Spontaneous Locomotor Activity In Rats Research Articles

Eplerenone modulates the inflammatory response in monosodium iodoacetate-induced knee osteoarthritis in rats: Involvement of RANKL/OPG axis

AimsOsteoarthritis (OA) is a multifactorial degenerative disease marked by the progressive deterioration of articular cartilage with inflammation of the synovium. OA's main symptoms include pain and function loss. Monosodium Iodoacetate (MIA) experimental model is widely-used for OS induction since it produces symptoms comparable to those occurring in humans. Materials and methodsThirty-two rats were divided into four groups (n = 8). The 1st group received saline and included the normal-control rats. Groups 2–4 received intra-articular injections of MIA (3 mg/50 μL) in the rats' knee joints to induce OA. Group 2 included the MIA-control rats. Groups 3 and 4 received intra-articular MIA followed by a 14-day oral eplerenone (50 and 100 mg/kg); respectively. Key findingsIntra-articular injection of MIA in rats' knee joints caused significant inflammation and pain, elevation of Akt and ERK gene expression in knee joints along with significant alterations in the histological pictures of knee joints and OARSI scores. RANKL/OPG Axis was significantly disrupted. SignificanceEplerenone treatment produced a significant improvement in motor coordination and spontaneous locomotor activity in rats and modulated the key inflammatory mediators in OA (TNF-α, NF-κβ, and IL-6). Eplerenone also suppressed the qRT–PCR gene expression of Akt and ERK in knee joint tissues and improved the histological pictures and OARSI scores of knee joints of treated rats. Eplerenone caused a decline in RANKL concentration accompanied by a rise in OPG concentration thus modulating the RANKL/OPG Axis. Consequently, eplerenone is a candidate for OA therapy due to its potential anti-inflammatory effects.

Effect of Clozapine and 5-NT2A-Antagonist RU-31 on electroencephalography and Motor Activity of Rats in a Model of Schizophrenia with Neonatal Destruction of the Ventral Hippocampus

Background. Schizophrenia is a socially signifi cant disease that takes a variety of forms. The form of the course determines prescribing antipsychotic drugs with a different range of clinical effects. The study of the pharmacological activity of neuroleptics involves an experimental model using animals which makes it possible to reproduce some aspects of schizophrenia.Objectives. The study is aimed at evaluating the antipsychotic activity of 5-HT2A— RU-31 antagonist and atypical neuroleptic clozapine in behavioral tests and electroencephalography (EEG).Methods. The research methodology involved a dysontogenetic model of schizophrenia, implemented via aspiration destruction of the ventral hippocampus of rats on day 7 of postnatal development. The study was carried out on white outbred male rats selected from the offspring of females, represented by a simple random sample, provided by Rappolovo animal breeding facility of the National Research Center “Kurchatov Institute”. Injection of the studied substances was initiated on day 35 of postnatal development. Motor activity was assessed on day 54 of postnatal development in the Open Field unit and included assessing vertical motor activity, measured as the number of acts of verticalization in 5 minutes, and horizontal motor activity of rats, recorded as the number of crossed squares in 5 minutes. EEG signals were recorded on day 55 of postnatal development; thereafter the spectral density was calculated in the delta- (д) (0.4–4 Hz), theta- (и) (4.8–8 Hz), alpha- (б) (8–12 Hz) and beta- (в) (12–30 Hz) frequency ranges and the effect of the “operation” and “substance” factors on spectral density was evaluated in comparison with control groups. Statistical data processing was performed using GraphPad Prism 9 (Insight Partners, USA).Results. The antipsychotic activity of 1-(2-diethylaminoethyl)-2-(4-methoxyphenyl)-imidazo[1,2-a] benzimidazole — RU-31 compound with 5-HT2A-antagonistic mechanism of action was evaluated. RU-31 compound (10 mg/kg, intraperitoneally (i.p.)) statistically signifi cantly reduced vertical and horizontal spontaneous locomotor activity in rats with psychotic disorder by 18.8% and 20.9%, while the atypical neuroleptic clozapine (2 mg/kg, i.p.) signifi cantly reduced these values by 41.15% and 27.67%, respectively. The 5-HT2A-receptor antagonist RU-31 increased EEG signal power in the delta range by 123.33% and decreased it in the alpha range by 41.86% in surgically operated animals (p < 0.05). Clozapine increased the EEG signal power in all studied frequency ranges: in delta — by 107.99%, theta — by 97.16%, alpha — by 41.86% and in beta — by 49.16% in animals with neonatal destruction of the ventral hippocampus (p < 0.05).Conclusion. The studied substances contributed to the correction of behavioural disturbances associated with hypermobility as well as electrophysiological changes induced by a surgical operation, while similar activity was not observed (or was observed to a lesser extent) in healthy animals.

Longevity, tumor, and physical vitality in rats consuming ginsenoside Rg1

BackgroundEffects of the major ginsenoside Rg1 on mammalian longevity and physical vitality are rarely reported. PurposeTo examine longevity, tumor, and spontaneous locomotor activity in rats consuming Rg1. MethodsA total of 138 Wistar rats were randomized into 2 groups: control (N = 69) and Rg1 (N = 69). Rg1 (0.1 mg/kg per day) were orally supplemented from 6 months of age until natural death. Spontaneous mobility was measured by video-tracking together with body composition (dual energy x-ray absorptiometry) and inflammation markers at 5, 14, 21, and 28 months of age. ResultsNo significant differences in longevity (control: 706 days; Rg1: 651 days, p = 0.77) and tumor incidence (control: 19%; Rg1: 12%, p = 0.24) were observed between the two groups. Movement distance in the control group declined significantly by ∼60% at 21 months of age, together with decreased TNF-α (p = 0.01) and increased IL-10 (p = 0.02). However, the movement distance in the Rg1 group was maintained ∼50% above the control groups (p = 0.01) at 21 months of age with greater magnitudes of TNF-α decreases and IL-10 increases. Glucose, insulin, and body composition (bone, muscle and fat percentages) were similar for both groups during the entire observation period. ConclusionThe results of the study suggest a delay age-dependent decline in physical vitality during late life by lifelong Rg1 consumption. This improvement is associated with inflammatory modulation. Significant effects of Rg1 on longevity and tumorigenesis were not observed.

Familiarity to testing environment affects spontaneous locomotor activity in rats

Familiarity to testing environment affects spontaneous locomotor activity in rats

Environmental Enrichment Increases Spontaneous Locomotor Activity In Rats

Environmental Enrichment Increases Spontaneous Locomotor Activity In Rats

THE INFLUENCE OF ZINC DONATOR ACYZOL INTO RAT'S LOCOMOTOR BEHAVIOR

The aim of the article. The article is devoted to investigation of zinc donator acyzol influence to spontaneous or conditioned reflex locomotor activity of the rats. Materials and methods of research. The study was performed on adult male Wistar rats. Acyzol in volume of 0.1 ml was injected intraperitoneal (24 мg/kg) twice with the time gap of three days. Parameters of spontaneous locomotor activity were evaluated in “open field”, and values of conditioned reflex behavior of avoidance were evaluated in “shuttle box”. Results. Spontaneous locomotor activity of rats (especially the number of research rearing iterations) has lowered after the first injection under the influence of acyzol soon. The realization of avoidance conditioned reflexes was worsened after the second injection of acyzol. Conclusion. There is reason to propose, that acyzol, increasing the zinc content in the body, is able to lower the locomotor activity of rats; and it has the indirect influence on the avoidance conditioned reflex behavior. It should be considered when application of acyzol as a medical, protective or tonic drug.

Group II mGlu receptor antagonist LY341495 enhances the antidepressant-like effects of ketamine in the forced swim test in rats.

RationaleNumerous preclinical and clinical studies have reported the rapid and sustained antidepressant effects of the NMDA receptor antagonist ketamine. Because ketamine induces several undesirable and dangerous effects, a variety of strategies have been suggested to avoid such effects.ObjectivesHere, we propose to enhance the sub-effective doses of ketamine by co-administration with the group II metabotropic glutamate (mGlu) receptor antagonist LY341495. This compound potentially acts as an antidepressant via a mechanism similar to that of ketamine.MethodsTo investigate the rapid and sustained antidepressant-like effects of these drugs, we administered ketamine and LY341495 individually or in combination, 40 min and 24 h before the forced swim test (FST).ResultsWe found that sub-effective doses of ketamine and LY341495, given jointly, induce significant antidepressant-like effects, at both 40 min and 24 h after administration. The results obtained using Western blot technique indicate that mammalian target of rapamycin (mTOR) pathway activation may be involved in the mechanism of this action. The effects of drugs, used at identical ranges of times and doses, on spontaneous locomotor activity in rats were excluded. Furthermore, the results obtained from the rota-rod test and the ketamine-induced hyperlocomotion test suggest a lack of potentially adverse effects from the combined administration of ketamine and LY341495 at doses previously used in the FST.ConclusionAltogether, these data suggest that the joint administration of ketamine and LY341495 might be a noteworthy alternative to the use of solely ketamine in the therapy of depression.

Improvement of spontaneous locomotor activity with JAK inhibition by JTE-052 in rat adjuvant-induced arthritis.

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint destruction, disability, and decreased quality of life (QOL). Inhibition of Janus kinase (JAK) signaling ameliorates articular inflammation and joint destruction in animal models of RA, but its effects on behaviors indicating well-being are poorly understood. In this study, we evaluated the effect of JAK inhibition on spontaneous locomotor activity in rats with adjuvant-induced arthritis, a rodent model of RA.MethodsArthritis was induced in male Lewis rats by a single subcutaneous injection of Freund’s complete adjuvant. The novel JAK inhibitor JTE-052 was orally administered for 7 days after the onset of arthritis.ResultsInduction of arthritis suppressed the spontaneous locomotor activity of the rats. Administration of JTE-052 completely improved the spontaneous locomotor activity, with partial reductions in articular inflammation and joint destruction. Hyperalgesia and motor functions were also improved, but the efficacy was not complete. However, serum interleukin (IL)-6 levels were completely decreased at 4 h after administration of the first dose of JTE-052.ConclusionsThis study demonstrated that JAK inhibition improved the spontaneous locomotor activity of rats with adjuvant-induced arthritis, in association with amelioration of pain and physical dysfunction as a consequence of suppression of joint inflammation. Moreover, although further studies are needed, there was possible participation of IL-6 downregulation in the improvement of locomotor activity by JAK inhibition.

CT imaging and spontaneous behavior analysis after osmotic blood-brain barrier opening in Wistar rat.

In our previous experiments we demonstrated that osmotic opening of the blood brain barrier (BBB) in rats by administration of mannitol into the internal carotid artery leads to cerebral edema. The aim of this study was to confirm objectively the development of brain edema and determine whether it affects spontaneous locomotor activity in rats (SLA). Brain edema was verified by computer tomography (CT) examination of the brain and SLA was observed during open field test. Twenty four adult male rats were divided into four groups of six: (1) control animals (C), (2) controls with anesthesia (CA), (3) controls with sham surgery (CS), (4) experimental - osmotic opening of the BBB (MA). Osmotic BBB disruption manifested by reducing the density of brain tissue (hypodensity), suggesting a higher water content in the brain tissue. SLA was compared between C, CA, CS and MA groups and between MA and CA groups. Significant difference was found only between the control group and MA group. In the first 30 min of the examination, rats after the mannitol administration revealed a marked limitation of spontaneous locomotor activity. Experimental results demonstrated reduction of spontaneous locomotor activity in rats with induced brain edema.

Somatostatin-28 modulates prepulse inhibition of the acoustic startle response, reward processes and spontaneous locomotor activity in rats

Somatostatins have been shown to be involved in the pathophysiology of motor and affective disorders, as well as psychiatric disorders, including schizophrenia. We hypothesized that in addition to motor function, somatostatin may be involved in somatosensory gating and reward processes that have been shown to be dysregulated in schizophrenia. Accordingly, we evaluated the effects of intracerebroventricular administration of somatostatin-28 on spontaneous locomotor and exploratory behavior measured in a behavioral pattern monitor, sensorimotor gating, prepulse inhibition (PPI) of the acoustic startle reflex, and brain reward function (measured in a discrete trial intracranial self-stimulation procedure) in rats. Somatostatin-28 decreased spontaneous locomotor activity during the first 10 min of a 60 min testing session with no apparent changes in the exploratory activity of rats. The highest somatostatin-28 dose (10 microg/5 microl/side) induced PPI deficits with no effect on the acoustic startle response or startle response habituation. The somatostatin-induced PPI deficit was partially reversed by administration of SRA-880, a selective somatostatin 1 (sst(1)) receptor antagonist. Somatostatin-28 also induced elevations in brain reward thresholds, reflecting an anhedonic-like state. The non-peptide sst(1) receptor antagonist SRA-880 had no effect on brain reward function under baseline conditions. Altogether these findings suggest that somatostatin-28 modulates PPI and brain reward function but does not have a robust effect on spontaneous exploratory activity. Thus, increases in somatostatin transmission may represent one of the neurochemical mechanisms underlying anhedonia, one of the negative symptoms of schizophrenia, and sensorimotor gating deficits associated with cognitive impairments in schizophrenia patients.

Effects of food deprivation on goal-directed behavior, spontaneous locomotion, and c-Fos immunoreactivity in the amygdala

Previous work in our laboratory has shown that food deprivation and food presentation produce different patterns of neuronal activity (as measured by c-Fos immunoreactivity) in the medial prefrontal cortex and nucleus accumbens of rats. Since the amygdala has been implicated in both motivational and reinforcement processes and has neuronal connections to both the prefrontal cortex and nucleus accumbens, it was of interest to assess amygdaloid c-Fos immunoreactivity during similar manipulations of food deprivation and presentation. In the current study, c-Fos counts in both basolateral and central amygdalar nuclei were observed to increase in rats 12- and 36-h food deprived (relative to 0-h controls)—an effect reversed by the presentation of either a small or large meal (2.5 or 20 g of food). In another experiment, rats working on a progressive ratio schedule of reinforcement exhibited elevated break-points as a function of food deprivation, a result consistent with the view that the feeding manipulations increased the subjects’ level of motivation. In contrast, food deprivation reduced the spontaneous locomotor activity of rats, presumably as a result of an inherent energy-conservation strategy when no food is readily available. These data suggest that the state of food deprivation is associated with: (a) enhanced behavioral output only when food is attainable (increased goal-directed behavior, but decreased spontaneous activity), and (b) increased synaptic engagement in neuronal circuits involved in affective valuation and related decision-making (increased c-Fos counts in the amygdala).

The opposite effect of a low and a high dose of serotonin-1A agonist on behavior induced by MK-801

The purpose of the present study was to investigate the opposite effect of the pre- and postsynaptic serotonin-1A (5-HT 1A) receptors on the psychotic-like behavior induced by a non-competitive antagonist of the NMDA receptor, dizocilpine (MK-801). Male Wistar rats received two doses (0.025 mg/kg and 1 mg/kg) of 5-HT 1A receptor agonist 8-OH-DPAT (8-hydroxy-2-(di- n-propylamino) tetralin) and/or MK-801 in two different doses, 0.1 mg/kg or 0.3 mg/kg. We measured sensorimotor gating by testing prepulse inhibition of acoustic startle response (PPI) and locomotor activity of rats. We found an opposite effect of the low and high 5-HT 1A receptor agonist doses on MK-801 induced deficit in PPI and hyperlocomotion in habituated rats. The low dose of 8-OH-DPAT, which preferentially acts on presynaptic 5-HT 1A receptors, restored the deficit in PPI and hyperlocomotion in MK-801 (0.1 mg/kg)-treated habituated rats. However, the high dose of 8-OH-DPAT, which activates both pre- and postsynaptic 5-HT 1A receptors, decreased PPI and increased locomotor activity after administration of the low dose of MK-801. Administration of 8-OH-DPAT itself dose-dependently decreased PPI. However, only the high dose of 8-OH-DPAT increased spontaneous locomotor activity of rats. Our results indicate that there is an interaction between the NMDA and 5-HT 1A receptors. In addition, these findings could indicate that activation of the 5-HT 1A autoreceptor could be effective as a treatment in schizophrenia, but full potent agonism of the receptor could worsen the psychotic symptoms.

L-Dopa− and Dopamine−(R)-α-Lipoic Acid Conjugates as Multifunctional Codrugs with Antioxidant Properties

A series of multifunctional codrugs (1-4), obtained by joining L-Dopa (LD) and dopamine (DA) with (R)-alpha-lipoic acid (LA), was synthesized and evaluated as potential codrugs with antioxidant and iron-chelating properties. These multifunctional molecules were synthesized to overcome the pro-oxidant effect associated with LD therapy. The physicochemical properties, together with the chemical and enzymatic stabilities of synthesized compounds, were evaluated in order to determine both their stability in aqueous medium and their sensitivity in undergoing enzymatic cleavage by rat and human plasma to regenerate the original drugs. The new compounds were tested for their radical scavenging activities, using a test involving the Fe (II)-H2O2-induced degradation of deoxyribose, and to evaluate peripheral markers of oxidative stress such as plasmatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the plasma. Furthermore, we showed the central effects of compounds 1 and 2 on spontaneous locomotor activity of rats in comparison with LD-treated animals. From the results obtained, compounds 1-4 appeared stable at a pH of 1.3 and in 7.4 buffered solution; in 80% human plasma they were turned into DA and LD. Codrugs 1-4 possess good lipophilicity (log P > 2 for all tested compounds). Compounds 1 and 2 seem to protect partially against the oxidative stress deriving from auto-oxidation and MAO-mediated metabolism of DA. This evidence, together with the "in vivo" dopaminergic activity and a sustained release of the parent drug in human plasma, allowed us to point out the potential advantages of using 1 and 2 rather than LD in treating pathologies such as Parkinson's disease, characterized by an evident decrease of DA concentration in the brain.

FK506 ameliorates spontaneous locomotor activity in collagen-induced arthritis: implication of distinct effect from suppression of inflammation

FK506 (tacrolimus), an immunosuppressive drug, improves quality of life (QOL) for patients with rheumatoid arthritis (RA). However, the mechanism of FK506 behind the improvement in QOL is still uncharacterized. To explain the improvement of QOL by FK506, we investigated the effect of FK506 on spontaneous locomotor activity in rats with collagen-induced arthritis (CIA). CIA was induced in 7- to 8-week-old female Lewis rats by immunization with bovine type II collagen. After initiation of paw inflammation (paw swelling, histopathological analysis), CIA rats were therapeutically administered FK506 or methotrexate (MTX) from day 15. Therapeutic treatment with FK506 ameliorated spontaneous locomotor activity without suppressing paw inflammation in CIA rats from day 27. FK506 also improved hyperalgesia and grip strength from day 27. Therapeutic treatment with MTX did not improve spontaneous locomotor activity, and simultaneously did not recover hyperalgesia or grip strength in CIA rats. Our results indicate that spontaneous locomotor activity in CIA rats correlates mainly with hyperalgesia and muscle strength, but not paw inflammation, implying that therapeutic treatment with FK506 ameliorates spontaneous locomotor activity via improvement of hyperalgesia and muscle strength in CIA rats.

The GABAB agonist baclofen blocks the expression of sensitisation to the locomotor stimulant effect of amphetamine.

The purpose of the present study was to test the possible influence of baclofen, a GABAB agonist, on the long-term sensitisation to amphetamine in rats. As expected, chronic amphetamine treatment (1.5 mg/kg i.p. daily for 10 days) led to an increased locomotor response to amphetamine (0.75 mg/kg i.p.), when the animals were challenged 20 days after the end of repeated treatment. Baclofen (2 mg/kg i.p.), administered before the test session, did not significantly modify the spontaneous locomotor activity of rats, but decreased the normal and, to a greater extent, the sensitised locomotor response to amphetamine; thus baclofen prevented the expression of sensitisation to amphetamine. Moreover a previous chronic treatment with baclofen (2 mg/kg i.p. daily for 10 days) attenuated the amphetamine-induced locomotor activity in sensitised, but not in control animals. This effect was observed 20 days after the last baclofen administration. In conclusion, the present results demonstrate that GABAB receptors play an important role in the expression of the sensitised behavioural response to amphetamine and further support a potential role of GABAB agonists in the treatment of psychostimulant addiction.

Central administration of ghrelin and agouti-related protein (83-132) increases food intake and decreases spontaneous locomotor activity in rats.

Ghrelin was recently identified as an endogenous ligand of the GH secretagogue receptor. The novel peptide hormone is produced by gastric A-like cells, and circulating levels rise before feeding, suggestive of ghrelin as an endogenous hunger factor. ghrelin stimulates food intake and promotes adiposity after peripheral or central administration, likely by activating hypothalamic neurons expressing the orexigenic neuropeptides neuropeptide Y (NPY) and agouti-related protein (AGRP). To examine whether ghrelin-induced feeding resembles NPY and AGRP [AGRP fragment (83-132)] induced orexia, we compared the short- and long-term orexigenic capacity of the three peptides. A single intracerebroventricular injection of ghrelin (0.2, 1.0, and 5.0 microg) increased food intake in a dose-dependent manner. A prolonged and uncompensated increase in feeding was seen after the highest dose of ghrelin. The prolonged effects on feeding (+72 h) closely resembled those of AGRP (83-132) but not NPY. Surprisingly, ghrelin injections reduced overall locomotor activity by 20% during the first 24-h observation period. AGRP (83-132) had similar effects on locomotor behavior, whereas NPY had no effect. In summary, ghrelin causes long-term increases of food intake and, like AGRP, plays a previously unknown role as a suppressor of spontaneous physical activity. Expanding the current model of food intake control to include mechanisms regulating physical activity may promote our understanding of two major etiological factors causing obesity.

Efffects of vigabatrin on spontaneous locomotor activity of rats

AbstractEffects of vigibatrin (saline, 125, 250, or 500 mg/kg i.p.) on spontaneous locomotor activity in Wistar rats were investigated. There was a dose dependent decrease in amount of locomotion for doses up to 250 mg/kg. This decrease was measurable 2–4 hours after injection and still became more pronounced in the following hours. The mean velocity during the movements 2–6 hours after injection remained intact and was higher in the 500 mg/kg group. In this high dose group an abnormal posture with a hunched back and pilo‐erection was observed. The decrease of the amount of motor activity with the preservation of the mean velocity in this non‐stimulating procedure, suggests that the level in which the experimental procedure imposes motor activity might be an important factor when measuring effects of vigabatrin. Postscript: Immediate post injection effects were observed, equivalent to those seen in the writhing test, a pain test using hyperosmolar saline injections. These observations stress the importance of controlling the osmolarity of the injection fluids.

Effect of repeated treatment with lamotrigine on locomotor activity and on DOI-elicited wet dog shakes in rats

Lamotrigine is a new anticonvulsant, and it is also effective for bipolar disorder, especially for bipolar depression. In this study, we have investigated the effect of single or repeated treatment with lamotrigine on some behavioral response in rats to understand its action mechanisms on mood disorder. As for acute effect of lamotrigine, single treatment with lamotrigine (5, 10 and 20 mg/kg) did not change the intensity of 8-OH-DPAT-induced flat body posture, the frequency of DOI-elicited wet dog shakes (WDSs), or spontaneous locomotor activity in rats. As for chronic effect of lamotrigine, rats were subcutaneously injected with dexamethasone (1 mg/kg) and/or lamotrigine (10 mg/kg) intraperitoneally for 14 days. One day after the last administration, spontaneous locomotor activity of the rats was measured, and subsequently DOIinduced WDSs were observed. Repeated treatment with lamotrigine (10 mg/kg) itself facilitated spontaneous locomotor activity. Repeated dexamethasone injection significantly enhanced DOIproduced WDSs, and the enhancement declined with repeated treatment with lamotrigine (10 mg/kg). These findings are similar to the effect of some antidepressants and mood stabilizers on these behaviors, and can explain some action mechanisms of lamotrigine on mood disorder.

The interaction of AR-A008055 and its enantiomers with the GABA A receptor complex and their sedative, muscle relaxant and anticonvulsant activity

AR-A008055 [(±)-1-(4-methyl-5-thiazolyl)-1-phenylmethylamine] is structurally related to clomethiazole and has been used to probe the mechanism of the neuroprotective effect of clomethiazole. Clomethiazole, (±)-AR-A008055 and ( S)-(−)-AR-A008055 all displaced [ 35 S] - t-butyl-bicyclophosphorothionate ( [ 35 S] TBPS) from rat cerebral cortex tissue (IC 50 values: GABA, 8.1±0.04 μM; clomethiazole, 130±30 μM; (±)-AR-A008055, 494±7 μM; ( S)-(−)-AR-A008055, 221±14 μM. ( R)-(+)-AR-A008055 was without significant effect (IC 50>1000 μM). None of the compounds interacted with NMDA or AMPA receptors or with sodium or calcium (N, P/Q) channels. Brain penetration of both enantiomers following their i.p. administration was excellent, with brain and plasma concentrations being similar. Clomethiazole dose-dependently inhibited spontaneous locomotor activity in rats and was approximately 10 times more sedative than either enantiomer of AR-A008055. Clomethiazole was more potent than ( S)-(−)-AR-A008055 in the “pull-up” test (muscle relaxation) and in producing loss of righting reflex, while ( R)-(+)-AR-A008055 had little effect. The time animals remained on a Rota-rod was of the order: clomethiazole<( S)-(−)-AR-A008055<( R)-(+)-AR-A008055. ( S)-(−)-AR-A008055 (210 μmol/kg) raised seizure threshold to pentylenetetrazole (i.v.) by 119±21%. The ( R)-(+)- enantiomer was not anticonvulsant. Overall, ( S)-(−)-AR-A008055 exhibited a similar pharmacology to clomethiazole. However, its sedative and muscle relaxant effects were substantially less than clomethiazole, emphasising that these properties are not directly related to neuroprotective efficacy. The current data suggest that the proposed GABA uptake inhibitory property of ( R)-(+)-AR-A008055 fails to produce significant sedative, myorelaxant or anticonvulsant activity.

Effects of the histamine H(1) receptor blocker, pyrilamine, on spontaneous locomotor activity of rats with long-term portacaval anastomosis.

To find out whether the changes in the brain histaminergic system are involved in the pathophysiology of portal-systemic encephalopathy, we examined the effects of histamine H(1) receptor blockade on spontaneous locomotor activity, feeding, and circadian rhythmicity in rats with portacaval anastomosis (PCA). Pyrilamine, an H(1) receptor blocker (15 mg/kg/day), was delivered with osmotic minipumps. Spontaneous locomotor activity was recorded for 72 hours in the open-field with an electromagnetic detector. Food intake was monitored twice daily at the end of the light (7 PM) and the dark (7 AM) phases for 3 days. Histamine H(1) receptor density in the suprachiasmatic nucleus (SCN) was examined with receptor autoradiography, employing [(3)H]pyrilamine. PCA surgery led to decreased movement time and velocity and flattened amplitude of the circadian rhythms of locomotion and feeding. In sham-operated rats, pyrilamine significantly decreased the movement time and velocity, as well as the total food consumption and completely abolished the circadian rhythmicity of locomotion. In contrast, pyrilamine increased the movement time and velocity in PCA-operated rats, particularly in the dark phase, and improved the precision of the circadian rhythms of locomotion and feeding. Histamine H(1) receptor density was not altered by PCA surgery, whereas pyrilamine treatment led to the complete blockade of H(1) receptors in both sham- and PCA-operated rats. We suggest that histaminergic imbalance has contributed to the generation and maintenance of the decreased spontaneous locomotor activity and altered circadian rhythmicity following PCA surgery in the rat, probably via an H(1) receptor-mediated mechanism.