Inhibition of anticholinergic drug-induced locomotor stimulation in mice by α-methyltyrosine

α-Methyltyrosine, administered in the diet to mice, inhibited locomotor stimulation induced by benztropine, scopolamine and atropine. FLA-63, administered in the same manner, did not alter any of the drug-stimulated activities. These results suggest that a dopaminergic system is involved in the pathway mediating anticholinergic drug-induced locomotor stimulation.     

Netrin-1 receptor-deficient mice show age-specific impairment in drug-induced locomotor hyperactivity but still self-administer methamphetamine

Rationale

The mesocorticolimbic dopamine system undergoes significant reorganization of neuronal connectivity and functional refinement during adolescence. Deleted in colorectal cancer (DCC), a receptor for the guidance cue netrin-1, is involved in this reorganization. Previous studies have shown that adult mice with a heterozygous (het) loss-of-function mutation in DCC exhibit impairments in sensitization and conditioned place preference (CPP) to psychostimulants. However, the commonly abused psychostimulant methamphetamine (METH) has not been assessed, and the role of DCC in drug self-administration remains to be established.

Objectives

Using dcc het mice and wildtype (WT) littermates, we extended previous findings on dcc haplodeficiency by examining self-administration of METH in adult mice, including cue-induced drug seeking following abstinence. We also examined hyperactivity, sensitization, and CPP to a METH-paired context in adult and adolescent mice.

Results

While adult dcc het mice expressed largely similar METH self-administration and cue-induced drug seeking as WT littermates, they failed to modulate responding according to dose of METH. Compared to WT, both adult and adolescent dcc het mice expressed impaired locomotor hyperactivity to acute METH but nevertheless showed comparable behavioral sensitization. Conditioned hyperactivity increased with age in WT but not in dcc het mice.

Conclusions

Impaired METH-induced hyperactivity and dose-related responding in adult dcc het mice suggest that reduced DCC alters METH-related behaviors. Adolescence is identified as a vulnerable period during which impairment in hyperactivity due to reduced DCC can be overcome with repeated METH injections. Nevertheless, DCC appears to have a somewhat limited role in METH-consumption and seeking following abstinence.     

Substance-P antagonists: effect on spontaneous and drug-induced locomotor activity in the rat

The substance P (SP) antagonists (D-Pro4, D-Trp7,9, Leu11) SP(4-11), (D-Pro4, D-Trp7,9, Phe11)SP(4-11) and (D-Pro4, D-Trp7,9,10, Leu11) SP (4-11) were infused into the lateral ventricles (i.c.v.) and their effects on spontaneous and drug-induced locomotor activity were investigated. The drug DiMeC7, the stable substance P agonist, was used to stimulate locomotor activity because of its prolonged action. Only (D-Pro4, D-Trp7,9,10) SP (4-11) was found to attenuate the drug-induced increases in motor activity, indicating that it is a substance P antagonist with activity in the CNS.     

Computerized evaluation of drug-induced changes in guinea-pig epicardial monophasic action potentials

The monophasic action potential (MAP) has been widely used for the study of drug effects on cardiac repolarization in vivo. There is, however, no study of drug-induced effects on MAP depolarization, i.e. effects on MAP Vmax and/or MAP rise-time. For this study, we developed a method in the anesthetized open chest guinea-pig. MAP signals were recorded and subjected to on-line computerized analysis, in which parameters describing both depolarization and repolarization were calculated. With the MAP electrode kept at the same epicardial position the MAP rise-time did not vary with time. If the influences of heart rate were eliminated, the intra- and interindividual variation in the MAP duration was very low. Sotalol significantly and dose-dependently prolonged MAP duration, but did not affect rise-time, whereas tocainide significantly and dose-dependently shortened MAP duration and increased rise-time. The effect of tocainide on rise-time is most likely secondary to a reduction in conduction velocity due to a decrease in Vmax in the single cell action potential. These results suggest that monophasic action potential recordings coupled with an on-line computerized analysis may be used for rapid and simple evaluation of drug effects, both on cardiac depolarization and repolarization.     

An evaluation of the locomotor stimulating action of ethanol in rats and mice

The locomotor activity of groups of three CD-1 female mice was increased by 1.0 and 2.0 g/kg ethanol, IP, was decreased during the first hour and increased during the second hour by 3.0 and 4.0 g/kg, and was decreased by 5.0 g/kg. The dose (2.0 g/kg) that caused the greatest increase in locomotor activity did not impair motor coordination, measured by the height of aerial righting in mice. Tests after oral administration of ethanol showed that the increase in locomotor activity of mice was not due to peritoneal irritation. The same dose (2.0 g/kg) did not increase the locomotor activity of C57BL/6J mice. Ethanol (0.1 to 3.0 g/kg) had no effect or decreased the locomotor activity of individual male Sprague-Dawley rats. These findings suggest that biological differences in strains and species of laboratory rodents contribute to the apparent variability of locomotor stimulation caused by ethanol. The presence or absence of an ethanol-induced increase in locomotor activity was not dependent on the sex or number of mice or rats tested. Intertrial-interval crossing by rats acquiring or performing an active avoidance task in a shuttle box was increased by ethanol. This action was dependent on the presentation of electric foot shock. Apomorphine (0.25 and 2.5 mg/kg) and fenmetozole (7.5 and 15.0 mg/kg) failed to inhibit the ethanolinduced increase in intertrial-interval crossing by rats, although these drugs have been shown previously to antagonize the ethanol-induced increase in the activity of mice ethanol treatment. The ethanol-induced increases in the spontaneous locomotor activity of CD-1 mice in photocell activity monitors and in intertrial-interval crosses in rats in a shuttle box task thus do not appear to share a common mechanism.     

Alteration of ethanol-induced changes in locomotor activity by adrenergic blockers in mice

The effects of various doses of ethanol (ETOH) on spontaneous locomotor activity (SLMA) in mice were measured using photocell activity chambers. Of the 4 i.p. doses injected, the 2 lowest doses (0.5 and 1.0 g/kg) stimulated SLMA, the next higher dose (2.0 g/kg) produced a biphasic effect of depression followed by stimulation, and the highest dose (4.0 g/kg) depressed SLMA. The mechanism of the biphasic effect of the 2.0 g/kg dose was studied in tests with central catecholamine antagonists at various doses 30 min before ETOH. Doses of 5, 10, and 20 mg/kg of propranolol, a -receptor blocker, significantly antagonized the depressant effect of ETOH but had no influence on the stimulant effect. High doses (10 and 20 mg/kg) of phentolamine, an -receptor blocker, significantly antagonized the stimulant phase of ETOH action but had no significant effect on the depressant phase. All doses (0.062–0.250 mg/kg) of spiroperidol, a dopaminergic blocking drug, significantly enhanced the SLMA depression produced by ETOH. These results indicate that the SLMA-depressant effect of ETOH may be mediated by central beta-type receptors, that the SLMA-stimulant effect of ETOH may be mediated by central alpha-type receptors, and that at least part of ETOH's action may be due to dopaminergic mechanisms.     

Aminotetralone analogues of ketamine: synthesis and evaluation of hypnotic and locomotor properties in mice

Ketamine and phencyclidine are structurally similar compounds that share many pharmacological actions, some of which are similar to the phenethylamines amphetamine and cathione. In order to integrate structural features of ketamine and cathinone, two groups of analogues, which are more conformationally restricted compared to the parent compounds, were synthesized for biological evaluation. These included 1-amino-1-methyl-2-tetralone and 2-amino-2-methyl-1-tetralone was well as several N-substituted derivatives of these molecules. Locomotor activity testing in mice revealed that 2-amino-2-methyl-1-tetralone caused an increase in locomotor activity while 1-amino-1-methyl-2-tetralone depressed spontaneous locomotor activity. None of the compounds produced hypnosis or profound ataxia.     

Dose-dependent changes in the locomotor responses to methamphetamine in BALB/c mice: Low doses induce hypolocomotion

The overall goal of the present study was to determine the effects of different doses of (+)-methamphetamine (meth) on locomotor activity of Balb/C mice. Four experiments were designed to test a wide range of meth doses in BALB/c female mice. In Experiment 1, we examined locomotor activity induced by an acute administration of low doses of meth (0.01 and 0.03 mg/kg) in a 90-min session. Experiment 2 was conducted to test higher meth doses (0.3-10 mg/kg). In Experiment 3, separate sets of mice were pre-treated with various meth doses once or twice (one injection/week) prior to a locomotor challenge with a low meth dose. Finally, in Experiment 4, we tested whether locomotor activation would be affected by pretreatment with a low or moderate dose of meth one month prior to the low meth dose challenge. Results show that low doses of meth induce hypolocomotion whereas moderate to high doses induce hyperlocomotion. Prior exposure to either one moderate or high dose of meth or to two, low doses of meth attenuated the hypolocomotor effect of a low meth dose one week later. This effect was also attenuated in mice tested one month after administration of a moderate meth dose. These results show that low and high doses of meth can have opposing effects on locomotor activity. Further, prior exposure to the drug leads to tolerance, rather than sensitization, of the hypolocomotor response to low meth doses.     

Effects of drug-induced changes in brain monoamines on aggression and motor behavior in mice

Mice maintained on a basal casein diet supplemented with 4% L-tyrosine potentiated L-DOPA effects on aggression. At low doses (12.5-25 mg/kg) L-DOPA increased aggression whereas at high doses (50-100 mg/kg) it decreased aggression. 5-HTP (50-200 mg/kg) produced a dose-dependent decrease in aggression and motor activity which was antagonized by pretreatment with dietary L-tyrosine (4%) or L-DOPA (50 mg/kg). L-DOPA induced reductions in motor activity were, in turn, antagonized by 5-HTP. Increases in motor activity following d-amphetamine (3 mg/kg) were sharply reduced by 5-HTP (50-100 mg/kg), but 5-HTP potentiated reductions in aggression following d-amphetamine. The concentration in brain of tyrosine, DOPA, dopamine (DA), noradrenaline (NA), DOPAC, HVA, tryptophan, serotonin (5-HT), and 5-HIAA were obtained following drug and diet treatments. The changes observed, particularly in DA and 5-HT metabolites, provide further evidence for an inhibitory role of brain 5-HT systems in the mediation of the behavioral effects of d-amphetamine and the catecholamine precursors, L-tyrosine and L-DOPA.     

Effect of subchronic treatment with methamphetamine on apomorphine-induced changes in locomotor activity in mice

Subchronic treatment with methamphetamine (3 mg/kg, s.c., twice daily for 14 days) attenuated hypomotility produced by a low dose of apomorphine (0.1 mg/kg, s.c.) and enhanced hypermotility induced by a high dose of apomorphine (3 mg/kg, s.c.) in mice. The treatment did not affect apomorphine-induced decrease in striatal DOPA accumulation following gamma-butyrolactone plus m-hydroxybenzylhydrazine, an L-amino acid decarboxylase inhibitor, administration. These results suggest that drug sensitivity of presynaptic dopamine receptors in the striatum may not be altered after subchronic methamphetamine treatment.     

Morphine-induced sensitization in mice: changes in locomotor activity by prior scheduled exposure to GABAA receptor agents

This study investigated the effects of a gamma-amino-butyric acid type A (GABAA) receptor agonist and antagonist on morphine-induced locomotor sensitization in male albino mice. Subcutaneous administration to mice of a high dose of morphine (30 mg/kg), but not lower doses (5, 10 and 20 mg/kg) increased locomotion. The maximum locomotor activity was achieved during a 20-min measurement period. The locomotor response to a low dose of morphine (5 mg/kg, subcutaneously) given on day 9 was enhanced in mice pretreated with morphine (7.5, 15 and 30 mg/kg/day x 3 days), indicating that sensitization had developed. Three-day intracerebroventricular (i.c.v.) administration of the GABAA receptor agonist, muscimol (0.025, 0.05, 0.1 and 0.2 microg/mouse/day) significantly decreased both morphine-induced motor stimulation and locomotor sensitization. On the other hand, a 3-day pretreatment with the GABAA-receptor antagonist, bicuculline (0.25, 0.5 and 1 microg/mouse/day) reduced morphine (15 mg/kg)-induced locomotor sensitization. Repeated i.c.v. injections of a lower dose of bicuculline (0.25 microg/mouse/day x 3 days) by itself also decreased morphine-induced locomotion. Furthermore, repeated i.c.v. administration of bicuculline (0.25, 0.5 and 1 microg/mouse/day x 3 days) decreased the effect of i.c.v. injection of muscimol (0.1 microg/mouse/day x 3 days) on locomotor activity induced by morphine (5 mg/kg) in both control and sensitized mice. The magnitude of this response was, however, variable. The results indicate that GABAA receptors might be involved in the acquisition of morphine-induced sensitization.     

A method for discriminating between chemically induced changes in locomotor activity and whole-body oxygen consumption in mice.

Concurrent measurements of O₂ consumption and locomotor activity were made in adult female mice at 20 and 34°C. As anticipated, activity and O₂ consumption were positively correlated with a high degree of statistical significance. A 30-fold increase in spontaneous motor activity, however, was accompanied by only a 30% increase in O₂ consumption. Extrapolation of the regression relationship to zero activity provided a novel means of estimating the basal metabolic rate (BMR) of mice. That value agreed with traditional estimates based on resting or sleeping animals. Under our conditions the respiratory quotient for mice was 0.83 at 20°C and 1.0 at 34°C. Oxygen consumption averaged over all levels of spontaneous activity was 4.79 ml g^?1 hr^?1 at 20°C and 2.21 ml g^?1 hr^?1 at 34°C. These estimates are actually lower than those of others who employed physical restraint to control activity. Because the BMR of mice constitutes about 70% of the O₂ consumption at the highest levels of spontaneous motor activity, drug-induced changes in motor activity may not significantly affect O₂ consumption. Alternatively, it may be obvious that the two changes are not correlated. For example, in our hands pentobarbital decreased motor activity without affecting O₂ consumption, and amphetamine increased motor activity but decreased O₂ consumption. When the changes are in the same direction, the problem of distinguishing between a metabolic or respiratory effect of the drug and a change related to increased or decreased motor activity becomes more difficult. Analysis of covariance offers one possible approach to this problem.     

Antihistaminic-opioid combination: effect on locomotor activity in mice

Various laboratory studies have been recently prompted by reports indicating abuse by heroin addicts of the narcotic agonist-antagonist pentazocine combined with the antihistaminic tripelennamine. For what concerns the effects on locomotor activity, it was demonstrated that three histamine H1 receptor antagonists, chlorpheniramine, diphenhydramine and tripelennamine enhance morphine-, but not amphetamine and scopolamine-induced hyperactivity in mice. These results suggested that antihistaminics may specifically interfere with locomotor effects of opioids. Such hypothesis was strengthened by further findings indicating enhancement by tripelennamine of the locomotor stimulation induced by buprenorphine, a drug possessing morphine-like properties.     

Differential tolerance to dietary amino acid-induced changes in aggressive behavior and locomotor activity in mice

Male albino mice were maintained on a semisynthetic 12% casein protein diet for 2 weeks, then switched to diets modified by the addition of a 4% L-amino acid supplement (L-tyrosine, L-phenylalanine, and L-tryptophan) or 4% casein (control). Territorial-induced aggressive behavior increased following 1 week on the amino acid supplements, especially after tyrosine, but an apparent tolerance developed to these effects after 5 weeks on the amino acid supplements. Locomotor activity also increased following 1 week on the supplements, most notably after phenylalanine alone or in combination with tyrosine, and these effects tended to persist after 5 weeks on the supplements. Endogenous whole brain levels of dopamine, norepinephrine, serotonin, 5-hydroxyindoleacetic acid, tyrosine, phenylalanine, and tryptophan showed no tolerance to increased concentrations of brain catecholamines and indoleamines over the 5-week period, and no clear relation between the concentrations of these monoamines and the behavioral changes.     

Morphine-induced place conditioning is not confounded by drug-induced alterations in locomotor activity

The influence of locomotor activity and environmental familiarity upon the reinforcing effects of morphine was examined in an unbiased place preference conditioning procedure. Groups of rats were trained to associate one distinctive environment with morphine and another with saline. One group was made tolerant to the locomotor activity effects of morphine by the SC administration of morphine (5.0 mg/kg/12 hr) for four days prior to conditioning. The other group received injections of saline. Administration of morphine, at doses which decreased locomotor activity, resulted in marked preferences for the drug-associated place in saline-treated rats. In contrast, chronic morphine treatment resulted in tolerance to the sedative effects of morphine and an abolition of the morphine-induced place preference. These results indicate that in the place conditioning procedure, measures of reinforcement are not confounded by drug-induced increases in activity.     

应用Actiwatch监测小鼠自主活动的研究

目的:将体动记录仪(Actiwatch)用于小鼠自主活动的监测,验证其与人工计数结果的相关程度。方法:30只小鼠随机分为3组(对照组、地西泮组和咖啡因组),用Actiwatch记录各组小鼠在抖笼中的活动情况,与同步人工计数的相关数据进行比较,并行相关性分析。结果:Actiwatch和人工记数的结果均显示地西泮组运动时间、活动次数与咖啡因组、正常组相比有统计学差异(P<0.01);而正常组与咖啡因组运动时间和活动次数无差异(P>0.05)。Actiwatch记录3组小鼠的运动时间与人工计数的大幅度活动运动时间之间无差异(P>0.05)。Actiwatch记录3组小鼠的运动时间、活动次数与人工计数的数据行相关性分析,r值分别为0.83和0.91。结论:Acti-watch对小鼠自主活动的记录数据与人工计数的数据密切相关,Actiwatch可以替代人工计数用于记录小鼠的自主活动。     

The analysis of drug-induced tremor in mice

An improved method of recording tremor in mice has been developed using a gramophone pick-up and a cathode ray oscillograph. Permanent records are made on 35 mm. film from which it is possible to determine qualitative differences in the tremor caused by various drugs. In addition, the severity of the tremor may be estimated quantitatively by a tremor index. The rate and variations in the rhythm and amplitude and in the tremor index have been determined for Tremorine (1,4-dipyrrolidin-1'-ylbut-2-yne), harmine, harmaline, 3-amino-1,1,3-triphenylpropan-1-ol and lysergic acid diethylamide. The incidence of side effects has also been noted.     

Effects of dietary tyrosine on L-dopa- and amphetamine-induced changes in locomotor activity and neurochemistry in mice

Recent findings suggest that intraperitoneal injections of L-tyrosine at high doses (100 mg/kg) alters amphetamine-induced changes in behavior by restoring amphetamine-induced decreases in whole brain norepinephrine (NE). The present study examined the motor effects of L-dihydroxyphenylalanine (L-dopa) and d-amphetamine sulfate in mice after treatment with a basal casein diet supplemented with L-tyrosine. The basal diet supplemented with 1-4% L-tyrosine, or 1-4% L-phenylalanine, produced no changes in motor activity in otherwise untreated mice. Whereas L-dopa (25-100 mg/kg) following inhibition of extracerebral decarboxylase by Ro 4-4602 (25 mg/kg) slightly decreased activity in diet control (casein) animals, this drug treatment enhanced motor activity in a dose-related fashion when L-tyrosine was added to the diet. Increases in motor activity following low doses of amphetamine (0.75-1.5 mg/kg) in casein control mice were antagonized by dietary L-tyrosine, but a higher dose of d-amphetamine (3 mg/kg) interacted with the addition of L-tyrosine producing an increase in motor activity. Neurochemical changes observed in brain concentrations of tyrosine, dopamine (DA), norepinephrine (NE), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), tryptophan, serotonin (5-HT) and 5-hydroxy-indoleacetic acid (5-HIAA) following drug and diet treatments suggest that 5-HT systems, in addition to catecholamine systems, may be involved in mediating these effects.     

Genetic differences in locomotor activation in mice

Two highly inbred strains of mice were found to differ in habituation of activity repeatedly assessed in a toggle-box exploration task. The recombinant inbred (RI) strains derived from their cross resembled either one or the other parent strain, suggesting that a single gene exerts a marked influence on this behavior. The influence of an acute ethanol injection on activity in an open field was found to differ among 19 inbred strains. In 6 strains significant decreases in activity from the previous day's scores were seen; in two strains activity increased; and in 11 strains, no significant change was seen. Genetic specificity must, therefore, be considered in the interpretation of pharmacologic substrates for activity in mice. Lines of mice selectively bred for high and low open-field activity are suggested to offer an ideal subject population for neuropharmacologic studies.     

Enhancement by chlordiazepoxide of the anticholinergic-induced locomotor stimulation in mice

Spontaneous locomotor activity has been studied in mice treated with chlordiazepoxide, atropine, and scopolamine, given alone or in combination. Chlordiazepoxide alone increased activity for a short time, while the two anticholinergic drugs produced longer lasting stimulatory effects. Locomotor stimulation was stronger when chlordiazepoxide and anticholinergics were given in combination.