Increase In Spontaneous Motor Activity Research Articles

Endogenous enkephalin modulation of dopamine neurons in ventral tegmental area.

Many lines of evidence support the possibility that the opioid pentapeptides Met- and Leu-enkephalin can modulate dopamine neurons in the ventral tegmental area (VTA). Thus microinjection of enkephalin analogues into the VTA of rats produces a dopamine-dependent increase in spontaneous motor activity and an increase in dopamine metabolism in certain mesolimbic dopamine terminal fields, such as the nucleus accumbens. To determine if these effects can be produced by endogenous enkephalins, an enkephalinase A inhibitor, thiorphan, was microinjected into the VTA to inhibit enkephalin metabolism. Thiorphan produced a dose-dependent (0.3-3.33 micrograms) increase in spontaneous motor activity that was blocked by pretreatment with the opioid antagonist naloxone (2.0 mg/kg ip) or the dopamine antagonist haloperidol (0.1 mg/kg ip). Thiorphan injection into the VTA increased dopamine metabolism in the nucleus accumbens, prefrontal cortex, and septum but not in the striatum. In all brain regions the increase in dopamine metabolism was blocked by pretreatment with naloxone. These data demonstrate that endogenous enkephalin in the VTA can increase the activity of A10 dopamine neurons, supporting a physiological role for enkephalin in mesolimbic and mesocortical dopamine-mediated behaviors.

Age-related changes in learning and memory in the senescence-accelerated mouse (SAM)

Age-related changes in learning ability were studied in senescence-accelerated mice (SAM) reared under specific pathogen-free (SPF) conditions. SAM-P/8/Ta (SAM-P/8, senescence-prone substrain) showed an age-associated increase in spontaneous motor activity (SMA) compared with SAM-R/1/Ta (SAM-R/1, senescence-resistant substrain) in a novel environment when the activity was measured in the light period, although there was no significant difference in the dark period. In observations of the circadian rhythm of SMA, SAM-P/8 showed a significant increase in diurnal SMA. In SAM-P/8 mice, the acquisition of passive avoidance response was slightly but significantly impaired even at 2 months of age, compared with SAM-R/1 control; the impairment became obvious with aging. In a one-way active avoidance task, SAM-P/8 did not show any impairment in the acquisition of avoidance response at 2 and 4 months of age. However, significant impairment was observed in SAM-P/8 at 12 months of age. The impairments of avoidance tasks were not due to a decrease in shock sensitivity, as indicated by no significant change in the flinch-jump threshold. In a water-filled multiple T-maze task, there was no difference in the number of errors between the two groups. With regard to the performance time to reach the goal, however, SAM-P/8 showed a mild prolongation at 2 months of age, and the prolongation became marked with advancing age. Furthermore, SAM-P/8 showed an age-related increase in the latency to escape onto the hidden platform in the Morris water task as compared with the control mice, whereas a slight but significant impairment was observed even at 2 months of age. These results indicate that SAM-P/8 shows age-related deterioration of ability in learning and memory, and the two factors of genetic strain difference and acceleration of aging are likely to be involved in the deterioration observed in SAM-P/8. Also, it is suggested that SAM-P/8 may be useful as an experimental animal model for senile memory impairment in humans.

Interactions between neuropeptides and dopamine neurons in the ventromedial mesencephalon

Cholecystokinin (CCK), enkephalin, neurotensin (NT), substance P (SP) and substance K (SK) are five neuropeptides that exist in neuronal perikarya or fibers in the vicinity of the A10 dopamine neurons in the ventromedial mesencephalon. Based upon this anatomical proximity, many investigators have been evaluating the possibility that these peptides may influence the function of the A10 dopamine neurons. A variety of experimental techniques have been employed in this regard, including anatomical, electrophysiological, neurochemical and behavioral methodologies. Measurement of immunoreactive peptide levels with radioimmunoassay, and visualization of peptidergic neurons and fibers with immunocytochemistry has demonstrated not only that peptides exist in the vicinity of A10 dopamine neurons, but using double labeling techniques NT and CCK have been found to coexist with dopamine in the same neuron. Further, by combining retrograde tracing techniques with immunocytochemistry, the origin of some peptidergic afferents to the ventromedial mesencephalon has been determined. With the exception of CCK-8, microinjection into the ventromedial mesencephalon of rats with all the peptides or potent analogues produces a dose-related increase in spontaneous motor activity. For SP, NT and enkephalin the motor response has been blocked by dopamine antagonists. Further, an increase in dopamine metabolism in mesolimbic dopamine terminal fields is produced concurrent with the behavioral hyperactivity. These data indicate that SP, SK, enkephalin and NT can activate dopamine neurons in the ventromedial mesencephalon. This postulate is supported by electrophysiological studies showing an excitatory action by iontophoretic administration of peptides onto dopamine neurons. However, in some studies, excitatory electrophysiological effects were not observed. While some observations are contradictory, sufficient data has accumulated that tentative postulates and conclusions can be made about how these peptides may influence the A10 dopamine neurons. Further, speculations are offered as to the role this modulatory action may play in the many behaviors and pathologies thought to involve these dopamine neurons.

Behavioral and neurochemical effect of daily injection with neurotensin into the ventral tegmental area

Many lines of evidence indicate an excitatory role by neurotensin (NT) on mesolimbic dopamine neurons in the ventral tegmental area (VTA). In support of this postulate, NT microinjection into the VTA of rats produces a dopamine-dependent increase in spontaneous motor activity that is associated with an increase in dopamine metabolism in the nucleus accumbens. In this study it was found that after daily intra-VTA injection with NT, both the motor hyperactivity and increase in dopamine metabolism were significantly enhanced. Further, the increased motor response to NT was present after 7 days without daily administration. While the augmented motor response could be produced with the car☐y-terminal fragment NT 8−13, the NH 2-terminal fragment, NT 1−8, was ineffective. The enhancement of motor activity was only produced by NT injection into the A10 dopamine region and not adjacent nuclei. These results suggest that daily administration with NT into the VTA will potentiate the responsiveness of mesolimbic dopamine neurons to subsequent injection with NT.

Neurotensin in the ventromedial mesencephalon of the rat: anatomical and functional considerations.

Neurotensin is an endogenous neuropeptide that fulfills some of the criteria for a neurotransmitter in the mammalian central nervous system. It exists in high concentrations in the ventral tegmental area and adjacent midline nuclei of the ventromedial mesencephalon, and recent microinjection studies have demonstrated that neurotensin can act in this brain region to produce both a decrease in colonic temperature, and an increase in spontaneous motor activity. In this study it was found that hypothermia was most successfully evoked following neurotensin injection along the midline of the ventral mesencephalon, corresponding to the nucleus linearis centralis. In contrast, behavioral hyperactivity was produced with greatest consistency in the ventral tegmental area, corresponding to the nucleus paranigralis and nucleus parabrachialis pigmentosus. However, in its caudal aspect, the nucleus paranigralis was found unresponsive to neurotensin. Behavioral hyperactivity was also observed after neurotensin injection along the midline into the nucleus interfascicularis. Only injections made into the nucleus linearis rostralis produced hypothermia and hyperactivity in the same rat. This distribution of neurotensin-responsive nuclei corresponded to the distribution of neurotensin containing perikarya and fibers. With the exception of the nucleus interfascicularis, neurotensin-containing neurons were distributed throughout the rostral portion of the ventromedial mesencephalon, the nucleus parabrachialis pigmentosus containing the greatest density. However, in the caudal portion, neurotensin neurons were found almost exclusively in the nucleus linearis centralis. Neurotensin-containing fibers were of greatest density in the nucleus interfascicularis and the nucleus linearis centralis. Considering the known capacity of neurotensin to activate dopamine neurons in the ventromedial mesencephalon, and the partial mediolateral topographical distribution of dopaminergic projections from this region to the limbic forebrain, it is possible that neurotensin may be activating two distinct populations of dopamine neurons to produce hypothermia and behavioral hyperactivity.

A TRH analog (DN-1417): Motor stimulation with rearing related to catecholaminergic mechanisms in rats

The effect of an analog of TRH, γ-butyrolactone-γ-carbonyl-histidyl-prolinamide citrate (DN-1417) on motor activity was studied in rats. Peripheral administration of DN-1417 (0.2–20 mg kg , i.p.) caused a significant, dose-dependent increase in total spontaneous motor activity, with a definite increase in rearing behaviour. Both increases in spontaneous motor activity and rearing behaviour were markedly inhibited by pretreatment with chlorpromazine (1, 5 mg kg , i.p.), haloperidol (0.1, 0.5 mg kg , i.p.), pimozide (1 mg kg , i.p.) or α-methyltyrosine (250 mg kg , i.p.). Only stimulation of rearing behaviour was selectively attenuated by phenoxybenzamine (5 mg kg , i.p.) or FLA-63 (25 mg kg , i.p.) at doses producing no significant effect on spontaneous motor activity. Although propranolol (10 mg kg , i.p.) and methysergide (10 mg kg , i.p.) had no effect, atropine (10 mg kg , i.p.) and mecamylamine (10 mg kg , i.p.) respectively potentiated and counteracted the effects of DN-1417. Concerning the stimulation of spontaneous motor activity, the nucleus accumbens and lateral hypothalamic area were most sensitive to DN-1417, and the lateral hypothalamic area was the most sensitive site for the stimulation of rearing. Furthermore, DN-1417 (5 × 10 −5 M) significantly enhanced the spontaneous release of [ 3H]dopamine from the rat nucleus accumbens slices in vitro. These findings indicate that the motor stimulatory action of DN-1417 appears to be mediated primarily via a dopaminergic mechanism by enhancing the release of dopamine from nerve terminals, including the nucleus accumbens in the mesolimbic dopamine system, and, in turn, the rearing may be mediated via noradrenergic mechanism.

Pharmacological study of S-adenosylmethionine (SAM)-1st Report-With special reference to spontaneous motor activity and brain monoamines in rats

Since S-adenosylmethionine (SAM) was identified as the most important methyl donor in the body by Cantoni et al. in 1951, various physiological actions have been shown for this substance. Among the various physiological actions of SAM, the effects on phospholipid metabolism, i.e. facilitative effects on phosphatidylcholine biosynthesis and on the metabolism of physiologically active brain amines. This report shows the effects of SAM in healthy animals determined using parameters such as spontaneous motor activity, levels of brain monoamines glucose, glucose-metabolites relating substances,ATP and phospholipids, in comparison with CDP-choline. these substances were injected intravenously or intraperitoneally. An injection of SAM at over 10mg/kg resulted in a slight increase in spontaneous motor activity, but CDP-choline caused no change. An inclination to awake was observed in spontaneous EGG with both of these substances. Regarding brain-monoamines related substance, DA tended to be increased with CDP-choline of over 50mg/kg, and tendencies for increases of HVA and 5-HIAA were observed with SAM of over 10mg/kg.

Pharmacological study of S-adenosylmethionine (SAM)-2nd Report : Influences of SAM on experimental cerebral ischemic animals

In the first report, our result showed that S-adenosylmethionine (SAM) produced a slight increase in spontaneous motor activity, awakeness in spontaneous EEG, increase in brain glucose, ATP and phospholipids, a slight facilitation of monoamine metabolism and rise in the lecithin/cephalin ratio. This report shows the results from experiments in animal models of cerebral ischemia performed for the purpose of determining the effects of SAM in cerebral circulatory disorders in comparison with CDP-choline. In order to obtain cerebral ischmic animals, the common carotid artery was bilaterally occluded. Influences of ischemia on general conditions, brain monoamine level, glucose, lactic acid, pyruvic acid, ATP, lipid peroxides and total phospholipids levels were determined, and fluoròhistlogical observations werealso performed on monoamines at the same time. The results obtained showed a decrease in motor activity, piroelection and sedation as qeneral symptoms in acute cerebral ischemia. A time-dependent decrease in catecholamines and ATP contents was found whereas no remarkable change was found in 5-HT level. Contents of glucose, lactic acid, pyruvic acid and lipid peroxides were increased in a time-dependent manner. On these effects, SAM and CDP-choline produced a slight improvement.

Increase in spontaneous motor activity following infusion of neurotensin into the ventral tegmental area

Microinjection of neurotensin (NT) into the ventral tegmental area (VTA) of the rat produced a dose-dependent increase in spontaneous motor activity. The NT-induced hyperactivity consisted of an increase in exploratory behaviors, such as locomotion, rearing and sniffing, and a decrease in sleep or resting. The structural specificity of this response was demonstrated by microinjecting NT analogues and endogenous neuropeptides into the VTA. The fact that high levels of immunoreactive NT have been demonstrated in the VTA indicates that the observed behavioral effects may reflect an underlying physiological action by endogenous NT.

Psychopharmacological studies on (--)-nuciferine and its Hofmann degradation product atherosperminine.

(--)-Nuciferine and its Hofmann degradation product atherosperminine showed divergent psychopharmacological effects. Because nuciferine has been reported to be a neuroleptic and atherosperminine has some chemical resemblance to dopamine, they were investigated for their dopamine-receptor activities. Nuciferine had a pharmacologic profile of action associated with dopamine-receptor blockade; i.e., it induced catalepsy, inhibited spontaneous motor activity, conditioned avoidance response, amphetamine toxicity and stereotypy. On the other hand, atherosperminine produced effects associated with dopamine receptor stimulation, i.e., stereotypy, increase in spontaneous motor activity and amphetamine toxicity, reversal of haloperidol-induced catalepsy and inhibition of conditioned avoidance response, inhibition of morphine analgesia, and potentiation of the anticonvulsant action of diphenylhydantoin. The results are discussed on the basis of the chemical configuration of the two compounds.

7) - Increase in spontaneous motor activity of lntracerebrally administered metaraminol in mice

7) - Increase in spontaneous motor activity of lntracerebrally administered metaraminol in mice

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

Concurrent measurements of O 2 consumption and locomotor activity were made in adult female mice at 20 and 34°C. As anticipated, activity and O 2 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 O 2 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 O 2 consumption at the highest levels of spontaneous motor activity, drug-induced changes in motor activity may not significantly affect O 2 consumption. Alternatively, it may be obvious that the two changes are not correlated. For example, in our hands pentobarbital decreased motor activity without affecting O 2 consumption, and amphetamine increased motor activity but decreased O 2 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.

On the mechanism of central action of amphetamine: The role of catecholamines

The effects of amphetamine were studied on the spontaneous motor activity and other behaviour in aggregated mice using a modified jiggle cage. Amphetamine alone (2.5, 7.5 and 10 mg/kg) produced a fairly dose-dependent increase in spontaneous motor activity, excitatory behaviours and mortality. The effects were almost totally abolished after pretreatment with α-methyl tyrosine (α-MT) but could be restored temporarily by l-DOPA-treatment preceding amphetamine. Multiple-dose pretreatments with reserpine and α-methyl-meta-tyrosine (α-MMT), singly or in combination, somewhat reduced but did not abolish the effects of amphetamine (at 8 hr) and invariably augmented these at longer intervals (16 hr), especially after combined pretreatments. Adrenergic blockers were used to block these augmented amphetamine effects. Chlorpromazine totally suppressed all amphetamine effects, whereas phenoxybenzamine blocked the hyperexcitability, aggressiveness and mortality but not the spontaneous motor activity-effects significantly. These results are discussed with relevance to the possible roles of noradrenaline and dopamine in mediating amphetamine-induced behaviour as observed in these experiments designed for depletion, repletion and blockade of endogenous catecholamines.

The spontaneous motility of rats after intraventricular injection of dopamine

The effects of dopamine administered intraventricularly in various doses (5–100 μg) on the spontaneous motility of rats were tested. The effects of dopamine were dosedependent: doses of 5–10 μg dopamine caused a small but statistically significant ( P< 0.05) increase in spontaneous motor activity 20–30 min after intra ventricular administration. Greater doses of dopamine (50–100 μg) produced initially (for 20 min) a decrease in the rat's motility with stuporous signs and assymetric body posture. During the next 20–60 min after injections of greater doses of dopamine there was an increase in the number of motions observed. Biochemical determinations showed that after the administration of 10μg dopamine to whole rat brain tissue no alterations in the levels of dopamine and noradrenaline occurred. After injection of 50 μg dopamine, a statistically significant rise in the dopamine level was found. Sixty minutes after injection of this dose the level of noradrenaline was also increased.

Effect of caffeine on spontaneous motor activity in mice

Caffeine was examined for influence upon the spontaneous motor activity in isolatedmice in relation to its doping effect by means of an electronic activity level counter(Natsume Seisakusho Co., Ltd.)") (Fig. l).The subjects used had been chosen at randoxn from among 8-week-old male miceweighing 20 to 31 g (80% variance of body weight; this range was estimated from anexperiment with 724 male mice.) of a closed colony of the ddY-F strain. Individual micewere used twice, or at 8 and 9 weeks of age, as control and test animals, respectively.Based upon the LD in isolated mice estimated prior to the experiment, caffeine50was given subcutaneously at single doses of l mg/kg (l /256 of LD..), 2, 4, 8, 16, 32, 64, 129, and l93mg/kg (3/4 of LD, .) in the form of caffeine and sodium benzoate whichcontained 9.48 or 9.90% of caffeine. Solutions of the same concentrations of sodiumbenzoate as those of the drug solutions served as controls.Measurements were made on five isolated mice for each dose. The spontaneousmotor activity was recorded for 30 minutes after a mouse had been first placed in themeasure cage without lll} treatment. Subsequently, the mouse was replaced in this cageafter having been removed for subcutaneous injection with the control or test drug.Then the spontaneous motor activity was recorded for 3 luours (room temperature:23.2+l.OC; humidity: 46.0-Hl0.4%). Behavior was also observed during the period ofrecording. The results obtained are summarized as follows.l. The LD.. of caffeine in isolated mice (8 weeks of age) calculated by Finneysgraphic approximate methods) was 257 mg/l<g by the subcutaneous route, and its 95%confidence lirait ranged from 247 to 267 mg/kg (Fig. 3).2. An appreciable increase occurred in spontaneous motor activity at as srnall adose as l mg/kg and a peak activity appeared within l hour after administration witha dose of over 2 mg/kg of caffeine. There was a progressive increase in spontaneous motoractivity with arz irncrease in dose of caffeine up to 16 mg/kg. The highest activity These results lend a positive pharmacological support to the marked doping effectof caffeine5). Furthermore, it was demonstrated that the "load cell for the strain gaugesystem" was useful for finding out qualitative changes in the spontaneous motility.

Effects of substantia nigra lesions on the locomotor and stereotypy responses to amphetamine.

IT is usually supposed that amphetamine produces behavioural effects which include an increase of spontaneous motor activity and the elicitation of stereotyped behaviours1, by causing a release of endogenous catecholamines in the central nervous system2. This view is, for example, supported by the observation that amphetamine can release the catecholamines noradrenaline (NA) and dopamine (DA) from the central nervous system in vitro2 and in vivo3, 4, and that inhibition of catecholamine biosynthesis blocks the amphetamine effect5. Anatomical studies of the distribution of neurones containing catecholamine however, raise, questions about the general applicability of this hypothesis6.

Studies on behavioral and biochemical changes in rats after lesion of midbrain raphé

Lesions of the midbrain raphé in rats produced a marked decrease of 5-HT and 5-HIAA levels in the forebrain. An increase of spontaneous motor activity and an onset of signs of abnormal behaviour were observed. A good correlation has been found between the intensity of behavioural excitation and the decrease of 5-HT and 5-HIAA in the forebrain. Bioelectrical investigations of frontal cortical activity showed a persistent arousal in EEG pattern.

PHARMACOLOGY OF PEMOLINE

Pemoline (5-phenyl-2-imino-4-oxo oxazolidine) produced an increase in spontaneous motor activity of a co-ordinated type in mice. It was observed to prevent and to reverse reserpine-induced motor depression in a manner analogous to that of d-amphetamine. The order of activity as a motor stimulant fell between that of d-amphetamine and caffeine but had a slower onset of action. At low doses, pemoline potentiated the loss of righting reflex induced by hexobarbital and ethanol but it antagonized these agents at high doses. Pemoline antagonized nicotine-induced clonic convulsions in mice. Like amphetamine it produced an increase in urine output and sodium and potassium excretion in the male guinea pig.

PHARMACOLOGY OF PEMOLINE

Pemoline (5-phenyl-2-imino-4-oxo oxazolidine) produced an increase in spontaneous motor activity of a co-ordinated type in mice. It was observed to prevent and to reverse reserpine-induced motor depression in a manner analogous to that of d-amphetamine. The order of activity as a motor stimulant fell between that of d-amphetamine and caffeine but had a slower onset of action. At low doses, pemoline potentiated the loss of righting reflex induced by hexobarbital and ethanol but it antagonized these agents at high doses. Pemoline antagonized nicotine-induced clonic convulsions in mice. Like amphetamine it produced an increase in urine output and sodium and potassium excretion in the male guinea pig.