Impact of postnatal blockade of N-methyl-D-aspartate receptors on rat behavior: a search for a new developmental model of schizophrenia.

The malfunction of glutamatergic neurotransmission in the neonatal or postnatal periods may be a risk factor for the appearance of neuroanatomical, neurochemical or functional changes that are characteristic of schizophrenia. Thus, the present study was undertaken to investigate whether blockade of N-methyl-d-aspartate (NMDA) receptors in the postnatal period influences rat behavior in tests characterizing schizophrenia-like deficits such as psychomotor agitation, impairments of sensorimotor gating, working memory, and intensity of social interactions. (E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), a competitive antagonist of NMDA receptors, was given postnatally (1.25 mg/kg on days 1, 3, 6, 9; 2.5 mg/kg on days 12, 15, 18; and finally 5 mg/kg on day 21, all injections s.c.), and rats were tested at 60 days old. We found that blockade of NMDA receptors in the postnatal period led to an enhancement of exploration, mimicking psychomotor agitation, impairments in sensorimotor gating as measured by a prepulse-evoked inhibition of acoustic startle response, and an impaired working memory, as measured by an increase in the latency to achieve accurate rate of response in the delayed alternation task. Decreases in non-aggressive social interactions and increases in aggressive interactions were also observed. In addition to cognitive deficits typical of schizophrenia, rats treated postnatally with NMDA receptor antagonists also showed higher level of fear exhibited in the elevated plus maze. Thus, the blockade of NMDA receptors in the postnatal period may model deficits that are characteristic of schizophrenia.

No nerve growth factor response to treatment with memantine in adult rats.

Nerve growth factor (NGF) is the most widely examined neurotrophin in the experimental models of Alzheimer's disease (AD) and has been shown to prevent the retrograde degeneration of cholinergic neurons. In this study we examined NGF and cholineacetyltransferase (ChAT) changes in several rat brain regions after excitotoxic lesion of the entorhinal cortex with quinolinic acid and tested the effect of memantine on spatial learning in the radial maze after lesion. We observed a significant increase (+26%, p=0.02) of NGF concentrations in the hippocampus of the lesioned rats when compared to sham-lesioned rats. Chronic treatment with memantine showed no significant effect on the NGF increase in the hippocampus (p=0.72). The ChAT activity was significantly increased in the lesioned rats when compared to controls (+16%, p<0.05) and did not depend on treatment with memantine. In spite of this, memantine improved performance of the radial maze. This indicates that memory improving effects of memantine observed in experimental animals and in clinical studies are probably not related to changes in brain NGF content, whereas the observed NGF increase in the denervated hippocampus is probably trauma-related reflecting impaired retrograde transport of hippocampal NGF.

Metyrapone, an inhibitor of corticosterone synthesis, blocks the kainic acid-induced expression of HSP 70.

It is shown in the present study that metyrapone (100 mg/kg), an inhibitor of corticosterone synthesis, given twice, 30 min before and 6 h after kainic acid (10 mg/kg) administration, blocks the kainic acid-evoked induction of heat shock proteins 72 kDa (HSP 70). Specifically, it was observed that metyrapone completely prevented kainic acid-induced appearance of HSP 70 in the rat amygdala, habenula, parietal cortex, and significantly decreased the number of HSP 70-positive neurons in the CA1, CA3, and CA4 subregions of hippocampus. The reduction in HSP 70 induction was paralleled by a complete prevention of the kainic acid-induced rise in the circulating corticosterone level by metyrapone; however, in applied doses metyrapone evoked slight enhancement of blood corticosterone. Despite the fact that metyrapone blocked/attenuated the kainic acid-evoked induction of HSP 70, its administration did not affect the behavioral effects of kainic acid, regarded as "limbic status epilepticus." It is concluded that the blockade of corticosterone synthesis might have neuroprotective effects in the pathological states associated with the overstimulation of glutamatergic receptors.

The role of glutamate receptors in antipsychotic drug action.

It has recently been postulated that disturbances in glutamatergic neurotransmission may contribute to the pathophysiology of schizophrenia. Therefore the aim of the present study was to evaluate the role of glutamate NMDA and group II metabotropic receptors in the antipsychotic drug action. To this aim the influence of some well-known neuroleptics on cortical NMDA receptors was examined. Furthermore, their behavioral effects were compared with those of the novel agonist of group II glutamate metabotropic receptors, LY 354740, in some animal models of schizophrenic deficits. We found that long-term administration of the typical neuroleptic haloperidol and the atypical one clozapine increased the number of NMDA receptors labelled with [3H]CGP 39653 in different cortical areas. Long-, but not short-term, treatment with haloperidol and raclopride diminished the deficit of prepulse inhibition produced by phencyclidine, which is a model of sensorimotor gating deficit in schizophrenia. In contrast, neither short- nor long-term treatment with clozapine influenced the phencyclidine effect in that model. Acute treatment with LY 354740 reversed neither (1) the deficit of prepulse inhibition produced by phencyclidine or apomorphine, nor (2) the impairment in a delayed alternation task induced by MK-801, which is commonly used to model the frontal lobe deficits associated with schizophrenia. The present study suggests that an increase in the density of cortical NMDA receptors may be important to a longterm neuroleptic therapy. Conversely, the results do not support the role of group II metabotropic glutamate receptors in the antipsychotic drug action.

WAY 100135, an antagonist of 5-HT1A serotonin receptors, attenuates psychotomimetic effects of MK-801.

In the present study, we investigated whether the antagonist of 5-HT1A receptors, WAY 100135, was capable of modifying the psychostimulant and psychotomimetic effects of MK-801, a non-competitive antagonist of NMDA receptors. It was found that: 1) WAY 100135 (10 and 20 mg/kg, but not 1.25, 2.5, and 5 mg/kg) transiently, in a dose dependent manner, attenuated the locomotor stimulant effects of MK-801 (0.4 mg/kg). Given alone, WAY 100135 had no effect on the locomotor activity of rats; 2) WAY 100135 (1.25 and 2.5 mg/kg, but not 10 or 20 mg/kg), attenuated or abolished the disruptive effects of MK-801 on the sensorimotor gating measured in a prepulse-induced inhibition of the acoustic startle response paradigm. WAY 100135 in all tested doses had no effect on the sensorimotor gating or amplitude of the acoustic startle response; 3) WAY 100135 (1.25, 2.5 mg/kg, but not 5 mg/kg) attenuated the detrimental effects of MK-801 on working memory and selective attention, measured in a delayed alternation task. Again, given alone, WAY 100135 did not influence the behavior of rats in that experimental paradigm; and 4) MK-801 (0.4 mg/kg) had no effect on the 5-HT1A receptor mRNA level in rat hippocampus, measured 2 and 24 hours after MK-801 administration. These data indicate that 5-HT1A receptors might be involved in the psychotomimetic effects of non-competitive NMDA receptor antagonists. In addition, 5-HT1A serotonin receptor antagonists and partial agonists may have potential antipsychotic properties.

Behavioural evaluation of long-term neurotoxic effects of NMDA receptor antagonists.

High doses of NMDA antagonists e.g. (+)MK-801 evoke neurodegeneration in retrosplenial cortex in rodents. To assess functional consequences of such treatment, three paradigms of two-way active avoidance learning (with visual or auditory conditioned stimuli) and additionally a spatial learning paradigm - radial maze - were used. Female rats were treated i.p. with 5 mg/kg of (+)MK-801. Recumbence, severe hypothermia and loss of body weight were observed for 3-7 days. Despite that, there were no statistically significant differences in performance of avoidance reaction between saline and (+)MK-801 treated animals trained 10-40 days after the drug administration. However, in the radial maze test (+)MK-801 impaired reference (but not working) memory in the experiment that started 8 days after the treatment. Similar effect was observed on reversal learning. The clinically used NMDA receptor antagonist memantine at the doses of 20 and 40 mg/kg had also no such long term negative effect on working memory during training (even positive effect was seen at 20 mg/kg) but at 40 mg/kg impaired learning on the first day of reversal. This indicates that (+)MK-801 neurotoxicity in the retrosplenial cortex is connected with subtle alterations in the learning performance that may be seen in some tests only. Moreover, memantine doses greatly exceeding therapeutically relevant range produce minimal functional alteration. An additional experiment revealed that the same dose of memantine results in two fold higher serum levels of the antagonist in female than male rats. Hence, considering that profiling studies are done in male rats, a safety factor of over 16 fold can be calculated for memantine.

NMDA receptor antagonists acting at the glycineB site in rat models for antipsychotic-like activity.

Several partial agonist and full antagonists acting at the glycine site of the NMDA receptors were tested for potential antipsychotic-like properties in rats. As models, amphetamine- and phencyclidine (PCP)-induced locomotor activation in the open field and PCP-induced impairment of prepulse inhibition of the acoustic startle response were employed. In the open field test, partial agonists, D-cycloserine failed to show any effect, aminocyclopropane carboxylic acid (ACPC) enhanced the action of PCP (but not that of amphetamine) and R(+)HA-966 attenuated the locomotor activation produced by both amphetamine and PCP. Both full glycineB antagonists, L-701,324 and MRZ 2/576 attenuated the action of amphetamine and PCP but at the doses that also produce transient behavioural inhibition in naive animals. A competitive NMDA receptor antagonist CGP 39551 was ineffective. In the prepulse inhibition test neither L-701,324 nor MRZ 2/576 changed sensorimotor gating in naive animals nor attenuated the disrupting effects of PCP. The present data do not support antipsychotic profile of glycineB full antagonists. However, psychotomimetic potential of glycineB antagonists seems to be low.

Uncompetitive NMDA receptor antagonists attenuate NMDA-induced impairment of passive avoidance learning and LTP.

In general, N-methyl-D-aspartate (NMDA) receptor antagonists inhibit learning and long term potentiation (LTP). However, it has been suggested that direct tonic, i.e. non-temporal, activation of NMDA receptors, in contrast to learning, may lead to an increase in synaptic "noise" and, in turn, to a loss of association detection. In the present study, a two-choice passive avoidance task and LTP in vitro (CA1 hippocampal region) were used to address this issue. Dark avoidance learning was impaired by systemic NMDA administration (starting at 25 mg/kg) that was not related to either toxic effects or state-dependent learning. NMDA-induced amnesia was antagonized by ((+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate (MK-801) and 1-amino-3,5-dimethyladamantane (memantine), starting at low doses of 0.05 and 2.5 mg/kg, respectively, in a bell-shaped dose-response relationship. A competitive NMDA receptor antagonist CGP-39551 failed to reverse NMDA-induced amnesia. In hippocampal slices, NMDA (10 microM) depressed (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolproprionic acid (AMPA) receptor-mediated field potentials in CA1 and also caused a moderate reduction of LTP induction/expression. It was this latter effect that was antagonized by memantine (1 microM). Thus, under conditions of tonic activation of NMDA receptors, uncompetitive NMDA receptor antagonists can paradoxically reverse deficits in learning and synaptic plasticity.

Neuroprotection of acetylcholinergic basal forebrain neurons by memantine and neurokinin B.

The present study investigated whether chronic, low dose therapy with memantine could (1) prevent the loss of basal forebrain cholinergic cells induced by injection of N-methyl-D-aspartate (NMDA) into the nucleus basalis magnocellularis (NBM) of rats, and (2) attenuate impaired performance in the radial maze of rats with entorhinal cortex lesions. In addition, we investigated whether neuroprotection could be provided by neurokinin B (NKB). Following an injection of NMDA (0.015 M) into the NBM, rats were implanted with osmotic minipumps containing memantine (20 or 0.20 mg/kg/day for 2 weeks). Other rats were given unilateral NBM injections of 1.0 microliter of Solution A (0.5 microliter containing 8.26 mM NKB and 0.24 units of bacitracin and 0.5 microliter containing 0.03 M NMDA) or Solution B (0.5 microliter of PBS containing 0.24 U of bacitracin and 0.5 microliter containing 0.03 M NMDA). Two weeks later, the anterior cortex was analyzed for choline acetyltransferase (ChAT), a specific marker for the loss of acetylcholinergic neurons. Both chronic administration of memantine, and acute administration of NKB, prevented the decline in cortical ChAT activity associated with injection of NMDA into the NBM, and attenuated a reference memory deficit in the radial maze produced by entorhinal cortex lesions. Thus, memantine infusion at low doses leading to steady-state serum levels within a therapeutic range provides both neuroprotection and cognitive enhancement-an optimal combination for the treatment of neurodegenerative disorders.

Effects of D-cycloserine and aniracetam on spatial learning in rats with entorhinal cortex lesions.

A great body of behavioural and neurophysiological evidence suggests that excitatory amino acids are involved in mechanisms of learning and memory. Moreover, degeneration of glutamatergic pathways may underlie the cognitive deficits seen in various disorders such as Alzheimer's dementia. As direct stimulation of glutamatergic receptors with agonists may increase the risk of toxicity and accelerate neuropathological changes, a more valid approach seems to be positive modulation of glutamatergic receptors that may reverse the symptoms with a lower risk of excitotoxic effects. Such a possibility offered by partial agonists of the strychnine-insensitive glycine site of the NMDA receptor (Gly-B site) or positive modulators of AMPA receptors, such as aniracetam. In the present study, the effects of d-cycloserine and aniracetam were tested in two animal models of cognitive deficits (entorhinal cortex lesion-induced deficits evaluated in the radial maze and scopolamine-induced amnesia evaluated in passive avoidance test). D-cycloserine (6 mg/kg, for 10 days) had no effect on spatial working memory deficit induced by entorhinal cortex lesions. It did, however, reverse scopolamine-induced deficits in the passive avoidance test when given acutely at the same dose. In contrast, aniracetam (50 mg/kg, for 10 days) produced beneficial effects in the radial maze test in rats with entorhinal cortex lesions, but given at the same dose acutely did not influence scopolamine-induced amnesia. The positive effect of d-cycloserine against scopolamine-induced amnesia may be probably related to the cholinergic-glutamatergic interaction in the hippocampus. The negative data obtained with d-cycloserine in the model of entorhinal cortex lesions-induced cognitive deficits could be taken as a hint that it is probably not suitable for the symptomatological therapy of Alzheimer's disease. The mechanism of positive action of aniracetam cannot be explained on the basis of AMPA receptor modulation, as the dose used (50 mg/kg) is well below that required for the effect at AMPA receptors. Other actions such as peripheral effects or modulation of metabotropic receptors seem more likely.

Discriminative stimulus effects of the NMDA receptor antagonists MK-801 and CGP 37849 in rats.

Rats were trained to discriminate MK-801 (0.05 mg/kg, IP), an uncompetitive, or CGP 37849 (3 mg/kg, IP), a competitive NMDA receptor antagonist from saline, using a two-lever, operant drug discrimination paradigm. In generalization tests the role of dopaminergic and serotonergic systems in the discriminative stimulus effects produced by both NMDA receptor antagonists was studied with amphetamine (0.5 mg/kg), cocaine (5.0 and 7.5 mg/kg), and fenfluramine (2.5 and 5.0 mg/kg). Additionally, memantine (5.0, 7.5 and 10.0 mg/kg), an uncompetitive NMDA receptor antagonist, was tested. The discriminative stimuli produced by MK-801 and CGP 37849 were not generalized to each other. Among the tested drugs only memantine generalized to the MK-801 discriminative stimulus. None of the tested drugs showed CGP 37849-like discriminative stimulus properties. The different mechanisms underlying NMDA antagonism by MK-801 and GP 37849 might explain the observed lack of cross-generalization. The results suggest that dopaminergic and serotonergic systems are not of major importance in the discriminative stimulus effects produced by both MK-801 and CGP 37849.

Infusion of (+) -MK-801 and memantine -- contrasting effects on radial maze learning in rats with entorhinal cortex lesion.

(+)-5-Methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate ((+)-MK-801) and 1-amino-3,5-dimethyladamantane (memantine), two uncompetitive antagonists of the NMDA receptor were tested in an allocentric version of the radial maze test (with four out of eight arms reinforced) both in normal rats and after quinolinic acid-induced entorhinal cortex lesions. Both agents were infused s.c. using Alzet osmotic minipumps in order to assure steady state drug levels in the serum and brain during the experiment. In non-lesioned rats, (+)-MK-801 (0.312 mg/kg per day) produced disturbances in learning of spatial information dependent on reference memory but not that involving working memory. In contrast, memantine (20 mg/kg per day) had no effect in normal rats. In rats with entorhinal cortex lesions, (+)-MK-801 enhanced the lesion-induced deficit in reference memory. In contrast, memantine reversed the lesion-induced increase in reference memory errors. The divergent effects of those two uncompetitive NMDA receptor antagonists could, at least partially, be due to the differences reported in their channel blocking kinetics and voltage dependence. The results indicate that under conditions of pathological impairment of brain structures such as entorhinal cortex lesion, memantine might produce beneficial effects on cognitive functions.

Modulation of learning processes by ionotropic glutamate receptor ligands.

A great body of evidence has been provided for the role of N-methyl-d-aspartate (NMDA) receptors in learning processes, since the pioneering work of Morris et al. (1986) showing impairment of water maze learning and long-term potentiation (LTP) during i.c.v. infusion of the NMDA receptor antagonst 2-amino-5-phosphonovaleric acid (AP5). The existing literature, based on pharmacological studies, suggests the importance of NMDA receptors for the acquisition and/or the initial phase of long-term memory consolidation in many, but not all, learning paradigms. Data on short-term memory are inconsistent, probably due to difficulties in separation of learning deficits from performance. Although it is generally accepted that NMDA receptor antagonists impair learning, more recent data suggest that, under certain conditions, the opposite effect, enhancement of learning, can be obtained. The role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors in learning, although accepted in LTP, is less well documented. It has been suggested that positive modulation of these receptors could result in cognitive enhancement that might find therapeutic application. The present paper reviews the literature dealing with these issues and discusses possible consequences for the therapy of dementia.

Effect of coadministration of glutamate receptor antagonists and dopaminergic agonists on locomotion in monoamine-depleted rats.

Combinations of dopaminergic agonists with glutamate receptor antagonists have been suggested to be a possible alternative treatment of Parkinson's disease. To gain further insights into this possibility, the antagonist of the competitive AMPA-type glutamate receptor NBQX and the ion-channel blocker of the NMDA glutamate receptor (+)-MK-801 in combination with the dopamine D1 receptor agonists: SKF 38393, SKF 82958 and dihydrexidine; the dopamine D2 receptor agonist bromocriptine and the dopamine-precursor L-DOPA were tested in rats pretreated with reserpine and alpha-methyl-p-tyrosine. MK-801 on its own induced locomotor behaviour and potentiated the antiakinetic effects of dihydrexidine and L-DOPA but not of the other dopamine agonists tested. NBQX neither on its own nor coadministered with the dopamine agonists tested had an antiakinetic effect. These results indicate that agents, blocking the ion-channel of the NMDA receptor, might be useful adjuvants to some but not all dopaminomimetics in therapy of Parkinson's disease. The same does not seem to be true for the AMPA-antagonist NBQX.

Are NMDA antagonistic properties relevant for antiparkinsonian-like activity in rats?--case of amantadine and memantine.

Amantadine (25, 50, 100 mg/kg), memantine (5, 10, 20 mg/kg) and MK-801 (0.05, 0.1, 0.2 mg/kg), all having NMDA channel blocking properties, were compared in three tests used for screening of antiparkinsonian agents in rats, namely: haloperidol-induced catalepsy, locomotor activity in monoamine depleted rats and rotation in rats with a unilateral substantia nigra lesion. Additionally, plasma levels of amantadine and memantine were assessed to gain an insight into the concentration ranges achieved at behaviorally active doses. Amantadine and (+)-MK-801 produced dose-dependent inhibition of haloperidol-induced catalepsy while memantine was less efficacious producing clear-cut anticataleptic action at a dose of 10 mg/kg only but failing at 20 mg/kg due to myorelaxant activity. All agents attenuated sedation in monoamine depleted rats with amantadine being the least and MK-801 being the most effective. The same rank order of efficacy was seen in inducing ipsilateral rotations in rats after a substantia nigra lesion. On the basis of the present study and published data, it can be assumed that the doses of amantadine, memantine and MK-801 showing antiparkinsonian-like activity in animals result in plasma levels leading to NMDA antagonism. However, in the haloperidol-induced catalepsy test the efficacy of amantadine was higher than memantine, while the opposite was true for rotation and reserpine-induced sedation indicating pharmacodynamic differences between both agents.

The effects of single and repeated administration of MAO inhibitors on acoustic startle response in rats.

In this paper the effects of single and repeated administration of brofaromine (BRO) and moclobemide (MOC)--monoamine oxidase A (MAO-A) inhibitors as well as deprenyl (DEP)--monoamine oxidase B (MAO-B) inhibitor on behavior of rats in acoustic startle response test were studied. For comparison the tricyclic antidepressant amitriptyline (AMI) was also studied. BRO given in a single dose of 10 mg/kg diminished the amplitude of acoustic startle response, while in a dose of 30 mg/kg had no effect. MOC diminished the amplitude when given in a single dose of 30 mg/kg, and had no effect in a dose of 10 mg/kg. Both MAO type A inhibitors diminished the startle reaction amplitude when tested 2 h after the last dose of a repeated treatment (twice daily for 14 days, 10 or 30 mg/kg, po). 5 days after the last dose the treatments did not affect the response. DEP given both in a single dose of 0.25 mg/kg and repeatedly for 15 and 21 days, increased the amplitude of startle reaction immediately after completion of the treatment. 9 days after drug withdrawal this effect was not observed. DEP in a dose of 1.0 mg/kg had no effect on the amplitude of startle reaction in any experiments described above. The above results demonstrate that MAO-A inhibitors--brofaromine and moclobemide and a MAO-B inhibitor--deprenyl show opposit activity in acoustic startle response test. BRO and MOC exert the inhibitory activity, whereas DEP has an excitatory effect on the startle reaction. The reference drug, AMI had no effect when given in a single doses (2 and 10 mg/kg, po). After repeated treatment (twice daily for 14 days, 2 or 10 mg/kg, po), AMI diminished the amplitude of the startle reaction only in higher dose when tested 2 h after the last dose and had no effect in the experiment carried out 5 days after the last dose.

The effect of imipramine after single and repeated administration on the apomorphine response in the acoustic startle reflex in rats.

The paper presents the results of studies into the effects of single and repeated (2 or 10 mg/kg po, twice daily for 14 days) administration of imipramine (IMI) on the behavior of male Wistar rats in an acoustic startle response test. Statistically significant attenuation of the animal reactivity was observed after 8 or 14 days administration of IMI in a dose of 10 mg/kg. Apomorphine APO (1.0 mg/kg, ip) enhanced the animals reactivity after repeated (but not single) administration of IMI in a dose of 2 mg/kg. The obtained results confirm the hypothesis about an increase of the dopaminergic system reactivity under the influence of repeated administration of tricyclic antidepressants.

Antidepressant activity of S-adenosyl-L-methionine in mice and rats.

S-Adenosyl-L-methionine (SAM), main methyl donor, was tested in mice and rats in several models which are predictive of possible antidepressant activity. In the forced swimming test in rats the effect of SAM was compared with that of the tricyclic antidepressant amitriptyline. SAM decreased dose-dependently immobility time in the forced swimming test in mice and rats, these effects being antagonized by haloperidol and prazosin (the latter only in rats). Locomotor or exploratory activity in mice and rats was not increased by SAM. D-Amphetamine-induced locomotor hyper-activity in rats was increased by repeated (14 days, twice daily) treatment with SAM. Behavioural stimulation induced by D-amphetamine or L-dopa (given with benserazide) in mice was not changed by a single dose of SAM. The drug reduced hypothermia induced by apomorphine in mice. Hypothermia induced by reserpine or clonidine in mice was not antagonized. SAM increased the amplitude of the acoustic startle reflex. The above results indicate that the psychopharmacological profile of SAM resembles that of antidepressants in only some tests. The mechanism by which SAM produces its antidepressant effect needs further investigation.

Light-dark phase differences in behavioral effects of moclobemide in rats.

Effects of single and repeated administration of the MAO-A-inhibitor moclobemide (MOC) on the spontaneous locomotor activity and the locomotor hyper- and hypoactivity induced by d-amphetamine and clonidine, resp., in male Wistar rats were studied in both the light (L) and the dark (D) phase of the diurnal cycle (L:0700-1900 h). In the light phase, two hours after single administration, MOC (10 and 50 mg/kg po) increased the basal activity and a dose of 50 mg/kg decreased the exploratory and gross activities and enhanced the effects of amphetamine and clonidine. On the other hand, in the dark phase MOC (50 mg/kg) increased the gross activity and potentiated amphetamine hyperactivity. Only exploration was diminished to the same extent as in the light phase. After repeated administration MOC increased only the gross activity in the light phase. In the dark phase, however, MOC diminished exploration and potentiated the d-amphetamine hyperactivity. MOC, in both doses used, diminished food and water consumption and the body weight gain during the treatment period. These results demonstrate that MOC influences the behavior of rats in a phase-dependent manner after both single and repeated administration.

Some central effects of brofaromine given repeatedly are phase-dependent.

Effects of the MAO-A-inhibitor brofaromine (BRO), 10 mg/kg po after repeated (twice daily for 14 days) administration on the spontaneous behavior (exploratory and basal locomotor activities) and the exploratory activity modified by methoxamine, clonidine and d-amphetamine in male Wistar rats were studied in both light and dark phases of a diurnal cycle (L: 0700-1900 h). After single administration BRO in the light phase had no effects. In the dark phase BRO decreased the exploration (62% of control, p less than 0.01), increased the clonidine-evoked hypoactivity and amphetamine-evoked hyperactivity. The L-D differences occurred also after repeated administration. BRO in the light phase did not influence the exploration, decreased basal locomotor activity, did not change methoxamine and clonidine action and potentiated the action of amphetamine. In the dark phase, however, it did not influence the exploration and basal locomotor activity, intensified the methoxamine effect, and did not change the clonidine and amphetamine actions. The results demonstrate that the effects of BRO on behavior in rats: 1) differ from the effects caused by other antidepressants which are not MAO inhibitors; 2) are phase-dependent after both single and repeated administration.