Spontaneous Locomotor Activity In Mice Research Articles

Synthesis and calming activity of helicid derivatives containing the 3,4-dihydropyrimidin-2(H)-one and 3,4-dihydropyrimidine-2(H)-thione moiety

A series of novel helicid derivatives containing 3,4-dihydropyrimidin-2(1H)-one and 3,4-dihydropyrimidine2(1H)-thione moiety (3a–3f and 4a–4f) were synthesized starting from helicid. The structure of the new compounds were characterized by 1H NMR, IR and HR-MS spectra. The sedative-hypnotic activities of the target compounds were evaluated using the test of spontaneous locomotor activity in mice. All of the derivatives produced moderate to high activities; in particular, compound 4a presented the most potent sedative-hypnotic effect in comparison to the other derivatives, and derivatives 3a, 3c, 3d, 3e and 3f also showed potent activities.

Effects of acute and chronic administration of atomoxetine and methylphenidate on extracellular levels of noradrenaline, dopamine and serotonin in the prefrontal cortex and striatum of mice

Acute administration of atomoxetine and methylphenidate, attention-deficit/hyperactivity disorder (ADHD) drugs, activates catecholaminergic systems in rat brain, but the effects of their chronic administration are not known. This study examined the effects of acute and chronic administration of ADHD drugs on the extracellular levels of noradrenaline (NA), dopamine (DA) and serotonin (5-HT), and the expression of the neuronal activity marker c-Fos in the prefrontal cortex and striatum of mice. Acute ADHD drugs increased NA and DA, but not 5-HT, levels in the prefrontal cortex of mice. Maximal effects of atomoxetine and methylphenidate were observed at 1 mg/kg and 3 mg/kg, respectively. At these doses, both drugs did not affect the spontaneous locomotor activity of mice. Chronic administration of atomoxetine 1 mg/kg and methylphenidate 3 mg/kg for 21 days also increased NA and DA, but not 5-HT, levels in the prefrontal cortex. The increases in NA levels induced by atomoxetine, but not methylphenidate, were reduced by chronic treatment. In contrast, acute and chronic administration of atomoxetine 1 mg/kg and methylphenidate 3 mg/kg did not affect the monoamine levels in the striatum. Acute and chronic atomoxetine 1 mg/kg and methylphenidate 3 mg/kg increased the expression of c-Fos in the prefrontal cortex, but not in the striatum, to a similar extent. These results suggest that acute and chronic administration of the ADHD drugs selectively activate the prefrontal catecholamine systems in mice.

ChemInform Abstract: Synthesis and Analgesic Effects of 5-[4-(Arylpiperazin-1-yl)alkylamino] -4-benzyl-3-methyl-1,2-oxazin-6-ones.

A series of 5-[4-(arylpiperazin-1-yl)alkylamino]-4-benzyl-3-methy1-1,2-oxazin-6-ones was synthesized and evaluated for analgesic activity. The structures of these new oxazine derivatives were confirmed by IR, 1 H-NMR spectra and by elemental analysis. The three most active compounds, 3c, 3e and 3g possessed significant antinociceptive effects in the phenylbenzoquin-one-induced wrigthing test (PBQ-test) in mice, with ED 50 values ranging from 19.7 to 68.0 mg/kg i.p. In addition these compounds presented a low toxicity (LD 50 > 800 mg/kg i.p.) and did not significantly reduce the spontaneous locomotor activity of mice. They interacted in a synergistic manner with morphine but nevertheless each compound presented its own profile. Thus the analgesic activity of 3c and 3e was naloxone sensitive, suggesting in µ, opioidergic mechanism. Otherwise 3c and 3d analgesia was attenuated by oral administration of yohimbine and therefore seemed to be mediated via noradrenergic pathway. Finally, 5-hydroxytryptophan associated to carbidopa only potentiated 3e analgesia, demonstrating an involvement of a serotoninergic mechanism.

In utero exposure to a low concentration of diesel exhaust affects spontaneous locomotor activity and monoaminergic system in male mice.

BackgroundEpidemiological studies have suggested that suspended particulate matter (SPM) causes detrimental health effects such as respiratory and cardiovascular diseases, and that diesel exhaust particles from automobiles is a major contributor to SPM. It has been reported that neonatal and adult exposure to diesel exhaust damages the central nervous system (CNS) and induces behavioral alteration. Recently, we have focused on the effects of prenatal exposure to diesel exhaust on the CNS. In this study, we examined the effects of prenatal exposure to low concentration of diesel exhaust on behaviour and the monoaminergic neuron system. Spontaneous locomotor activity (SLA) and monoamine levels in the CNS were assessed.MethodsMice were exposed prenatally to a low concentration of diesel exhaust (171 μg DEP/m3) for 8 hours/day on gestational days 2-16. SLA was assessed for 3 days in 4-week-old mice by analysis of the release of temperature-associated infrared rays. At 5 weeks of age, the mice were sacrificed and the brains were used for analysis by high-performance liquid chromatography (HPLC).Results and DiscussionMice exposed to a low concentration of diesel exhaust showed decreased SLA in the first 60 minutes of exposure. Over the entire test period, the mice exposed prenatally to diesel exhaust showed decreased daily SLA compared to that in control mice, and the SLA in each 3 hour period was decreased when the lights were turned on. Neurotransmitter levels, including dopamine and noradrenaline, were increased in the prefrontal cortex (PFC) in the exposure group compared to the control group. The metabolites of dopamine and noradrenaline also increased in the PFC. Neurotransmitter turnover, an index of neuronal activity, of dopamine and noradrenaline was decreased in various regions of the CNS, including the striatum, in the exposure group. The serum corticosterone level was not different between groups. The data suggest that decreased SLA in mice exposed prenatally to diesel exhaust is due to facilitated release of dopamine in the PFC.ConclusionsThese results indicate that exposure of mice in utero to a low concentration of diesel exhaust decreases SLA and alters the neurochemical monoamine metabolism of several regions of the brain.

The effects of pancreatic polypeptide on locomotor activity and food intake in mice

Pancreatic polypeptide (PP) has been shown to inhibit food intake in both rodents and humans. Acute peripheral administration of PP increases oxygen consumption in obese mice. To further investigate the function of PP in the modulation of energy balance, we examined its effects on spontaneous locomotor activity and food intake in mice by using a 24-chamber Comprehensive Laboratory Animal Monitoring System. Effects of intraperitoneal (i.p.) administration of PP on spontaneous locomotor activity were measured using the optical beam technique. Administration of PP dose dependently inhibited cumulative food intake. The inhibition remained significant for up to 6, 17 and 36 h at doses of 30, 100 and 300 nmol kg(-1) PP, respectively. At 10 nmol kg(-1), PP increased locomotor activity (cumulative beam breaks) significantly for 4 h following administration without affecting food intake and at 30 nmol kg(-1), PP increased locomotor activity by 79% compared with the controls for 5 h post injection. However, at 100 and 300 nmol kg(-1), PP had no significant effect on locomotor activity. This study shows for the first time that PP increases spontaneous locomotor activity in mice.

Vasopressin Increases Locomotion through a V1a Receptor in Orexin/Hypocretin Neurons: Implications for Water Homeostasis

Water homeostasis is a critical challenge to survival for land mammals. Mice display increased locomotor activity when dehydrated, a behavior that improves the likelihood of locating new sources of water and simultaneously places additional demands on compromised hydration levels. The neurophysiology underlying this well known behavior has not been previously elucidated. We report that the anti-diuretic hormone arginine-vasopressin (AVP) is involved in this response. AVP and oxytocin directly induced depolarization and an inward current in orexin/hypocretin neurons. AVP-induced activation of orexin neurons was inhibited by a V1a receptor (V1aR)-selective antagonist and was not observed in V1aR knock-out mice, suggesting an involvement of V1aR. Subsequently activation of phospholipase Cbeta triggers an increase in intracellular calcium by both calcium influx through nonselective cation channels and calcium release from calcium stores in orexin neurons. Intracerebroventricular injection of AVP or water deprivation increased locomotor activity in wild-type mice, but not in transgenic mice lacking orexin neurons. V1aR knock-out mice were less active than wild-type mice. These results suggest that the activation of orexin neurons by AVP or oxytocin has an important role in the regulation of spontaneous locomotor activity in mice. This system appears to play a key role in water deprivation-induced hyperlocomotor activity, a response to dehydration that increases the chance of locating water in nature.

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.

Neuroleptic Properties of the Ion‐Channel‐Forming Peptaibol Zervamicin: Locomotor Activity and Behavioral Effects

Zervamicins IIA and IIB are members of the peptaibol family of peptide antibiotics. They are produced by the fungus Emericellopsis salmosynnemata. Peptaibols are known to be of potential usefulness for chemotherapeutic applications, as are other secondary fungal metabolites. Previously, we have found zervamicins to decrease spontaneous locomotor activity in mice, suggesting their neurotropic properties on an equal footing with antimicrobial activity. The current study deals with behavioral effects of zervamicins IIA and IIB in mice. According to our results, both zervamicins induce a reliable decrease in locomotion and exploratory activity measured in the hole-board test. The behavioral effects of zervamicin IIA become apparent at lower dosages (0.05-2.0 mg/kg) as compared with zervamicin IIB (0.5-12.0 mg/kg). The experiments on behavioral effects in the elevated plus maze test showed that both zervamicins caused a reliable decrease in the number of head-dippings, open-arm entries, and rearings. The observed behavioral effects may be rather associated with a decrease in the exploratory activity than with anxiety-related responses in mice. Zervamicins induced depression-like behavior of experimental animals in the forced-swim test. Both peptaibols reduce physical endurance and change motor coordination of experimental animals in the bar-holding test. Taken together, the data obtained clearly indicate that both zervamicins possess neuroleptic activity.

2-Amino/Azido/Hydrazino-5-alkoxy-5H-[1]benzopyrano[4,3-d]pyrimidines:Synthesis and Pharmacological Evaluation

New series of 5-alkoxy-benzopyranopyrimidine derivatives were developed from the chemical modulation of the substituent in position 2 of the scaffold, with the aim to produce analgesic/antiphlogistic agents more potent than analogues previously reported. The 2-hydrazino derivatives exhibited a good analgesic activity in writhing test; the analgesic doses of the compounds did not affect mice spontaneous locomotor activity thus any confounding sedative effect could be excluded. These derivatives revealed an aspirin-like profile with a strong inhibition of AA-induced platelet aggregation, probably due to a strong, non selective, inhibition of cyclooxygenases. In spite of the inhibition of COX activity displayed in vitro, the compounds did not cause gastric damage in rats after acute oral administration. A different pharmacological profile was observed for the 2-azido derivatives, particularly in vivo.

Involvement of dopamine D 1 receptors and α 1-adrenoceptors in the antidepressant-like effect of chlorpheniramine in the mouse tail suspension test

It has been reported that chlorpheniramine, a classical antihistamine, has antidepressant-like effects in animal models of depression. In this study, we examined the involvement of dopaminergic (dopamine D 1 and dopamine D 2 receptors), noradrenergic (α 1- and β-adrenoceptors) and serotonergic (5-HT 1A and 5-HT 2 receptors) receptors in the antidepressant-like effect of chlorpheniramine in the mouse tail suspension test. We also investigated the involvement of these monoamine receptors in the antidepressant-like effect of imipramine for comparison with the mechanisms of the effect of chlorpheniramine. Both imipramine and chlorpheniramine significantly reduced the duration of immobility in the tail suspension test without affecting spontaneous locomotor activity in mice. The anti-immobility effect of imipramine (30 mg/kg, i.p.) was significantly antagonized by the selective dopamine D 1 receptor antagonist SCH23390 but not by the other receptor antagonists. In contrast, the anti-immobility effect of chlorpheniramine was significantly inhibited by SCH23390 and the selective α 1-adrenoceptor antagonist prazosin, but not by the other receptor antagonists. In conclusion, these results suggest that chlorpheniramine exerts an antidepressant-like effect in the mouse tail suspension test that is mediated by at least the activation of dopamine D 1 receptors and α 1-adrenoceptors. In addition, the antidepressant-like effect of chlorpheniramine may be induced by several mechanisms that are different from those involved in the antidepressant-like effect of imipramine.

Effects of Chlorogenic Acid and Its Metabolites on Spontaneous Locomotor Activity in Mice

Chlorogenic acid possessed a weak caffeine-like psychostimulant property when assessed for its effect on spontaneous locomotor activity in mice. In the evaluation of the effects for the major metabolites of chlorogenic acid which were detected upon incubation with rat feces and/or excreted in urine after oral administration to rats, caffeic and m-coumaric acids were found to be the principal active metabolites, while the others contributed little to this caffeine-like psychostimulant activity.

Enhancement of the anti-immobility action of antidepressants by a selective 5-HT 7 receptor antagonist in the forced swimming test in mice

Using the forced swimming test in mice, we examined the effect of the following antidepressants: citalopram, imipramine, desipramine and moclobemide (which are characterized by different mechanisms of action), administered in combination with the selective 5-HT 7 receptor antagonist (2 R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]-pyrrolidine (SB 269970). All those drugs were given in doses which did not shorten the immobility time of mice. Citalopram (1.25 mg/kg), imipramine (10 mg/kg), desipramine (5 mg/kg) or moclobemide (10 mg/kg) administered jointly with SB 269970 (5 mg/kg), produced a significant antidepressant-like effect. None of the compounds studied, given alone or in combination, increased the spontaneous locomotor activity of mice. The obtained results indicate that blockade of 5-HT 7 receptors may facilitate the anti-immobility effect of antidepressants in mice.

Effect of the selective 5-HT 7 receptor antagonist SB 269970 in animal models of anxiety and depression

The aim of the present study was to examine the effect of the selective 5-HT 7 receptor antagonist SB 269970 (0.25–20 mg/kg) in the behavioral tests commonly used for predicting anxiolytic- and antidepressant-like activity. Diazepam and imipramine were used as standard drugs. SB 269970 (in one medium dose of 0.5 or 1 mg/kg) exerted a specific antianxiety-like effect in the Vogel drinking test in rats, in the elevated plus-maze test in rats and in the four-plate test in mice. Moreover, SB 269970 (in one medium dose of 5 or 10 mg/kg) showed antidepressant-like activity in the forced swimming and the tail suspension tests in mice. At the same time, the tested compound at doses of 1–20 mg/kg did not change the spontaneous locomotor activity of mice. The potential anxiolytic and antidepressant effects produced by SB 269970 were weaker than those of the reference drugs employed. It is noteworthy that the active doses of SB 269970 were devoid of any visible motor side-effects. In conclusion, the results of our studies indicate that 5-HT 7 receptor antagonists may play a role in the therapy of both anxiety and depression.

Effects of anti-inflammatory [1, 2, 4]triazolo[4, 3-a] [1, 8]naphthyridine derivatives on human stimulated PMN and endothelial cells: an in vitro study

Background[1,2,4] triazolo [4, 3-a][1,8]naphthyridine derivatives (including NF161 and NF177) were tested for anti-inflammatory, analgesic and antipyretic properties and for their effects on spontaneous locomotor activity in mice and acute gastrolesivity in rats. Both NF161 and NF177 appeared to be anti-inflammatory and analgesic agents without toxic effects or acute gastrolesivity, but NF161 showed stronger anti-inflammatory activity, whereas NF177 was more active as analgesic.MethodsAn EIA kit was used to investigate the ability of NF161 and NF177 to affect prostaglandin E2 (PGE2) and prostacyclin (PGI2) production by human umbilical vascular endothelial cells (HUVEC).The compounds' effects on the production of reactive oxygen species (ROS) by human polymorphonuclear cells (PMNs) were studied in an in vitro cell model, evaluating inhibition of superoxide anion (O2-.) production induced by N-formylmethionyl-leucyl-phenylalanine (FMLP). Their effects on PMN adhesion to HUVEC were also investigated; they were incubated with PMNs and endothelial cells (EC) and challenged by stimuli including Platelet Activating Factor (PAF), FMLP, Phorbol Myristate Acetate (PMA), Tumor Necrosis Factor-α (TNF-α) and Interleukin-1β (IL-1β). Adhesion was quantitated by computerized micro-imaging fluorescence analysis.ResultsNeither compounds modified PGE2 or PGI2 production induced by IL-1α.O2-. production and myeloperoxidase release from PMNs stimulated by FMLP was inhibited in a dose- but not time-dependent manner by both [1,8]naphthyridine derivatives, NF161 being statistically more active than NF177 (P < 0.01).The compounds inhibited adhesion evoked by the pro-inflammatory stimuli PAF, FMLP, TNF-α and IL-1β in a concentration-dependent manner in the 10-6–10-4M range, being more active when PAF was used as stimulus and inactive when cells were challenged by PMA. Both compounds acted both on PMN and HUVEC.ConclusionConsidering the interesting anti-inflammatory effects of these compounds in in vivo models and the absence of acute gastrolesivity, the study improved knowledge of anti-inflammatory properties of NF161 and NF177, also demonstrating their potential in vitro, through inhibition of O2-. production, myeloperoxidase release and PMN adhesion to HUVEC. Negative results on PG production suggest a cyclooxygenase (COX)-independent mechanism.

Effects of Perinatal Stress on the Emotion-Related Behavior of the Adolescent Mouse

We examined the effects of perinatal stress on the emotion-related behavior of the mouse during their adolescent period. Firstly, we applied the sound noise and/or the forced swim stress to the maternal pregnant mice in the pregnant mice at 10 to 18 d gestation. The stress applied during the fetal period did affect neither the spontaneous locomotor activity of the offspring mice in a new environment at an age of 4 weeks, nor those sound-induced changes in the locomotor activity. Secondly, we applied the stress to the neonatal mouse during the late lactation period, 14 to 18 d after birth. The mice that underwent the forced swim stress accompanied by the sound noise stress showed a significant reduction of the locomotor activity. On the other hand, the mice that underwent the forced swim stress during the lactation period showed a significant increase in the locomotor activity after the stimulation by the sound noise. Lastly, we applied the stress to the neonatal mouse immediately after the weaning period, 21 to 25 d after birth. The spontaneous locomotor activity of the mice was not changed compared to that of the non-stressed group. Thus, it was found that the stress applied to the mice during the lactation period, thought to be the critical period of mouse brain development, selectively influenced the emotion-related behavior in the subsequent adolescent period. These results suggested that second postnatal week may be the critical period for establishing proper behavioral responses to emotional stress in the adolescent mouse.

Effects of new nitric oxide synthase inhibitors on spontaneous locomotor activity

New nitric oxide synthase (NOS) inhibitors: 3-bromo-7-nitroindazole (3-Br-7-NI), 1-(2-trifluoromethylphenyl) imidazole (TRIM), S-methyl-L-thiocitrulline (S-Me-TC) and 7-nitroindazole (7-NI) reduce spontaneous locomotor activity in mice. In order to elucidate central effects of NOS inhibitors on locomotor activity, the influence of 7-NI on electroencephalographic (EEG) power spectrum in rats was investigated. 7-NI reduced the EEG power density in all frequency bands in rats, suggesting a depression of the central neuronal activity. The electrophysiologic power was most reduced in the range of 7-9 Hz of the rhythmic slow activity (theta rhythm), which is in accordance with decreased locomotor activity observed following administration of NOS inhibitors. The present results indicate that nitric oxide exerts an excitatory effect on central neuronal structures involved in regulation of locomotion.

Naloxone's suppression of spontaneous and food-conditioned locomotor activity is diminished in mice lacking either the dopamine D 2 receptor or enkephalin

Mice lacking the D 2 dopamine receptor (D 2 −/−) and congenic to the C57BL/6J background were tested for opioid-mediated locomotor activity to examine the involvement of the D 2 dopamine receptor in opioid pharmacology. Morphine-stimulated locomotor activity did not significantly differ between the two genotypes. The opioid antagonist naloxone dose-dependently decreased spontaneous motor activity in wild-type mice but was without significant effect in D 2 −/− mice. The magnitude of food-conditioned increases in locomotor activity in wild-type mice and D 2 −/− mice was similar but naloxone did not decrease conditioned motor activity in D 2 −/− mice. Spontaneous locomotor activity of mice lacking the endogenous opioids β-endorphin and/or enkephalin was also tested and we found that naloxone did not reduce activity in mice specifically lacking enkephalin. We suggest that the D 2 dopamine receptor is necessary for modulation of spontaneous locomotor activity stimulated by the endogenous opioid enkephalin.

Investigations on the synthesis and pharmacological properties of N-substituted derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones

Synthesis of N-substituted derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones ( 10– 14, 18– 21) is described. In the “writhing syndrome” test all compounds studied exhibited potent analgesic activity which was superior than that of acetylsalicylic acid. In the “hot plate” test imides 10, 12, 13, 18– 20 acted also stronger than aspirin. Furthermore all compounds tested significantly suppressed the spontaneous locomotor activity of mice and prolonged barbiturate sleep of these animals.

Antinociceptive and gastroprotective effects of inhaled and orally administered Lavandula hybrida Reverchon “Grosso” essential oil

In this study the antinociceptive and the gastroprotective effects of orally administered or inhaled Lavandula hybrida Reverchon “ Grosso” essential oil, and its principal constituents linalool and linalyl acetate were evaluated in rodents. Either when orally administered (100 mg/kg) or inhaled for 60 min lavender essential oil significantly reduced the acetic acid-writhing response in a naloxone-sensitive manner. In the hot plate test, analgesic activity observed after oil inhalation was inhibited by naloxone, atropine, mecamylamine pretreatment suggesting the involvement of opioidergic as well as cholinergic pathways. Regardless of the administration route and the experimental model used both linalool and linalyl acetate did not produce significant analgesic response. Oral or inhalatory treatment with analgesic doses of essential oil did not affect mice spontaneous locomotor activity. Concerning the gastric effects, lavender oil, linalool and linalyl acetate oral administration protected against acute ethanol-induced gastric ulcers but did not prevent indomethacin-induced lesions indicating no interference with arachidonic acid metabolic cascade. In conclusion, besides this gastroprotection, lavender oil reveals an interesting analgesic activity mainly relevant after inhalation, at doses devoid of sedative side effect, suggesting the interest for potential application of this oil in aromatherapy.

Blockade of neurotensin receptors affects differently hypo-locomotion and catalepsy induced by haloperidol in mice

Antipsychotic drug treatment increases neurotensin (NT) neurotransmission, and the exogenous administration of NT produces antipsychotic-like effects in rodents. In order to investigate whether “endogenous” NT may act as a natural occurring antipsychotic or may mediate antipsychotic drug activity, the effects of the selective NT receptor antagonists SR 48692 and SR 142948A were analyzed in different behavioural tests of locomotor activity using vehicle, amphetamine, or haloperidol in mice. SR 48692 (0.1–1 mg/kg, i.p.) and SR 142948A (0.03–0.1 mg/kg, i.p.) failed to affect mouse spontaneous locomotor activity and amphetamine-induced (2.5 mg/kg, i.p.) hyper-locomotion. However, SR 48692 (0.1 and 0.3 mg/kg, i.p.) and SR 142948A (0.03 and 0.05 mg/kg, i.p.) significantly alleviated the reduction of locomotor activity elicited by haloperidol (0.01 and 0.04 mg/kg, s.c.) in vehicle- or amphetamine-treated mice. Finally, SR 48692 (0.3 mg/kg, i.p.) and SR 142948A (0.05 and 0.1 mg/kg, i.p.) increased mouse catalepsy produced by haloperidol (0.3 mg/kg, s.c.). The present results indicate that while endogenous NT is not involved in the modulation of either mouse spontaneous locomotor activity or amphetamine-induced hyper-locomotion, it might act by enhancing the therapeutic effects of haloperidol and by attenuating the extrapyramidal side effects elicited by this antipsychotic.