like symptoms can be induced by pharmacological manipulations in humans by psychotomimetic drugs, e.g. phencyclidine (PCP) and d-amphetamine (d-AMP). Recent studies show that the behavioural and biochemical effects of PCP in rodents are blocked by nitric oxide synthase (NOS) inhibitors, suggesting that NO plays an important role in at least the pharmacological effects of PCP.Objectives The first aim of the present study was to investigate if PCP, MK-801 and d-AMP impair habituation of acoustic startle in mice. Secondly, we examine the effect of the NOS inhibitor, l-NAME, and the dopamine receptor antagonist, haloperidol, on drug-induced deficit in habituation.Results PCP (4 mg/kg), MK-801 (0.4 mg/kg) and d-AMP (5.0 mg/kg), impaired habituation of the acoustic startle response in mice. This effect was reversed by the NOS inhibitor, l-NAME. The typical antipsychotic, haloperidol, reversed the effects of PCP and d-AMP, but not that of MK-801.Conclusions The finding that PCP, MK-801 and d-AMP impair habituation in mice is consistent with the idea that these treatments model certain filter deficits seen in schizophrenic patients. Furthermore, the present results suggest that NO is critically involved in these effects on habituation, whereas that of dopamine is less clear.     

Co-administration of 5-HT6 receptor antagonists with clozapine, risperidone, and a 5-HT2A receptor antagonist: effects on prepulse inhibition in rats

Rationale

Some novel antipsychotics manifest antagonistic activity at serotonin-6 receptors; however, little is known about the role of 5-HT6 receptors in ameliorating sensory gating deficits.

Objective

We evaluated the effects of the combined administration of the 5-HT6 receptor antagonist SB 271046 with clozapine and haloperidol, as well as the co-administration of SB 271046 or SB 399885 with risperidone and the 5-HT2A antagonist M100907, to overcome the deficits induced by MK-801 in the prepulse inhibition (PPI) test.

Results

MK-801 (0.1 mg/kg) produced reliable PPI deficits. Administration of SB 271046 (6 and 9 mg/kg), SB 399885 (3 and 6 mg/kg), clozapine (2.5 mg/kg), haloperidol (0.1 and 0.2 mg/kg), risperidone (0.25–1 mg/kg), and M100907 (0.5 and 1 mg/kg) did not affect the MK-801-induced deficits, but the administration of clozapine (5 mg/kg) did reverse the effects of MK-801. In MK-801-treated rats, the co-administration of inactive doses of clozapine (2.5 mg/kg) and SB 271046 (6 mg/kg) reversed the PPI impairments compared to animals that were administered inactive doses of either clozapine or SB 271046 alone. Co-administration of risperidone (1 mg/kg) or M100907 (0.5 mg/kg) with SB 271046 (6 mg/kg) or SB 399885 (3 mg/kg) also attenuated the MK-801-induced PPI deficits. In contrast, joint administration of haloperidol and SB 271046 had no effect on the PPI deficit.

Conclusion

The present results suggest that the 5-HT6 receptors may play adjunctive roles in antipsychotic drug action, and that the combination of 5-HT2A and 5-HT6 antagonism may represent an important element in the pharmacological profile of antipsychotic drugs.     

Cannabidiol Attenuates Sensorimotor Gating Disruption and Molecular Changes Induced by Chronic Antagonism of NMDA receptors in Mice

Background:

Preclinical and clinical data suggest that cannabidiol (CBD), a major non-psychotomimetic compound from Cannabis sativa, induces antipsychotic-like effects. However, the antipsychotic properties of repeated CBD treatment have been poorly investigated. Behavioral changes induced by repeated treatment with glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been proposed as an animal model of schizophrenia-like signs. In the present study, we evaluated if repeated treatment with CBD would attenuate the behavioral and molecular modifications induced by chronic administration of one of these antagonists, MK-801.

Methods:

Male C57BL/6J mice received daily i.p. injections of MK-801 (0.1, 0.5, or 1mg/kg) for 14, 21, or 28 days. Twenty-four hours after the last injection, animals were submitted to the prepulse inhibition (PPI) test. After that, we investigated if repeated treatment with CBD (15, 30, and 60mg/kg) would attenuate the PPI impairment induced by chronic treatment with MK-801 (1mg/kg; 28 days). CBD treatment began on the 6th day after the start of MK-801 administration and continued until the end of the treatment. Immediately after the PPI, the mice brains were removed and processed to evaluate the molecular changes. We measured changes in FosB/ΔFosB and parvalbumin (PV) expression, a marker of neuronal activity and a calcium-binding protein expressed in a subclass of GABAergic interneurons, respectively. Changes in mRNA expression of the NMDAR GluN1 subunit gene (GRN1) were also evaluated. CBD effects were compared to those induced by the atypical antipsychotic clozapine.

Results:

MK-801 administration at the dose of 1mg/kg for 28 days impaired PPI responses. Chronic treatment with CBD (30 and 60mg/kg) attenuated PPI impairment. MK-801 treatment increased FosB/ΔFosB expression and decreased PV expression in the medial prefrontal cortex. A decreased mRNA level of GRN1 in the hippocampus was also observed. All the molecular changes were attenuated by CBD. CBD by itself did not induce any effect. Moreover, CBD effects were similar to those induced by repeated clozapine treatment.

Conclusions:

These results indicate that repeated treatment with CBD, similar to clozapine, reverses the psychotomimetic-like effects and attenuates molecular changes observed after chronic administration of an NMDAR antagonist. These data support the view that CBD may have antipsychotic properties.     

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.     

Modulation of MK-801 response by dopaminergic agents in mice

Various doses of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists, MK-801 (0.1–0.5 mg/kg) and ketamine (2.5–10 mg/kg), produced a dose-dependent increase in stereotypic behaviour in naive mice. MK-801 (0.1 mg/kg) and ketamine (2.5 mg/kg) potentiated the stereotypic response of apomorphine (0.1–0.5 mg/kg) in mice pretreated with reserpine (5 mg/kg, 24 h prior) and alpha-methyl-p-tyrosine (150 mg/kg, 1 h prior) but not in naive mice. SKF 38393, a D₁ dopamine agonist, enhanced whereas B-HT 920, a D₂ dopamine agonist, reduced the stereotypic response of MK-801 in naive mice. The response of MK-801 was blocked by pretreatment with haloperidol (0.5 mg/kg), molindone (2.5 mg/kg), clozapine (7.5 mg/kg) and SCH 23390 (0.1 mg/kg). The present data suggest involvement of endogenous DA transmission in the stimulant action of non-competitive NMDA antagonists in mice. Dopamine D₁ and D₂ receptor stimulation, respectively, exert opposing effects on the behavioural expression of MK-801 in mice.     

Effects of dizocilpine [(+)-MK-801] on the expression of associative and non-associative sensitization to <Emphasis Type="SmallCaps">d</Emphasis>-amphetamine

Blockade of glutamate receptors of the NMDA type inhibits the sensitization to psychostimulant drugs, such as amphetamine, that occurs after repeated administration. Both associative (conditioning) and non-associative (pseudo-conditioning) mechanisms may contribute to sensitization phenomena. The aim of the present study was, thus, to determine which type of sensitization is influenced by blockade of NMDA-type receptors by examining the expression (manifestation) of sensitization. Locomotor activity was assessed and, in some experiments, extracellular dopamine in the nucleus accumbens was also assessed using in vivo microdialysis in non-anaesthetized, almost freely moving rats. Male albino Wistar rats of 225–250 g were given 1 mg/kg i.p. d-amphetamine every 2nd day for 7 days and with saline on the other days. Half the rats were exposed to d-amphetamine in the presence of conditioning stimuli (test cage, auditory and olfactory stimulus) and to saline in the home cage in absence of these stimuli, the other half were treated with saline and exposed to the conditioning stimuli and were placed into their home cages (without conditioning stimuli) after treatment with d-amphetamine. Ten days after the end of this treatment, both groups were exposed to the conditioning stimuli and half of each group were pretreated with dizocilpine [(+)-MK-801, 0.1 mg/kg i.p.], a blocker of NMDA receptors, 30 min before administration of 1 mg/kg d-amphetamine.(+)-MK-801 reduced the locomotor activity in rats sensitized associatively, but not in those sensitized non-associatively. It had no significant effect on spontaneous locomotor activity or that induced by acute administration of 1 mg/kg d-amphetamine. Similarly, (+)-MK-801 inhibited the increase in extracellular dopamine in the nucleus accumbens induced by the test dose of d-amphetamine in rats sensitized associatively but not non-associatively. The results suggest that the expression of both types of sensitization to d-amphetamine are dependent on glutamatergic NMDA mechanisms, although in different ways. Inhibition of sensitization, in particular of the associative type, might be of therapeutic value in drug dependence.