A behavioural pattern analysis of hypoglutamatergic mice--effects of four different antipsychotic agents.

J Neural Transm. 2001;108(10):1181-96.

A behavioural pattern analysis of hypoglutamatergic mice--effects of four different antipsychotic agents.

Nilsson M, Waters S, Waters N, Carlsson A, Carlsson ML.

Department of Pharmacology, Institute of Physiology and Pharmacology, Göteborg University, Sweden. marie.nilsson@pharm.gu.se

In a hypoglutamatergic rodent model, we have observed certain behaviours that might have relevance for the cognitive impairments seen in autism and schizophrenia.

Thus, hypoglutamatergic mice show defective habituation, impaired attention, a meagre behavioural repertoire and a general behavioural primitivization.

The aim of the present study was to characterise and quantify changes in movement pattern in mice rendered hypoglutamatergic by means of MK-801 treatment, using an automated video tracking system.

Further, the effects of four different antipsychotic drugs, the classical neuroleptic haloperidol, the atypical antipsychotic clozapine, the DA D2/5-HT2A antagonist risperidone and the selective 5-HT2A-receptor antagonist M100907, were compared with respect to effects on NMDA antagonist-induced movement pattern alterations.

We found that each receptor antagonist had a unique effect on the MK-801-induced behavioural primitivization.

Haloperidol was unable to affect the monotonous behaviour induced by MK-801, while risperidone, clozapine and M100907 produced movement patterns of high intricacy.

The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist- than dopamine agonist-induced hyperactivity in mice.

J Neural Transm. 1999;106(2):123-9.

The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist- than dopamine agonist-induced hyperactivity in mice.

Carlsson ML, Martin P, Nilsson M, Sorensen SM, Carlsson A, Waters S, Waters N.

Department of Pharmacology, University of Göteborg, Sweden.

The purpose of the present study was to compare the effectiveness of the selective 5-HT2A antagonist M100907 in different psychosis models.

The classical neuroleptic haloperidol was used as reference compound. Two hyperdopaminergia and two hypoglutamatergia mouse models were used.

Hyperdopaminergia was produced by the DA releaser d-amphetamine or the DA uptake inhibitor GBR 12909.

Hypoglutamatergia was produced by the un-competitive NMDA receptor antagonist MK-801 or the competitive NMDA receptor antagonist D-CPPene.

M100907 was found to counteract the locomotor stimulant effects of the NMDA receptor antagonists MK-801 and D-CPPene, but spontaneous locomotion, d-amphetamine- and GBR-12909-induced hyperactivity were not significantly affected.

Haloperidol, on the other hand, antagonized both NMDA antagonist- and DA agonist-induced hyperactivity, as well as spontaneous locomotion in the highest dose used.

Based on the present and previous results we draw the conclusion that 5-HT2A receptor antagonists are particularly effective against behavioural anomalies resulting from hypoglutamatergia of various origins.

The clinical implications of our results and conclusions would be that a 5-HT2A receptor antagonist, due to i a the low side effect liability, could be the preferable treatment strategy in various disorders associated with hypoglutamatergia; such conditions might include schizophrenia, childhood autism and dementia disorders.

Antipsychotic action exerted through 5-Ht2A receptor antagonism is dependent on increased serotonergic tone.

J Neural Transm. 1998;105(4-5):365-96.

Rodent data and general hypothesis: antipsychotic action exerted through 5-Ht2A receptor antagonism is dependent on increased serotonergic tone.

Martin P, Waters N, Schmidt CJ, Carlsson A, Carlsson ML.

Department of Pharmacology, Göteborg University, Sweden.

The locomotor stimulation induced by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) in mice was regarded as a model of at least some aspects of schizophrenia.

The serotonin synthesis inhibitor dl-p-chlorophenylalanine (PCPA) was used to evaluate the involvement of endogenous serotonin in (a) the induction of MK-801-induced hyperlocomotion in NMRI mice, and (b) the inhibition of MK-801-induced hyperlocomotion by each of five monoaminergic antagonists (M100907, clozapine, olanzapine, raclopride, SCH23390).

Further, brain monoaminergic biochemistry was characterised in rats and mice after various drug treatments. PCPA pretreatment did not significantly reduce MK-801-induced hyperlocomotion in any of the experiments performed; however in a meta-analysis of six experiments, the locomotion displayed by MK-801-treated animals was diminished 17% by PCPA pretreatment.

The selective 5-HT2A receptor antagonist M100907 exerted a dose-dependent inhibition of MK-801-induced hyperlocomotion. This effect was abolished in mice pretreated with PCPA, but could be restored in a dose-dependent manner by restitution of endogenous 5-HT by means of 5-hydroxytryptophan (5-HTP).

On the other hand, the inhibition of MK-801-induced hyperlocomotion exerted by the selective dopamine D-2 receptor antagonist raclopride or the dopamine D-1 receptor antagonist SCH23390 was unaffected by PCPA pretreatment.

The antipsychotics clozapine and olanzapine displayed a split profile. Hence, the inhibitory effect on MK-801-induced hyperlocomotion exerted by low doses of these compounds was diminished after PCPA pretreatment, while inhibition exerted by higher doses was unaffected by PCPA.

These results suggest that:

(1) MK-801-induced hyperlocomotion is accompanied by an activation of, but is not fully dependent upon, brain serotonergic systems.

(2) In the hypoglutamatergic state induced by MK-801, endogenous serotonin exerts a stimulatory effect on locomotion through an action at 5-HT2A receptors, an effect that is almost completely counterbalanced by a concomitant inhibitory impact on locomotion, mediated through stimulation of serotonin receptors other than 5-HT2A receptors.
M100907, by blocking 5-HT2A receptors, unveils the inhibitory effect exerted on locomotion by these other serotonin receptors.

(3) Dopamine D-2 receptor antagonistic properties of antipsychotic compounds, when they come into play, override 5-HT2A receptor antagonism. Possible implications for the treatment of schizophrenia with 5-HT2A receptor antagonists are discussed. It is hypothesized that treatment response to such agents is dependent on increased serotonergic tone.

M100907, a serotonin 5-HT2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in rats

Neuropsychopharmacology. 1999 Apr;20(4):311-21.

M100907, a serotonin 5-HT2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in Sprague-Dawley and Wistar rats.

Varty GB, Bakshi VP, Geyer MA.

Department of Psychiatry, University of California San Diego, La Jolla, USA.

In a recent study using Wistar rats, the serotonergic 5-HT2 receptor antagonists ketanserin and risperidone reduced the disruptive effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine on prepulse inhibition (PPI), suggesting that there is an interaction between serotonin and glutamate in the modulation of PPI.

In contrast, studies using the noncompetitive NMDA antagonist phencyclidine (PCP) in Sprague-Dawley rats found no effect with 5-HT2 antagonists.

To test the hypothesis that strain differences might explain the discrepancy in these findings, risperidone was tested for its ability to reduce the PPI-disruptive effects of dizocilpine in Wistar and Sprague-Dawley rats.

Furthermore, to determine which serotonergic receptor subtype may mediate this effect, the 5-HT2A receptor antagonist M100907 (formerly MDL 100,907) and the 5-HT2C receptor antagonist SDZ SER 082 were tested against dizocilpine.

Recent studies have found that the PPI-disruptive effects of PCP are reduced by the alpha 1 adrenergic receptor antagonist prazosin.

Furthermore, the alpha 1 receptor agonist cirazoline disrupts PPI.

As risperidone and M100907 have affinity at the alpha 1 receptor, a final study examined whether M100907 would block the effects of cirazoline on PPI.

Risperidone partially, but nonsignificantly, reduced the effects of dizocilpine in Wistar rats, although this effect was smaller than previously reported.

Consistent with previous studies, risperidone did not alter the effects of dizocilpine in Sprague-Dawley rats.

Most importantly, M100907 pretreatment fully blocked the effect of dizocilpine in both strains; whereas SDZ SER 082 had no effect. M100907 had no influence on PPI by itself and did not reduce the effects of cirazoline on PPI.

These studies confirm the suggestion that serotonin and glutamate interact in modulating PPI and indicate that the 5-HT2A receptor subtype mediates this interaction. Furthermore, this interaction occurs in at least two rat strains.

Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity.

Mol Psychiatry. 2002;7(7):726-33.

Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity.

Farber NB, Jiang XP, Heinkel C, Nemmers B.

Department of Psychiatry, Washington University, St Louis, MO 63110-1093, USA. fabern@psychiatry.wustl.edu

N-methyl-D-aspartate (NMDA) glutamate receptor antagonists are used in clinical anesthesia and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma.

However, the ability of these agents to produce neurotoxicity in adult rats and psychosis in adult humans compromises their clinical usefulness.

In addition, an NMDA receptor hypofunction (NRHypo) state might play a role in neurodegenerative and psychotic disorders, like Alzheimer's disease, bipolar disorder and schizophrenia.

Thus, developing pharmacological means of preventing these NRHypo-induced effects could have significant clinically relevant benefits.

NRHypo neurotoxicity appears to be mediated by a complex disinhibition mechanism that results in the excessive stimulation of certain vulnerable neurons.

Here we report our findings that five agents (phenytoin, carbamazepine, valproic acid, lamotrigine, and riluzole), thought to possess anticonvulsant activity because they inhibit voltage-gated sodium channels, prevent NRHypo neurotoxicity.

The ability of tetrodotoxin, a highly selective inhibitor of voltage-gated sodium channels, to prevent the same neurotoxicity suggests that inhibition of this ion channel is the likely mechanism of action of these five agents.

We also found that three other anticonvulsants (felbamate, gabapentin and ethosuximide), whose mechanism is less clear, also prevent NRHypo neurotoxicity, suggesting that inhibition of voltage-gated sodium channels is not the only mechanism via which anticonvulsants can act to prevent NRHypo neurotoxicity.

Several of these agents have been found to be of clinical use in bipolar disorder. It would be of interest to determine whether these agents might have therapeutic benefits for conditions in which a NRHypo state may exist.

Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity.

Neuropsychopharmacology. 1998 Jan;18(1):57-62.

Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity.

Farber NB, Hanslick J, Kirby C, McWilliams L, Olney JW.

Department of Psychiatry, Washington University, St. Louis, Missouri, USA.

Phencyclidine, ketamine, and other agents that block NMDA glutamate receptors trigger a schizophrenia-like psychosis in humans and induce pathomorphological changes in cerebrocortical neurons in rat brain.

Accumulating evidence suggests that a complex network disturbance involving multiple transmitter receptor systems is responsible for the neuronal injury, and it is proposed that a similar network disturbance is responsible for the psychotomimetic effects of NMDA antagonists, and might also be involved in the pathophysiology of schizophrenia.

In the present study we present evidence that serotonergic agents possessing 5HT2A agonist activity prevent NMDA antagonist neurotoxicity in rat brain.

It is proposed that 5HT2A agonists may also prevent the psychotomimetic effects of NMDA antagonists.

Among the 5HT2A agonists examined and found to be neuroprotective are LSD and related hallucinogens. The apparent contradiction in proposing that these agents might have antipsychotic properties is resolved by evidence linking their hallucinogenic activity to agonist action at 5HT2C receptors, whereas antipsychotic activity would be attributable to agonist action at 5HT2A receptors.