Reduction In Spontaneous Locomotor Activity Research Articles

Effect of dosage duration on oropharyngeal and locomotor in a toxicological rat model of Parkinson’s disease

Parkinson’s Disease (PD) is a prevalent and devastating neurodegenerative disorder that causes progressively worsening motor symptoms affecting locomotor and oropharyngeal function. There is limited research in animal models on swallowing dysfunction in PD. To examine how neurodegeneration in PD produces progressive impairment in the oropharyngeal and locomotor processes, rotenone, a type II mitochondrial inhibitor, was injected into Lewis rat models to reproduce a parkinsonian phenotype. We hypothesized that the animal models injected with the rotenone will exhibit both oropharyngeal dysfunction and locomotor deficiency with an increased deficit that correlates with prolonged treatment. We utilized 18 rats receiving either 2.75 mg/kg of rotenone or vehicle intraperitoneal injections. Animals received daily injections for 17 or 8 days. At the end of the injections in each group brains were perfused and immunostained for striatal tyrosine hydroxylase (TH). High speed (200 fps) videofluoroscopic recording was taken of these rats and average chew cycle length, chewing rate, and total chewing time data were collected from days 0, 1, 4, 7 and 16 of those recordings. The number of rears by a rat in a glass cylinder over 4 minutes was counted on the same days to assess locomotor behavior. We used mixed model ANOVA, controlling for the effect of individual variation, to test the impact of rotenone treatment on feeding and locomotor variables. We used a Kruskall-Wallis non parametric test to test the effect of rotenone treatment on striatal TH levels. Total chewing time, and average chew cycle duration increased in rotenone treated rats from day 0 to day 4, but the difference disappeared from day 7 onwards. However, rearing behavior was consistently reduced in rotenone treated rats for all 16 days. TH staining intensity in the striatum decreased consistently over the course of the injections. These results suggest that rotenone treated rats have temporary/short term deficiency in chewing function, despite sustained reduction in spontaneous locomotor activity. The restoration of function after day 4 may indicate a learned behavior to compensate for this dysfunction in chewing, or point to a different neurological impairment than that seen in locomotor behavior. Further research needs to be undertaken to understand this phenomenon. Internal Rowan funding to F. Gould supported this work. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Liver damage in a mouse model of methamphetamine overdose.

Currently, the incidence of death due to methamphetamine (METH) overdose is increasing rapidly in the US. Liver damage is a consequence of METH overdose. Our objective was to produce acute METH-induced hepatotoxicity observable by the clinical serum biomarker alanine aminotransferase (ALT).
 In this study, 9 week old male CD-1 IGS mice (n=6-7/group) were administered 0 (saline), 10, or 20 mg/kg intraperitoneal (ip) METH every 2 hours for a total of 4 doses. One day after the first METH dose, mice were weighed and 30 minutes of spontaneous locomotor activity was measured. Immediately afterward, serum was collected for the determination of ALT.
 Both the 10 and 20 mg/kg METH regimens increased animal stress as measured by a significant reduction in spontaneous locomotor activity and weight loss (p<.05), but there were no significant differences between the two doses. While the 10 mg/kg regimen did not produce any significant elevations in ALT compared to saline control, the 20 mg/kg METH regimen significantly increased ALT compared to both saline and the 10 mg/kg METH regimen (p<.05).
 In conclusion, this 20 mg/kg METH overdose regimen produced acute hepatotoxicity in mice. It will be used in the future development of pharmacotherapies protective against METH-induced liver damage.

Pharmacological and physicochemical profile of arylacetamides as tools against human cancers

Arylacetamides are widely used as synthetic intermediates to obtain medicinal substances. This work evaluated in vitro antiproliferative activity of ten 2-Chloro-N-arylacetamides on human normal and cancer cells and detailed in vivo toxicological and anticancer investigations. Initially, cytotoxic colorimetric assays were performed using tumor lines, peripheral blood mononuclear cells (PBMC) and erythrocytes. Compounds 2, 3 and 4 were tested for acute toxicity (50, 150 and 300 mg/kg) and for subacute antitumoral capacity in HCT-116 colon carcinoma-bearing xenograft mice for 15 days at 25 mg/kg/day. Most compounds revealed cytotoxic action on tumor lines and PBMC, but activity on human erythrocytes were not detected. Molecular dipole moment, lipophilicity and electronic constant of aryl substituents had effects upon in vitro antiproliferative capacity. More common in vivo acute behavioral signals with compounds 2, 3 and 4 were muscle relaxation, reduction of spontaneous locomotor activity and number of entries in closed arms and increased number of falls andtime spent in open arms, suggesting diazepam-like anxiolytic properties. Decrease of grabbing strength and overall activity were common, but palpebral ptosis and deaths occurred at 300 mg/kg only. Compounds 2 and 3 reduced colon carcinoma growth (21.2 and 27.5%, respectively, p < 0.05) without causing apparent signals of organ-specific toxicity after subacute exposure. The structural chemical simplicity of arylacetamides make them cost-effective alternatives and justifies further improvements to enhance activity, selectivity and the development of pharmaceutical formulations.

Electrophysiological Characterization of Novel Effects of the Uptake-2 Blocker Decynium-22 (D-22) on Dopaminergic Neurons in the Substantia Nigra Pars Compacta

Extracellular levels of dopamine (DA) and other monoamines in the brain depend not only on the classic transporters encoded by SLC6A gene family such as DAT, NET and SERT, but also a more recently identified group of low-affinity/high-capacity ‘Uptake-2’ transporters, mainly OCT3 and PMAT. The most frequently used pharmacological tool in functional studies of Uptake-2 is decynium-22 (D-22) known to block these transporters. However, the effectiveness of this drug in enhancing extracellular DA remains uncertain. Our aim was to test the hypothesis that D-22 increases extracellular levels of DA released from the somatodendritic region of dopaminergic neurons in the substantia nigra pars compacta (SNc) by reducing the OCT3/PMAT-dependent component of DA uptake. Extracellular DA was assessed indirectly, by evoking D2-IPSCs in SNc neurons following stimulated release of this neurotransmitter in midbrain slices obtained from mice. Recordings were conducted after partial inhibition of DAT with nomifensine, and after application of L-DOPA which increased the releasable DA pool. Contrary to our expectations, D-22 reduced, rather than increased, the amplitude of D2-IPSCs. Other effects included inhibition of GABAB-IPSCs and Ih current, and a reduction in firing frequency of nigral neurons. These results show that in addition to the previously known non-specific inhibitory action on α1 adrenoceptors, D-22 exerts additional off-target effects by inhibiting dopaminergic and GABAergic synaptic transmission in the SNc and the spontaneous (pacemaker) activity of nigral neurons. It remains to be established if these novel effects contribute to a reduction in spontaneous locomotor activity reported in previous studies after systemic drug administration.

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.

Adenosine through the A2A adenosine receptor increases IL-1β in the brain contributing to anxiety.

Anxiety is one of the most commonly reported psychiatric conditions, but its pathogenesis is poorly understood. Ailments associated with activation of the innate immune system, however, are increasingly linked to anxiety disorders. In adult male mice, we found that adenosine doubled caspase-1 activity in brain by a pathway reliant on ATP-sensitive potassium (KATP) channels, protein kinase A (PKA) and the A2A adenosine receptor (AR). In addition, adenosine-dependent activation of caspase-1 increased interleukin (IL)-1β in the brain by 2-fold. Peripheral administration of adenosine in wild-type (WT) mice led to a 2.3-fold increase in caspase-1 activity in the amygdala and to a 33% and 42% reduction in spontaneous locomotor activity and food intake, respectively, that were not observed in caspase-1 knockout (KO), IL-1 receptor type 1 (IL-1R1) KO and A2A AR KO mice or in mice administered a caspase-1 inhibitor centrally. Finally, adenosine administration increased anxiety-like behaviors in WT mice by 28% in the open field test and by 55% in the elevated zero-maze. Caspase-1 KO mice, IL-1R1 KO mice, A2A AR KO mice and WT mice treated with the KATP channel blocker, glyburide, were resistant to adenosine-induced anxiety-like behaviors. Thus, our results indicate that adenosine can act as an anxiogenic by activating caspase-1 and increasing IL-1β in the brain.

Opioid receptor types involved in the development of nicotine physical dependence in an invertebrate (Planaria) model

Recent data suggest that opioid receptors are involved in the development of nicotine physical dependence in mammals. Evidence in support of a similar involvement in an invertebrate (Planaria) is presented using the selective opioid receptor antagonist naloxone, and the more receptor subtype-selective antagonists CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) (μ, MOR), naltrindole (δ, DOR), and nor-BNI (norbinaltorphimine) (κ, KOR). Induction of physical dependence was achieved by 60-min pre-exposure of planarians to nicotine and was quantified by abstinence-induced withdrawal (reduction in spontaneous locomotor activity). Known MOR and DOR subtype-selective opioid receptor antagonists attenuated the withdrawal, as did the non-selective antagonist naloxone, but a KOR subtype-selective antagonist did not. An involvement of MOR and DOR, but not KOR, in the development of nicotine physical dependence or in abstinence-induced withdrawal was thus demonstrated in a sensitive and facile invertebrate model.

The α-asarone/clofibrate hybrid compound, 2-methoxy-4-(2-propenyl)phenoxyacetic acid (MPPA), is endowed with neuroprotective and anticonvulsant potentialities

2-methoxy-4-(2-propenyl)phenoxy acetic acid (MPPA) is a synthetic drug previously developed to mimic hypolipidemic activity and reduce side-effects of α-asarone, a vegetal extract used in traditional medicine to treat cardiovascular, neurological and other human disorders. MPPA was here evaluated in a battery of tests previously used to characterize anticonvulsant/neuroprotective and toxic potential of α-asarone in mice. MPPA toxicity was limited and doses up to 100 mg/kg induced neither hypothermia, nor reduction of spontaneous locomotor activity nor failure in rotarod test. Dose-dependent potentiation of the pentobarbital-induced sleeping was, however, observed at doses higher than 12.5 mg/kg. Little or no protection was provided by MPPA against seizures induced by N-methyl-D-aspartate. Moderate protection against subcutaneous pentylenetetrazol- and picrotoxin-induced seizures in mice, along with potentiation of pentobarbital-induced sleep, suggested GABAergic mechanisms. In maximal electroshock-induced seizures, MPPA protected 20% tested mice at 30 mg/kg and shortened recovery phase in convulsing mice, suggesting some action on neuronal voltage-gated sodium channels. High efficacy of MPPA was further observed in magnesium-dependent audiogenic seizures test, a murine model responsive to a variety of anticonvulsant, neuroprotective and antioxidant compounds. In this test, 50% animals were protected by 10 mg/kg MPPA, highlighting strong brain protective potential. In vitro, MPPA exhibited a superoxide-scavenging capacity about two-fold higher than that of α-asarone. Taken as a whole, present data support that MPPA is less toxic and more brain protective than α-asarone, and represents a worthy emerging neuroprotective/anticonvulsant compound endowed with a large activity spectrum including antioxidant, neuroprotective-like, moderate pro-GABAergic and sodium blockade mechanisms.

Neuropeptide S receptor deficiency modulates spontaneous locomotor activity and the acoustic startle response

The present study investigated the phenotype of heterozygous and homozygous neuropeptide S receptor (Npsr) deficient C57BL/6 mice in NPS- and cocaine induced hyperactivity, spontaneous and reactive locomotor activity, elevated plus maze, conditioned fear, and prepulse inhibition of the acoustic startle response. In Npsr-deficient mice, a strong reduction of spontaneous locomotor activity and of the startle magnitude was observed; heterozygous mice had an intermediate phenotype. In the other experiments, Npsr deficiency leads to no or only a very modest phenotype. These results support an important role of neuropeptide S in regulating locomotor activity.

Chronic A 2A antagonist treatment alleviates parkinsonian locomotor deficiency in MitoPark mice

Adenosine A 2A receptor (A 2AR) antagonists are being investigated as promising treatment strategy for Parkinson's disease (PD). To test whether A 2AR antagonists are beneficial in early PD stages we used MitoPark mice, a genetic model with gradual degeneration of DA cells. Daily treatment of young MitoPark mice for eight weeks with the A 2AR antagonist MSX-3 prevented the reduction of spontaneous locomotor activity observed in saline or L-DOPA treated animals. Chronic A 2AR antagonist treatment neither induced desensitization of receptors nor accumulation of the drug in brain tissue. Despite beneficial effects on behavior, which are not improved upon addition of a low dose of L-DOPA, the characteristic decline of dopamine levels was not changed. Our results indicate that effective dosing with A 2AR antagonists should be tested as monotherapy in early PD, and serves to remind us that positive behavioral effects of such treatment need not be reflected in rescue of striatal dopamine levels.

Biochemical and behavioural characterization of EMPA, a novel high-affinity, selective antagonist for the OX2receptor

Background and purpose: The OX2 receptor is a G-protein-coupled receptor that is abundantly found in the tuberomammillary nucleus, an important site for the regulation of the sleep-wake state. Herein, we describe the in vitro and in vivo properties of a selective OX2 receptor antagonist, N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA). Experimental approach: The affinity of [3H]EMPA was assessed in membranes from HEK293-hOX2-cells using saturation and binding kinetics. The antagonist properties of EMPA were determined by Schild analysis using the orexin-A- or orexin-B-induced accumulation of [3H]inositol phosphates (IP). Quantitative autoradiography was used to determine the distribution and abundance of OX2 receptors in rat brain. The in vivo activity of EMPA was assessed by reversal of [Ala11,D-Leu15]orexin-B-induced hyperlocomotion during the resting phase in mice and the reduction of spontaneous locomotor activity (LMA) during the active phase in rats. Key results: [3H]EMPA bound to human and rat OX2-HEK293 membranes with KD values of 1.1 and 1.4 nmol·L−1 respectively. EMPA competitively antagonized orexin-A- and orexin-B-evoked accumulation of [3H]IP at hOX2 receptors with pA2 values of 8.6 and 8.8 respectively. Autoradiography of rat brain confirmed the selectivity of [3H]EMPA for OX2 receptors. EMPA significantly reversed [Ala11,D-Leu15]orexin-B-induced hyperlocomotion dose-dependently during the resting phase in mice. EMPA, injected i.p. in rats during the active phase, reduced LMA dose-dependently. EMPA did not impair performance of rats in the rotarod procedure. Conclusions and implications: EMPA is a high-affinity, reversible and selective OX2 receptor antagonist, active in vivo, which should prove useful for analysis of OX2 receptor function.

Biochemical and behavioural characterization of EMPA, a novel high‐affinity, selective antagonist for the OX2 receptor

The OX(2) receptor is a G-protein-coupled receptor that is abundantly found in the tuberomammillary nucleus, an important site for the regulation of the sleep-wake state. Herein, we describe the in vitro and in vivo properties of a selective OX(2) receptor antagonist, N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA). The affinity of [(3)H]EMPA was assessed in membranes from HEK293-hOX(2)-cells using saturation and binding kinetics. The antagonist properties of EMPA were determined by Schild analysis using the orexin-A- or orexin-B-induced accumulation of [(3)H]inositol phosphates (IP). Quantitative autoradiography was used to determine the distribution and abundance of OX(2) receptors in rat brain. The in vivo activity of EMPA was assessed by reversal of [Ala(11),D-Leu(15)]orexin-B-induced hyperlocomotion during the resting phase in mice and the reduction of spontaneous locomotor activity (LMA) during the active phase in rats. [(3)H]EMPA bound to human and rat OX(2)-HEK293 membranes with K(D) values of 1.1 and 1.4 nmol x L(-1) respectively. EMPA competitively antagonized orexin-A- and orexin-B-evoked accumulation of [(3)H]IP at hOX(2) receptors with pA(2) values of 8.6 and 8.8 respectively. Autoradiography of rat brain confirmed the selectivity of [(3)H]EMPA for OX(2) receptors. EMPA significantly reversed [Ala(11),D-Leu(15)]orexin-B-induced hyperlocomotion dose-dependently during the resting phase in mice. EMPA, injected i.p. in rats during the active phase, reduced LMA dose-dependently. EMPA did not impair performance of rats in the rotarod procedure. EMPA is a high-affinity, reversible and selective OX(2) receptor antagonist, active in vivo, which should prove useful for analysis of OX(2) receptor function.

Dopamine receptor agonists reverse behavioral abnormalities of α‐synuclein transgenic mouse, a new model of Parkinson's disease

Parkinson's disease (PD) is characterized by loss of nigral dopaminergic (DAergic) neurons and presence of Lewy bodies, whose major component is alpha-synuclein. We had previously generated transgenic mice termed Syn130m that express truncated human alpha-synuclein (amino acid residues 1-130) in DAergic neurons. Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta. Subsequently, the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly. In the present study, we investigated behavioral responses of Syn130m mice to L-DOPA and DA receptor agonists. Administration of L-DOPA dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice. Similarly, D(2) agonists, quinpirole and talipexole, and a D1/D2 agonist, pergolide, were effective against the reduction. Syn130m mice also showed significant reduction in exploratory behavior compared with non-Tg littermates when they were placed in a novel environment, but this abnormality was ameliorated by treatment with pergolide. These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content. On the other hand, the expression of postsynaptic D(2)-like receptors (DRD2) in the striatum was not increased in Syn130m mice, although the low striatal DA level is known to induce compensatory expression of DRD2. Because the abnormalities could be rectified by treatment with DA receptor agonists, it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease.

Neuroprotective effects of Polygonum multiflorum on nigrostriatal dopaminergic degeneration induced by paraquat and maneb in mice

The neuroprotective effects of Polygonum multiflorum extract (PME) and its two fractions, ethanol-soluble PME (PME-I) and -insoluble PME (PME-II), on the degeneration of nigrostriatal dopaminergic neurons induced by a combination of paraquat and maneb (PQMB) were investigated in male C57BL/6 mice. The mice were treated twice a week for 6 weeks with intraperitoneal injections of PQMB. This combination caused a reduction of spontaneous locomotor activity, motor incoordination, and declines of dopamine level in the striatum and tyrosine hydroxylase-positive neurons in the substantia nigra. Administration of PME and PME-I once daily for 47 days during 6 weeks of PQMB treatment and last 8 days after PQMB significantly attenuated the impairment of behavioral performance and the decrease in striatal dopamine level and substantia nigral tyrosine hydroxylase-positive neurons in the PQMB-treated animals, whereas the administration of PME-II had no effect on these behavioral, neurochemical and histological indices. The present findings suggest that PME has a beneficial influence on parkinsonism induced by PQMB and that the effects of PME are attributable to some substance(s) included in the ethanol-soluble fraction of PME (PME-I).

Ras/ERK signalling in cannabinoid tolerance: from behaviour to cellular aspects

We investigated the role of the Ras/extracellular-regulated kinase (ERK) pathway in the development of tolerance to Delta(9)-tetrahydrocannabinol (THC)-induced reduction in spontaneous locomotor activity by a genetic (Ras-specific guanine nucleotide exchange factor (Ras-GRF1) knock-out mice) and pharmacological approach. Pre-treatment of wild-type mice with SL327 (50 mg/kg i.p.), a specific inhibitor of mitogen-activated protein kinase kinase (MEK), the upstream kinase of ERK, fully prevented the development of tolerance to THC-induced hypolocomotion. We investigated the impact of the inhibition of ERK activation on the biological processes involved in cannabinoid tolerance (receptor down-regulation and desensitization), by autoradiographic cannabinoid CB1 receptor and cannabinoid-stimulated [(35)S]GTPgammaS binding studies in subchronically treated mice (THC, 10 mg/kg s.c., twice a day for 5 days). In the caudate putamen and cerebellum of Ras-GRF1 knock-out mice and SL327 pre-treated wild-type mice, CB1 receptor down-regulation and desensitization did not occur, suggesting that ERK activation might account for CB1 receptor plasticity involved in the development of tolerance to THC hypolocomotor effect. In contrast, the hippocampus and prefrontal cortex showed CB1 receptor adaptations regardless of the genetic or pharmacological inhibition of the ERK pathway, suggesting regional variability in the cellular events underlying the altered CB1 receptor function. These findings suggest that at least in the caudate putamen and cerebellum, the Ras/ERK pathway is essential for triggering the alteration in CB1 receptor function responsible for tolerance to THC-induced hypomotility.

NEW 1,4-DISUSTITUTED-6-HYDROXYPERHYDRO-1,4-DIAZEPINE2,3-DIONE DERIVATIVES

A series of 1,4-disubstituted-6-hydroxyperhydro-1,4-diazepine-2,3-diones were designed and synthesized through the reaction of epichlorohydrin with an excess of the appropriate primary amine. The resulting secondary diamine derivatives were allowed to react with diethyl oxalate to afford the target compounds in good yields. Structures of the target compounds were verified on the basis of spectral and elemental methods of analysis. Twelve new derivatives were subjected to preliminary pharmacological screening regarding their CNS depressant activity such as sedative, hypnotic, anticonvulsant as well as muscle relaxant activities, in addition to evaluation of the hypotensive activity of some representative compounds. Most of the tested compounds gave high percentage reduction in spontaneous locomotor activity (SLA) compared with diazepam. Concerning the rota-rod coordination test, mice cannot remain on the rod more than 20 seconds in comparison with the reference drug used indicating a good muscle relaxant activity of the test compounds. Moreover, these compounds gave 100% protection against pentylenetetrazole-induced convulsions with a rapid onset of action. On the other hand, most of the test compounds gave mild to comparable reduction in blood pressure in comparison to that produced by using propranolol. Moreover, the acute toxicity (LD50) test was carried out for only one representative compound.

Induction of tolerance to the suppressant effect of the neurotensin analogue NT69L on amphetamine-induced hyperactivity

Although several studies have indicated that neurotensin administered acutely has several pharmacological properties common with those of antipsychotic drugs, the effects of repeated exposure to neurotensin receptor agonism have been less well characterised. Here, we investigated the effect of the novel neurotensin-(8–13) analogue NT69L [( N-methyl-Arg), Lys, Pro, l- neo-Trp, tert-Leu, Leu] in animal models sensitive to central neurotensin receptor stimulation as well as in predictive models for antipsychotic activity and motor side-effect liability. Acute injection of NT69L (0.19–6.1 μmol/kg, s.c./i.p.) caused hypothermia (>2.5 °C) and reduction in spontaneous locomotor activity but failed to induce catalepsy. Furthermore, NT69L (0.10 μmol/kg, s.c.) counteracted the hyperlocomotion elicited by amphetamine (0.5 mg/kg, s.c.). However, repeated injections of NT69L (0.19 μmol/kg, s.c. for 6 days, twice daily) significantly reduced its effect on spontaneous locomotor activity and completely abolished its effect on amphetamine-elicited hyperactivity. Our data obtained after single injections of NT69L indicate that this drug stimulates central neurotensin receptors after peripheral administration and collectively support the notion that neurotensin receptor agonism is associated with an attractive pre-clinical profile as regards both antipsychotic activity and motor side-effect liability. However, the present results also indicate that repeated neurotensin receptor stimulation may cause a desensitisation of neurotensin receptor mediated effects.

Dopamine deficiency in mice.

Dopamine is the principal neurotransmitter that mediates a wide range of brain functions, including locomotion, emotion, learning, and neuroendocrine modulation. To clarify the role of dopamine during postnatal development, it is useful to have mutant mice genetically deleting dopamine. In this paper, we describe the mice lacking expression of tyrosine hydroxylase (TH), the first and rate-limiting enzyme of catecholamine biosynthetic pathway, in the dopaminergic neuronal type. In these mice, TH expression in noradrenergic and adrenergic cells was restored. Lack of TH expression in dopaminergic neurons resulted in a marked reduction of dopamine accumulation. This led to multiple behavioral abnormalities at the juvenile stage, which were characterized by a reduction in spontaneous locomotor activity, blockade of methamphetamine-induced hyperactivity, cataleptic behavior, and defect in active avoidance learning. In contrast, development of pituitary gland as well as production and secretion of the pituitary peptide hormones dependent on hypothalamic dopaminergic control were normally maintained in spite of the reduced dopamine synthesis. Our findings provide genetic evidence that dopamine is essential for controlling spontaneous and voluntary movement and emotional learning during postnatal development through the nigrostriatal and mesocorticolimbic pathways.

Motor and learning dysfunction during postnatal development in mice defective in dopamine neuronal transmission.

Mice lacking expression of tyrosine hydroxylase (TH), the first and rate-limiting enzyme of the catecholamine biosynthetic pathway, in dopaminergic neuronal cell types were generated by a transgenic rescue approach to clarify the role of dopamine signaling during postnatal development. Introduction of the TH transgene directed by the dopamine beta-hydroxylase gene promoter into TH knockout mice restored noradrenaline and adrenaline synthesis, preventing perinatal lethality and cardiac dysfunction in the knockout mice. Lack of TH expression in the cells that normally express the dopaminergic phenotype resulted in a marked reduction of dopamine accumulation in the tissues, which led to multiple behavioral abnormalities at the juvenile stage. These abnormalities were characterized by a reduction in spontaneous locomotor activity, blockade of methamphetamine-induced hyperactivity, cataleptic behavior, and defects in active avoidance learning. In contrast, development of the pituitary gland as well as production and secretion of the pituitary peptide hormones dependent on hypothalamic dopaminergic control were normally maintained, despite defective dopamine synthesis. These results demonstrate that dopamine neurotransmission is essential for controlling spontaneous and voluntary movement and associative learning during postnatal development through the nigrostriatal and mesocorticolimbic pathways.

Diurnal and gender effects by chronic portacaval shunting in rats on spontaneous locomotor and rearing activities in an open-field

Behavioural disturbances in chronic experimental hepatic encephalopathy (HE) have been investigated for several decades, but only in recent years, the possibility for gender-dependent reduction of spontaneous locomotor activity has come under attention. Unfortunately though, the results of such gender dependency have been discrepant. We therefore performed an open-field behaviour study in unhabituated female and male portacaval shunted (PCS) rats during both day- and night-time, monitoring locomotor as well as rearing activity for a 60 min period. The results revealed lower locomotor and rearing activities in both male and female PCS rats during night-time, compared to sham-operated controls. Daytime differences could only be detected in the rearing activity of female PCS versus control rats. Female PCS rats also spent less cumulated time rearing, compared to controls but no differences regarding the overall locomotor/rearing activity ratio or portion of the behaviours exerted in the central area of the open-field could be detected between PCS and controls, or between the sexes. Diurnal activity differences were found between control groups of both sexes but not between the female versus male PCS rats. Thus, our results are not supportive of any major gender-dependent behavioural disturbance between PCS and control rats.