Spontaneous Locomotor Activity In Mice Research Articles

Effects of diabetes on spontaneous locomotor activity in mice

Spontaneous locomotor activity in diabetic mice was significantly greater than that in non-diabetic mice. Haloperidol and SCH23390, a selective dopamine D 1-receptor antagonist, significantly reduced spontaneous locomotor activity in diabetic mice, but not in non-diabetic mice. Spontaneous locomotor activity in diabetic mice was also reduced by pretreatment with naltrindole, a selective δ-opioid receptor antagonist, and 7-benzylidenenaltrexone, a selective δ 1-opioid receptor antagonist. The rate of dopamine turnover in the limbic forebrain in diabetic mice was significantly higher than that in non-diabetic mice. These findings suggest that the enhanced spontaneous locomotor activity in diabetic mice may result from increased dopamine neurotransmission, which might be due to an increase in dopamine release in mesolimbic dopamine systems. The increased dopamine neurotransmission in diabetic mice may also be due to the up-regulation of δ-opioid receptor-mediated functions.

Organic Hydroperoxide-Induced Activation of Liver Microsomal Glutathione S-Transferase of Rats In Vitro

Neurochemical and behavioral investigations were made to assess the role of central dopaminergic systems in mouse locomotor activity and analgesia by spiradoline mesylate. Analgesic activities of the kappa-opioid-receptor agonists spiradoline and U-50488H were not altered by haloperidol or L-dopa, whereas morphine analgesia was enhanced by haloperidol but attenuated by L-dopa. Spiradoline decreased spontaneous locomotor activity in mice and inhibited methamphetamine- or morphine-induced locomotor activity. In contrast, morphine given alone increased locomotor activity and enhanced methamphetamine-induced locomotor activity. In a neurochemical study, spiradoline decreased the amounts of dopamine metabolites in the striatum, but did not alter them in the brainstem and cerebral cortex. Morphine increased the dopamine metabolite contents in all three brain regions tested. These results suggest that inhibition of the dopaminergic pathway in the brain by spiradoline may be involved in its suppression of locomotor activity, but not in its analgesia; whereas, stimulation of the dopaminergic pathway by morphine seems to function in both behaviors: enhancement of locomotor activity and inhibition of analgesia.

Pharmacological properties of a lyophilizate from Galeopsis ladanum on the central nervous system of rodents

AbstractThe influence of a fraction obtained from Galeopsis ladanum L. on the central nervous system of rodents was examined. The results of these investigations show that the fraction impeded CNS activity. It is practically nontoxic and at a dose of 2000 mg/kg i.p. it does not have a soporific influence on mice. It reduces considerably the spontaneous locomotor activity of mice as well as the locomotor activity of mice stimulated by caffeine, but did not influence the locomotor activity induced by amphetamine. The extract did not exhibit a synergetic effect with barbiturates. The results suggest that the pharmacological activity of the extract resembled the activity of drugs which generally depress the CNS, being on the border between ataractic and sedative drugs.

New Hybrids of Quipazine and Trazodone as Selective Inhibitors of Uptake of 5-Hydroxytryptamine

Two new congeners, 4-(chloropropyl)-1-(2-quinolyl)piperazine- and 2-[3-[4-[2-(quinolyl)]-1-piperazinyl]propyl]-1,2,4-triazolo]4,3-a]pyridin-3(2H)-one, of trazodone were synthesized and found to be potent and selective inhibitors of synpatosomal uptake of 5-hydroxy-tryptamine [5-HT, serotonin; IC50 = norepinephrine > 5 μM, 5-HT = 210-890 nM], with minimal effects in antagonizing (−)-apomorphine-induced climbing behavior and suppression of spontaneous locomotor activity in mice (ED50 > 50 mg/kg). The two compounds behaved like atypical antidepressants, since they weakly antagonized reserpine-induced hypothermia. The acute toxicity studies have shown that these compounds were less lethal when compared with imipramine or quipazine. Furthermore, chronic treatments (20 mg/kg, daily for 10 and 21 days) significantly decreased the isoprenaline-induced increase in cyclic AMP in the rat brain cortex, suggesting desensitization of 0-adrenocep-tors. These findings point to the effects of these compounds as potential antidepressants dealing with specific serotonergic mechanisms.

Synthesis, brain uptake, and pharmacological properties of a glyceryl lipid containing GABA and the GABA-T inhibitor .gamma.-vinyl-GABA

1-O-Linolenoyl-2-O-(4-aminobutyryl)-3-O-(4-vinyl-4-aminobutyryl)glycerol (LGV) was synthesized as an example of a prodrug which readily penetrates the blood-brain barrier (brain penetration index 97% +/- 15%) and releases two active substances in the central nervous system (CNS): GABA (4-aminobutanoic acid) and the GABA transaminase inhibitor (GABA-T) of GABA breakdown. In vitro studies showed that the compound can inhibit GABA-T after hydrolysis by CNS esterases and that it enhanced GABAergic inhibition when applied to rat hippocampus slices. In vivo studies indicate that LGV depresses the spontaneous locomotor activity of mice. Its activity on a molar basis was some 300 times greater than that of gamma-vinyl-GABA.

Leu-enkephalin, tamoxifen and ethanol interactions: Effects on motility and hepatic ethanol metabolizing enzymes

1. 1. Short-term treatment with tamoxifen (a nonsteroidal antiestrogen) decreased mouse spontaneous locomotor activity compared to controls. 2. 2. Short-term pretreatment with tamoxifen prior to an acute sedative dose of ethanol potentiated ethanol-medicated behavioral depression in the mouse. 3. 3. Injection of a small dose of Leu-enkephalin, which is devoid of effect on mouse motility, prior to an acute sedative dose of ethanol to tamoxifen pretreated female mice counteracted ethanol-produced suppression of motor activity. 4. 4. Mouse liver aldehyde dehydrogenase was inhibited by the short-term administration of tamoxifen when given alone or preceding acute dosages of Leu-enkephalin. Concomitantly, there was an increase in blood plasma ethanol concentration from corresponding control. 5. 5. The results of the behavioral performance test used suggest that tamoxifen possesses depressant property and exerts synergestic effect with Leu-enkephalin in antagonizing ethanol-produced behavioral depression in the mouse. 6. 6. The enzymatic part of the study indicates an adverse metabolic influence by tamoxifen on hepatic metabolism of ethanol-derived acetaldehyde which could contribute to the potentiation of the sedative effect of ethanol.

Comparison of the behavioral effects of adenosine agonists and dopamine antagonists in mice

The adenosine agonists 5'-N-ethylcarboxamideadenosine (NECA), 2-chloroadenosine (2-CLA), N6-cyclohexyladenosine (CHA), N6-cyclopentyladenosine (CPA), 2-(phenylamino)adenosine (CV-1808) and R and S isomers of N6-phenylisopropyladenosine (R-PIA and S-PIA) decreased spontaneous locomotor activity in mice and, except for CPA, did so at doses that did not impair motor coordination, a profile shared by dopamine antagonists. CV-1808, the only agent with higher affinity for A2 as compared with A1 adenosine receptors, displayed the largest separation between locomotor inhibitory and ataxic potency. Like dopamine antagonists, NECA and CV-1808 also decreased hyperactivity caused by d--amphetamine at doses that did not cause ataxia whereas A1-selective adenosine agonists reduced amphetamine's effects only at ataxic doses. Unlike dopamine antagonists, adenosine agonists inhibited apomorphine-induced cage climbing only at doses that caused ataxia. Involvement of central adenosine receptors in these effects was suggested by the significant correlation obtained between potency for locomotor inhibition after IP and ICV administration. Affinity for A1 but not A2 adenosine receptors was significantly correlated with potency for inducing ataxia. These results suggest that the behavioral profile of adenosine agonists in mice is related to their affinity for A1 and A2 adenosine receptors and indicate that adenosine agonists produce certain behavioral effects that are similar to those seen with dopamine antagonists.

Effects of 5-HT and alpha 1 adrenoceptor antagonists on kappa opioid-induced sedation

The kappa opioid agonists PD-117302 and U-50488 were found to produce dose-dependent reductions in spontaneous locomotor activity in mice. The magnitude of the response to a given dose of each kappa agonist was found to be clearly potentiated by pretreating the animals with either ketanserin (1 mg/kg) or prazosin (0.5 mg/kg). Pretreatment with the selective 5-HT 2 receptor antagonist ritanserin given at a high dose (1 mg/kg), the nonselective 5-HT antagonist methysergide or the 5-HT synthesis inhibitor parachlorophenylalaline did not alter the magnitude of the response to the kappa agonist. These results suggest that 5-HT systems are not involved in the sedative effects of kappa opioid agonists and that the potentiating effect seen in animals pretreated with ketanserin is due to the alpha 1 blocking properties of this compound since the effect was mimicked by the alpha 1 antagonist prazosin.

Partial da-agonists as potential anti-schizophrenic agents : D.M. Coward, A. Enz∗ and S. Urwyler Sandoz Research Institute Berne ltd., P.O. Box 2173, CH-3001 Berne, and ∗Preclinical Research, Sandoz Ltd., CH-4002, Basle; Switzerland

The pharmacological profile of 2 proposed selective dopamine (DA) autoreceptor agonists 3-PPP and 3-phenethyl-PP was compared with that of apomorphine in test systems for detection of dopaminergic and antidopaminergic activity. In vitro 3-PPP and 3-phenethyl-PP showed preferential affinity for D-2 DA receptors and only very low affinity for D-1 DA receptors. Accordingly, and in contrast to apomorphine, no stimulation of DA-sensitive adenylate cyclase was observed. A weak to moderate inhibitory activity of all 3 compounds was shown in uptake systems for DA, NA and 5-HT. A weak or no effect on α1-or α2-adrenergic receptors was observed. 3-PPP, 3-phenethyl-PP and apomorphine inhibited spontaneous locomotor activity in mice and rats, induced contralateral circling behaviour in 6-hydroxy-DA-lesioned rats and induced emesis in dogs. The DA involvement in these effects was confirmed by antagonistic effects of neuroleptics in all three test systems. Apomorphine was the only compound inducing stereotyped behaviour in normal rats and neuroleptically induced supersensitive mice and inducing ipsilateral circling behaviour in hemitransected rats. 3-PPP did not show activity in several tests for neuroleptic effects in vivo, including inhibition of apomorphine- and methylphenidate-induced stereotyped gnawing, cataleptogenic effect, inhibition of conditioned avoidance response and inhibition of 6,7-ADTN-induced hyperactivity after injection into the nucleus accumbens. In contrast 3-PPP and 3-phenethyl-PP antagonized d-amphetamine-induced stereotyped licking/gnawing and hyperactivity. 3-PPP did not influence the cateleptogenic or methylphenidate antagonistic effect of cis-(Z)-flupentixol or haloperidol. 3-PPP increased the methylphenidate antagonistic effect of spiroperidol and the apomorphine antagonistic effect of cis-(Z)-flupentixol, cis-(Z)-clopenthixol and spiroperidol. It is concluded that 3-PPP and its more potent derivative 3-phenethyl-PP show high selectivity for DA receptors mediating sedation in rodents but that these compounds activate DA receptors mediating emesis and activate denervation supersensitive DA receptors, while not affecting neuroleptic supersensitive DA receptors. The neuroleptic-like activity of 3-PPP and 3-phenethyl-PP is only shown as a d-amphetamine antagonistic effect, indicating a presynaptic site of action. The increase of some neuroleptic effects may have clinical relevance for treatment of diseases associated with DA hyperactivity.

5-Hydroxytryptamine involvement in the locomotor activity suppressant effects of amphetamine in the mouse.

d-Amphetamine, in doses lower than required to increase motor activity, reduced mouse spontaneous locomotor activity when this was assessed using cages equipped with photocell units, using treadwheels, or the measurement of spontaneous climbing behaviour. Acute treatments with the serotonergic agonists quipazine and 5-hydroxy-DL-tryptophan also reduced wheel running activity, spontaneous locomotor activity assessed using photocell cages, and spontaneous climbing behaviour; fenfluramine caused a similar effect. Pretreatment with 5-hydroxy-DL-tryptophan enhanced the inhibitory effects of d-amphetamine. A 3-day treatment with fenfluramine, or lesions of the median raphe nucleus (but not the dorsal raphe nucleus) abolished the ability of d-amphetamine to reduce motor activity in the three test systems. It is concluded that low doses of d-amphetamine can reduce locomotor activity and that the effects may be mediated via an enhancement of the release of 5-hydroxytryptamine from the system arising in the median raphe nucleus.

A possible role of endogenous adenosine in the sedative action of meprobamate

The behavioral interaction of intraperitoneal (i.p.) injections of meprobamate with intracerebroventricular (i.c.v.) injections of adenosine or 5'-N-ethylcarboxamidoadenosine (NECA) was examined on spontaneous locomotor activity in mice. The locomotor depressant effect of meprobamate, an adenosine uptake inhibitor, was potentiated by adenosine, but not by NECA, an uptake-resistant adenosine analogue. These findings suggest that heightened endogenous adenosine levels could mediate some of the central actions of meprobamate.

Locomotor effects of cocaine, cocaine congeners, and local anesthetics in mice

Spontaneous locomotor activity of mice was stimulated by IP administration of cocaine and its closely related phenyltropane analogs. In contrast, locomotion was inhibited by IP administration of cocaine congeners such as norcocaine, (+)-pseudococaine, and tropacocaine, and of isomers of phenyltropane analogs. Also inhibitory were the local anesthetics procaine, tetracaine, benzocaine, lidocaine, and prilocaine. The locomotor inhibition induced by IP norcocaine or tetracaine could be reversed by subsequent treatment with cocaine. Both cocaine and norcocaine were centrally stimulatory when injected intracerebroventricularly. The rank order of potencies of cocaine congeners and local anesthetics in depressing locomotion was similar to that of their potencies in interacting with sodium channels. From these results we infer that the locomotor depression induced by systemic administration of cocaine congeners results from a local anesthetic action involving inhibition of the ion conductance of sodium channels.

Muscle relaxant properties of aqueous extract of Lippia multiflora.

Aqueous leaf extracts of LIPPIA MULTIFLORA administered intraperitoneally produced a profound calming effect, muscle relaxing action, and significant reduction in the spontaneous locomotor activity of mice measured in the Ugo Basile activity cage. The extract (0.25-1.0 g kg -1 ) reduced amphetamine induced locomotor activity in mice. The extract (0.5-1.0 mg ml -1 ) inhibited contractions of the isolated rat diaphragm in response to the phrenic nerve stimulation. The muscle relaxant effect was considered to be primarily responsible for the calming effect, bordering on tranquilizing activity observed in mice and rats.

Involvement of the serotonergic system in the prolongation of pentobarbital sleeping time produced by prostaglandin D 2

In the present study, the depressant and sedative actions of prostaglandin D 2 (PGD 2) were investigated. Intravenous (IV) administration of PGD 2 produced a significant decrease in the spontaneous locomotor activity of mice from 1 to 15 minutes following injection. Prostaglandin D 2 was also able to potentiate pentobarbital sleeping time at doses of 0.4 and 4.0 mg/kg when administered intravenously. Distribution studies with 3H-PGD 2 (6 μCi, 4 mg/kg) showed that only 0.04% of the tritium administered could be found in brain at 5 min after the injection, and that only 50% of this was parent 3H-PGD 2. The role of the serotonergic neurotransmitter system in the depressant action of PGD 2 was investigated with drugs which modulate this system. The ability of PGD 2 to potentiate pentobarbital sleeping time was diminished by pretreatment with agents that reduce brain level or synthesis rate of serotonin. Such agents include para-chlorophenylalanine (PCPA), a tryptophan hydroxylase inhibitor, 5,7-dihydroxytryptamine (5,7-DHT), a neurotoxin with selectivity for serotonergic neurons, and quipazine, a serotonergic autoreceptor stimulant. On the other hand, pretreatment with 5-hydroxytryptophan (5-HTP), the precursor of serotonin, further enhanced the potentiation of pentobarbital sleeping time by PGD 2. These data suggest that the depressant actions of PGD 2 are linked to the serotonergic neurotransmitter system.

Depressant effect of forskolin on spontaneous locomotor activity in mice

1. 1.|Forskolin, an activator of adenylate cyclase, depressed spontaneous locomotor activity when injected intracerebroventricularly into mice in doses of 10 and 100 μg. 2. 2.|The findings suggest that increases in brain cAMP levels may be associated with a reduction in excitability.

Multi-dimensional analyses of behavior in mice treated with morphine, endorphins and [des-tyrosine 1]-γ-endorphin

An investigation was made as to the effects of an intracerebral injection of morphine, endorphins and [des-tyrosine 1]-γ-endorphin (DTγE) on spontaneous locomotor activity in mice. This was done by exploiting a newly devised multi-dimensional behavioral analyser with a capacitance system. This apparatus simultaneously recorded nine different degrees of behavior ( 1 1 , 1 2 , 1 4, 1 8 , 1 16 , 1 32 , 1 64 , 1 128 and 1 256 ) according to the movement sizes in mice. Within 15 min after injection, γ-endorphin (5 and 10 μg), leucine-enkephalin (200 μg) and methionine-enkephalin (100 μg) produced a significant increase in the 1 1 size of movement. Fifteen to 30 min after injection, the movement patterns induced by morphine (40 μg) and DTγE (40 μg) became similar, although morphine (40 μg) caused a significant decrease in the 1 1 and 1 2 sizes of movement. β-Endorphin (2 μg) significantly decreased most of the movement sizes for 30 min compared with saline-treated group. [D-alanine 2]-methionine-enkephalinamide (20 μg) significantly decreased almost all the movement sizes within 15 min after injection. The significant alteration in the movement sizes induced by morphine and endorphins except for DTγE was antagonized by pretreatment with naloxone (1 mg/kg). These results strongly suggest the qualitative difference in the behavioral effects of each of the opioids and nonopioid.

Reduction in motor responding of the mouse by actions of dopamine agonists in the midbrain

Mice were implanted stereotaxically with chronically indwelling bilateral guide cannulae to allow the intracerebral injection of dopamine or the dopamine agonist 2-di- n-propylamino-5,6-dihydroxytetralin into the centre of the substantia nigra, above the substantia nigra or anterior and posterior to the nigra. The intranigral injection of dopamine and the tetralin compound could be shown to dose-dependently reduce the spontaneous locomotor activity of mice. The effectiveness of dopamine decreased with a delayed onset when injections were made anterior or posterior to the substantia nigra; this spectrum of reduced and delayed responding was also apparent when dopamine and the tetralin compound were injected 1 or 2 mm above the nigra. The inhibitory action of dopamine on motor activity, when injected into the substantia nigra, was antagonised by a small dose of spiroperidol which did not influence spontaneous locomotor responding in its own right; prazosin and yohimbine were ineffective. It is suggested that the inhibitory actions of dopamine and 2-di- n-propylamino-5,6-dihydroxytetralin on motor activity may reflect an ability to stimulate dopamine “autoreceptors” in the midbrain area containing the dopamine cell bodies which innervate striatal and mesolimbic forebrain regions.

Effects of methylmercury on the hypnotic action and pharmacokinetics of hexobarbital

Receptor binding and behavioral profiles of N-(4-chloro-2-phenoxyphenyl)-N-(2-isopropoxybenzyl)acetamide (DAA1097) and N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (DAA1106), novel, selective agonists for the peripheral benzocliazepine receptor (PBR) were examined. DAA1097 and DAA1106 inhibited [3H]PK 11195 binding to crude mitochondrial preparations of rat whole brain, with IC50 values of 0.92 and 0.28 nM. Likewise, DAA1097 and DAA1106 inhibited [3H]Ro 5-4864 binding to the same mitochondrial preparation, with IC50 values of 0.64 and 0.21 nM. In contrast, DAA1097 and DAA1106 did not inhibit [3H]-flunitrazepam, the central benzodiazepine receptor (CBR) ligand, binding to membranes of rat whole brain (IC50 > 10,000nM). Oral administration of DAA1097 and DAA1106 had anxiolytic effects in the mouse light/dark exploration test and in the rat elevated plus- maze test. Oral administration of DAA1106, diazepam and buspirone but not DAA1097 significantly increased sleeping time in hexobarbital-induced anesthesia in mice. The order of potency of potentiation of hexobarbital anesthesia was diazepam > buspirone > DAA1106 > DAA1097. Oral administration of DAA1097 and DAA1106 but not diazepam and buspirone did not affect spontaneous locomotor activity in mice. These findings indicate that DAA1097 and DAA1106 are PBR selective ligands with potent anxiolytic-like properties, in laboratory animals.

Effects of the opioid benzodiazepine tifluadom and its optical isomers on spontaneous locomotor activity of mice

The opioid benzodiazepine tifluadom and its (+) and (-) enantiomers affect locomotor activity of mice with patterns different from those of diazepam or the prototype opioids morphine (mu) or bremazocine (kappa). Lacking the initial locomotor inhibition, the sum of activity of the two enantiomers does not comply with the effects of the racemic mixture, thus indicating a non-additive interaction. In addition to the opioid effects of tifluadom, the effective antagonisms to the locomotor stimulatory phase of this compound and its enantiomers by Ro 15-1788 points to some interaction with the benzodiazepine/GABA-receptor complex.

A comparison of naloxone and naltrexone in laboratory tests predictive of antipsychotic potential

AbstractNaloxone and naltrexone were compared neuropharmacologically, especially in several rodent models considered to be predictive of antipsychotic activity, since narcotic antagonists have been reported to be effective in the treatment of schizophrenia. Naltrexone was found to be a potent antagonist of amphetamine‐induced aggregate toxicity in mice; this was in marked contrast to naloxone, which enhanced amphetamine's toxicity. Both naloxone and naltrexone exhibited an unusual profile of activity in the apomorphine‐induced stereotypy test in mice in that they antagonized the chewing behavior but failed to antagonize the rearing; this is in contrast to the activity of standard neurolepitcs (e.g., haloperidol, clozapine) which antagonize both behaviors induced by apomorphine. Neither of the narcotic antagonists exhibited any activity in several other tests predictive of antipsychotic activity. Naltrexone was a potent inhibitor of spontaneous locomotor activity in mice; naloxone, although much weaker, also antagonized motor activity. Thus, endorphins may play a role in the modulation of exploratory or locomotor activity. The marked difference in activity between the two antagonists in the amphetamine aggregate toxicity study may indicate a significant neuropharmacological difference between these agents; i.e., naltrexone may be much more than merely a more potent naloxone. Furthermore, naltrexone's potent activity as an antagonist of amphetamine‐induced aggregate toxicity in mice may be predictive of a better therapeutic effect in schizophrenia than has been observed with naloxone.