Stimulation Of Locomotor Activity Research Articles

Reduced anticipatory locomotor responses to scheduled meals in ghrelin receptor deficient mice

Ghrelin, an orexigenic hormone produced by the stomach, is secreted in anticipation of scheduled meals and in correlation with anticipatory locomotor activity. We hypothesized that ghrelin is directly implicated in stimulating locomotor activity in anticipation of scheduled meals. To test this hypothesis, we observed 24 h patterns of locomotor activity in mice with targeted mutations of the ghrelin receptor gene (GHSR KO) and wild-type littermates, all given access to food for 4 h daily for 14 days. While wild type (WT) and GHSR KO mice produced increases in anticipatory locomotor activity, anticipatory locomotor activity in GHSR KO mice was attenuated ( P<0.05). These behavioral measures correlated with attenuated levels of Fos immunoreactivity in a number of hypothalamic nuclei from GHSR KO placed on the same restricted feeding schedule for 7 days and sacrificed at ZT4. Interestingly, seven daily i.p. ghrelin injections mimicked hypothalamic Fos expression patterns to those seen in mice under restricted feeding schedules. These data suggest that ghrelin acts in the hypothalamus to augment locomotor activity in anticipation of scheduled meals.

The Dopamine Uptake Inhibitor 3α-[bis(4′-fluorophenyl)metoxy]-tropane Reduces Cocaine-Induced Early-Gene Expression, Locomotor Activity, and Conditioned Reward

Benztropine (BZT) analogs, a family of high-affinity dopamine transporter ligands, are molecules that exhibit pharmacological and behavioral characteristics predictive of significant therapeutic potential in cocaine addiction. Here, we examined in mice the effects of 3 alpha-[bis(4'-fluorophenyl)metoxy]-tropane (AHN-1055) on motor activity, conditioned place preference (CPP) and c-Fos expression in the striatum. AHN-1055 produced mild attenuation of spontaneous locomotor activity at a low dose (1 mg/kg) and weak stimulation at a higher dose (10 mg/kg). In parallel, the BZT analog significantly increased c-Fos expression in the dorsolateral caudoputamen at the high dose, whereas producing marginal decreases at low and moderate doses (1, 3 mg/kg) in both dorsal and ventral striatum. Interaction assays showed that cocaine's ability to stimulate locomotor activity was decreased by AHN-1055 treatment, but not by treatment with D-amphetamine. Such reduced ability did not result from an increase in stereotyped behavior. Another dopamine uptake inhibitor, nomifensine, decreased cocaine-induced locomotor activity but evoked by itself intense motor stereotypies. Remarkably, the BZT analog dose-dependently blocked cocaine-induced CPP without producing CPP when given alone, and blocked in conditioned mice cocaine-stimulated early-gene activation in the nucleus accumbens and dorsomedial striatum. These observations provide evidence that AHN-1055 does not behave as a classical psychomotor stimulant and that some of its properties, including attenuation of cocaine-induced striatal c-Fos expression, locomotor stimulation, and CPP, support its candidacy, and that of structurally related molecules, as possible pharmacotherapies in cocaine addiction.

Fluoxetine potentiates the effects of corticotropin-releasing factor on locomotor activity and serotonergic systems in the roughskin newt, Taricha granulosa

The anxiety- and stress-related neuropeptide corticotropin-releasing factor (CRF) elicits behavioral changes in vertebrates including increases in behavioral arousal and locomotor activity. Intracerebroventricular injections of CRF in an amphibian, the roughskin newt (Taricha granulosa), induces rapid increases in locomotor activity in both intact and hypophysectomized animals. We hypothesized that this CRF-induced increase in locomotor activity involves a central effect of CRF on serotonergic neurons, based on known stimulatory actions of serotonin (5-hydroxytryptamine, 5-HT) on spinal motor neurons and the central pattern generator for locomotor activity in vertebrates. In Experiment 1, we found that neither intracerebroventricular injections of low doses of CRF (25 ng) nor the selective serotonin reuptake inhibitor fluoxetine (10, 100 ng), by themselves, altered locomotor activity. In contrast, newts treated concurrently with CRF and fluoxetine responded with marked increases in locomotor activity. In Experiment 2, we found that increases in locomotor activity following co-administration of CRF (25 ng) and fluoxetine (100 ng) were associated with decreased 5-HT concentrations in a number of forebrain structures involved in regulation of emotional behavior and emotional states, including the ventral striatum, amygdala pars lateralis, and dorsal hypothalamus, measured 37 min after treatment. These results are consistent with the hypothesis that CRF stimulates locomotor activity through activation of serotonergic systems.

Simultaneous anhedonia and exaggerated locomotor activation in an animal model of depression

Anhedonia, or hyposensitivity to normally pleasurable stimuli, is a cardinal symptom of depression. As such, reward circuitry may comprise a substrate with relevance to this symptom of depression. Our aim was to characterize in the rat changes in the rewarding properties of a pharmacological and a natural stimulus following olfactory bulbectomy (OBX), a pre-clinical animal model of depression. We measured amphetamine enhancement of brain stimulation reward, changes in sucrose intake, as well as striatal cAMP response element binding protein (CREB) activity, a molecular index previously associated with depressant-like behavior. Moreover, since alteration of psychomotor activity is also a common symptom of depression, and psychostimulant reward and locomotion are thought to share common neurobiology, we used the same treatment schedule of amphetamine to probe for changes in locomotion. Our findings show that OBX produces a behavioral phenotype characterized by both anhedonia and exaggerated locomotor activation. Thus, we observed a blunted response to the rewarding properties of amphetamine (1 mg/kg, 21 days post-lesion), a long-lasting reduction in sucrose intake and increased striatal CREB activity. In addition, the same dose of amphetamine, at a coincident time post-lesion, triggered an exaggerated response to its locomotor-stimulant actions. These paradoxical findings are not consistent with the notion that reward and locomotion are mediated by a common substrate; this dissociation may be useful in modeling psychiatric disorders such as mixed depressive states. In addition, our findings suggest that central reward circuitry may constitute a possible target for rationally designed therapeutics for depression.

Discovery of a novel avian neurosteroid, 7α-hydroxypregnenolone, and its role in the regulation of the diurnal rhythm of locomotor activity in Japanese quail

The discovery of two novel avian neurosteroids in the quail brain, 7α- and 7β-hydroxypregnenolone is described. Intracerebroventricular administration of 7α-hydroxypregnenolone, but not 7β-hydroxypregnenolone was found to stimulate locomotor activity of male quail when spontaneous nocturnal activity is low. Diurnal changes in locomotor activity in male quail were found to be correlated with a diurnal change in the concentration of diencephalic 7α-hydroxypregnenolone. This correlation was a not seen in female quail which have a lower amplitude diurnal rhythm of locomotor activity and lower daytime concentrations of diencephalic 7α-hydroxypregnenolone. Treatment of male quail with melatonin was found to depress the synthesis of 7α-hydroxypregnenolone in the diencephalon. This is a previously undescribed role for melatonin in the regulation of neurosteroid synthesis in the brain of any vertebrate. We therefore deduced in male quail, that the nocturnal depression in locomotory activity is a consequence of a depression in diencephalic 7α-hydroxypregnenolone resulting from the inhibitory action of the nocturnal increase in melatonin. This observation may be of widespread significance for the molecular control of rhythmic locomotor activity in all vertebrates.

Diurnal Changes in the Synthesis of the Neurosteroid 7α‐Hydroxypregnenolone Stimulating Locomotor Activity in Newts

We recently identified 7alpha-hydroxypregnenolone as a novel amphibian neurosteroid stimulating locomotor activity in newts. Because male newts show marked diurnal changes in locomotor activity, we hypothesized that 7alpha-hydroxypregnenolone may be a key factor for the induction of diurnal changes in locomotor activity in male newts. In this study, we found diurnal changes in 7alpha-hydroxypregnenolone synthesis in the brain of male newts, which paralleled locomotor activity. Interestingly, the production of 7alpha-hydroxypregnenolone in the male newt brain increased during the dark phase when locomotor activity of males was high.

Seasonal Changes in the Synthesis of the Neurosteroid 7α‐Hydroxypregnenolone Stimulating Locomotor Activity in Newts

We recently found that the newt brain actively produces 7alpha-hydroxypregnenolone, a novel amphibian neurosteroid stimulating locomotor activity. It is well known that locomotor activity of male newts increases during the breeding period. To understand the physiological role of 7alpha-hydroxypregnenolone, we investigated seasonal changes in 7alpha-hydroxypregnenolone synthesis in the brain of male newts. Interestingly, 7alpha-hydroxypregnenolone synthesis in the brain showed marked changes during the annual breeding cycle, with a maximal level in the breeding period when locomotor activity of male newts increases. These results suggest that 7alpha-hydroxypregnenolone induces seasonal locomotor changes in male newts.

Acute nicotine and phencyclidine increase locomotor activity of the guinea pig

While the behavioral effects of nicotine and phencyclidine have been well characterized in rats and mice, substantially less is known about their effects in guinea pigs. Understanding the pharmacology of these compounds has relevance to both addictive behaviors and psychoses. In some circumstances, human pharmacology may be better represented by guinea pigs than by rats or mice. The goal of this study was to determine the utility of the guinea pig as a model for assessing the behavioral actions of nicotine and phencyclidine, drugs that have locomotor stimulant activity in rat and mouse.Nicotine (1‐3 mg/kg) dose‐dependently increased locomotor activity. The time courses of the responses were also dose‐dependent. Phencyclidine (3‐10 mg/kg) increased locomotor activity with effects that were longer‐lasting than those of nicotine.Both the magnitude and duration of the increased locomotor activity are less than that seen with mouse or rat models under otherwise similar conditions. Additionally, higher doses of nicotine and phencyclidine are required to produce locomotor stimulation in the guinea pig. These data suggest that, in terms of responsiveness to psychomotor stimulants, the guinea pig is a less sensitive model species than rats or mice.

Assessment of the efficacy and side effect profile of morphine and MMP2200, a mixed delta/mu agonist

We have previously reported on the chemistry and preclinical pharmacology of a series of glycosylated enkephalin analogs. These compounds exhibit high affinity/efficacy at delta and mu opioid receptors (DOR and MOR). The current studies present a more detailed characterization of the pharmacology of MMP2200, a lead glycopeptide that incorporates the disaccharide lactose into the peptide structure. MMP2200 produced dose‐related antinociception in the mouse 55°C tail‐flick assay following a variety of routes of administration. The compound was also effective at reversing thermal hyperalgesia (CFA model) and tactile allodynia (plantar incision) in rats. At equi‐antinociceptive doses MMP2200 produced significantly less stimulation of locomotor activity compared to morphine in mice. MMP2200 produced dose‐related inhibition of gastrointestinal transit and respiration similar to that produced by morphine. In summary, MMP2200 acts as a mixed delta/mu agonist in vivo. This profile may account in part for the potent antinociceptive effects seen in several different rodent models of pain, as well as the decreased propensity to produce locomotor stimulation compared to morphine. For other measures (inhibition of GI transit and respiratory depression), the compound may exert too strong an effect on the MOR to differentiate it from morphine.

Identification, Biosynthesis, and Function of 7α‐Hydroxypregnenolone, a New Key Neurosteroid Controlling Locomotor Activity, in Nonmammalian Vertebrates

It is now clearly established that steroids can be synthesized de novo by the brain and the peripheral nervous systems. Such steroids are called neurosteroids, and de novo neurosteroidogenesis from cholesterol is a conserved property of vertebrate brains. Our studies over the past decade have demonstrated that the brain expresses several kinds of steroidogenic enzymes and produces a variety of neurosteroids in submammalian species. However, the biosynthetic pathway of neurosteroids in nonmammalian vertebrates as well as in mammals may be still incompletely mapped out. We recently found that the brain of newts and quail actively produces 7alpha-hydroxypregnenolone, a novel bioactive neurosteroid, from pregnenolone. Interestingly, 7alpha-hydroxypregnenolone stimulates locomotor activity by means of the dopaminergic system. Subsequently, we demonstrated that melatonin regulates synthesis of 7alpha-hydroxypregnenolone, a key factor for induction of locomotor activity, thus inducing diurnal locomotor changes.

The Effects of Methylphenidate on Knockin Mice with a Methylphenidate-Resistant Dopamine Transporter

Methylphenidate (Ritalin) is one of the most commonly abused prescription drugs. It is a psychostimulant that inhibits the dopamine and norepinephrine transporters with high affinity. In mice, methylphenidate stimulates locomotor activity, is self-administered, and produces conditioned place preference, typical properties of an addictive drug. We have generated a knockin mouse line bearing a mutant dopamine transporter that is approximately 80-fold less sensitive to cocaine inhibition than wild type. It is interesting to note that this mutant is also almost 50-fold less sensitive to methylphenidate inhibition, suggesting similarities in the binding site for cocaine and methylphenidate. Because methylphenidate is not effective at inhibiting the mutant dopamine transporter, we hypothesized that it would not stimulate locomotor activity or produce reward in the knockin mice. In these knockin mice, doses up to 40 mg/kg methylphenidate either inhibit or fail to stimulate locomotor activity and do not produce conditioned place preference. Doses up to 40 mg/kg methylphenidate also fail to produce stereotypy in the knockin mice. Nisoxetine and desipramine, selective norepinephrine transporter inhibitors, also reduce locomotor activity in wild-type and knockin mice. These results indicate that enhanced dopaminergic neurotransmission is required for methylphenidate's stimulating and rewarding effects. In addition, we observed that drugs enhancing noradrenergic neurotransmission inhibit locomotor activity in mice, which is consistent with the notion that methylphenidate's ability to inhibit the norepinephrine transporter may contribute to its efficacy in treating attention deficit hyperactivity disorder.

Antidepressant-Like Pharmacological Profile of a Novel Triple Reuptake Inhibitor, (1S,2S)-3-(Methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS)

Due to the putative involvement of dopaminergic circuits in depression, triple reuptake inhibitors are being developed as a new class of antidepressant, which is hypothesized to produce a more rapid onset and better efficacy than current antidepressants selective for serotonin or norepinephrine neurotransmission. (1S,2S)-3-(Methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS), a new triple reuptake inhibitor, potently bound to the human serotonin, norepinephrine, and dopamine transporters with K(d) values of 2.3, 0.63, and 18 nM, respectively. Inhibition of serotonin, norepinephrine, and dopamine uptake by PRC200-SS was also shown in cells expressing the corresponding transporter (K(i) values of 2.1, 1.5, and 61 nM, respectively). In vivo, PRC200-SS dose-dependently decreased immobility in the forced-swim test in rats and in the tail-suspension test in mice, models predictive of antidepressant activity, with effects comparable with imipramine. These results in the behavioral models did not seem to result from the stimulation of locomotor activity. Consistent with the in vitro data and behavioral effects, peripheral administration of PRC200-SS (5 and 10 mg/kg i.p.) significantly increased extracellular levels of serotonin and norepinephrine in the medial prefrontal cortex, and of serotonin and dopamine in the core of nucleus accumbens, with reduction of levels of 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid compared with levels for saline control. Furthermore, PRC200-SS self-administration, which was used as a marker of abuse liability, was not observed with rats. Therefore, it seems that PRC200-SS may represent a novel triple reuptake inhibitor and possess antidepressant activity.

Evidence for a role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine

This experiment was aimed at exploring the role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine. During the induction phase (Days 1, 3, 5 and 7), male Long–Evans adult rats were treated with the neurotensin antagonist SR-48692 (160, 320 or 640 µg/kg, i.p.) or its vehicle, followed by morphine (5.0 mg/kg, i.p.) or its vehicle, and their locomotor activity (ambulatory, non-ambulatory and vertical activity) was measured for 2 h. One week after the last injection, each group received a single injection of morphine (2.5 mg/kg, i.p.) and their locomotor activity was again measured for 2 h (sensitization test, day 14). Results show that SR-48692 alone did not change locomotion. Morphine stimulated locomotor activity, an effect that was stronger on day 7 than on day 1. The two higher doses of SR-48692 attenuated the acute stimulant effect of morphine and prevented the observed increase from day 1 to day 7. The sensitization test on day 14 showed that rats pre-treated with morphine alone displayed significantly stronger ambulatory and vertical activity than vehicle pre-treated rats, a sensitization effect that was attenuated by SR-48692. The present results suggest that endogenous neurotensin contributes to the acute locomotor stimulant effect of morphine and to the induction of its sensitization.

Antidepressant-like effect of peony glycosides in mice

Aim of the study The root part of Paeonia lactiflora Pall. (Ranunculaceae), known as peony, is often used in Chinese herbal formulae for the treatment of depression-like disorders. Previous studies in our laboratory have shown that an ethanol extract of peony produced antidepressive effects in mouse models of depression. It is well known that peony contains glycosides such as paeoniflorin and albiflorin, yet it remains unclear whether the total glycosides of peony (TGP) are effective. The present study aims to evaluate the antidepressant-like effects of TGP. Materials and methods The antidepressant-like effects of TGP was determined by using animal models of depression including forced swim and tail suspension tests. The acting mechanism was explored by determining the effect of TGP on the activities of monoamine oxidases. Results Intragastric administration of TGP at 80 and 160 mg/kg for seven days caused a significant reduction of immobility time in both forced swim and tail suspension tests, yet TGP did not stimulate locomotor activity in the open-field test. In addition, TGP treatment antagonized reserpine-induced ptosis and inhibited the activities of monoamine oxidases in mouse cerebrum. Conclusion These results suggest that the antidepressive effects of TGP are mediated, at least in part, by the inhibition of monoamine oxidases.

Behavioral Actions of Intranasal Application of Dopamine: Effects on Forced Swimming, Elevated Plus-Maze and Open Field Parameters

Background: Recently, we found evidence that intra-nasally administered dopamine (DA), can enter the brain, leading to an immediate increase in extracellular DA levels in striatal subregions. This offers a potential alternative approach to target the brain with exogenous DA, which otherwise cannot cross the blood-brain barrier. Here, we examined whether intra-nasally applied DA also exerts behavioral activity on mesocortical and nigrostriatal dopaminergic functions. Method: Male Wistar rats (3–4 months) were tested for potential behavioral effects of intra-nasally applied DA (0.03, 0.3 or 3.0 mg/kg) in the forced swimming test (FST) for antidepressant-like activity, elevated plus-maze for anxiety-related behavior, and on motor activity in a novel and familiar environment. Results: Intra-nasally administered dopamine in a dose of 0.3 mg/kg exerted antidepressant-like activity in the FST, but had neither anxiolytic-like nor anxiogenic-like effects in the elevated plus-maze. Furthermore, intra-nasal dopamine stimulated locomotor activity in a familiar, but not novel, open field. Conclusions: These results support the view that intra-nasally applied DA can act on the central nervous system by entering the brain via the nose-brain pathway, making this kind of application procedure a promising alternative for targeting the brain, and thus treating disorders involving mesocortical and/or nigrostriatal dopaminergic disturbances.

Altered behavioural and neurochemical profile of l-DOPA following deuterium substitutions in the molecule

In Parkinson's disease patients, a prolonged half-life of dopamine formed from l-DOPA may reduce the risk of developing l-DOPA-induced side-effects. Deuterium substitutions in the l-DOPA molecule are expected to yield dopamine with an altered half-life because C–D bonds are more stable than C–H bonds. Therefore we tested, in the rat, the neurochemical and behavioral effects of different types of l-DOPA with deuterium substitutions at the α-carbon and/or the β-carbon. By means of microdialysis, we found that l-DOPA with 3 deuterium substitutions (D3- l-DOPA) enhanced dopamine output in the striatum more effectively than l-DOPA and all the other deuterium variants. Moreover, D3- l-DOPA produced a more pronounced stimulation of locomotor activity in reserpinized rats compared to conventional l-DOPA. In contrast β,β-D2- l-DOPA was less effective than l-DOPA in raising striatal dopamine levels and was ineffective at restoring locomotor activity in reserpinized rats. These results demonstrate that the introduction of deuterium at different positions in the l-DOPA molecule dramatically changes its behavioral and neurochemical profile and suggest that l-DOPA treatment of Parkinson's disease may be improved in this way.

Effect of &lt;i&gt;catha edulis&lt;/i&gt; (Khat) on behaviour and its potential to induce seizures in sprague dawley rats

Khat is a plant whose young shoots and leaves are habitually used in Eastern Africa and the Arabian Peninsula as a drug of recreation. Although it is used without any control in these regions, it contains two controlled substances, cathinone (schedule I) which is present in fresh khat and cathine (schedule VI) which is a degradation product of cathinone abundant in old khat. To determine the effect of khat on locomotor behaviour and seizures in rats. Experimental study. University of Nairobi. Adult male rats in groups of six were given fresh khat, old khat, methylphenidate and saline at varying doses and observed over three hours. Fresh khat at low doses and old khat at high doses stimulated locomotor activity. High doses of fresh and old khat induced stereotype behaviour and seizures. The results show that khat stimulates locomotor and stereotypic behavioural activity and can induce seizures; results similar to those observed with amphetamine analogs.

Locomotor reactivity to a novel environment and sensitivity to MK-801 in five strains of mice

The ability of a noncompetitive antagonist of the N-methyl-D-aspartate receptor, MK-801, to stimulate locomotor activity (LMA) in mice was compared across CD-1, MF1, NIH Swiss (NIHS), C57BL6/J and BALB/C strains with the aim of identifying the most suitable strain for a putative model of schizophrenia. Animals were habituated to novel LMA cages for 1 h before receiving either saline or MK-801 (0.1, 0.32, or 0.5 mg/kg; i.p.) and activity recorded for 2 h. At the end of the test, blood and brain samples were taken and the total concentrations of MK-801 determined. Mice strains differed in habituation; C57BL6/J mice were the most active, whereas BALB/C mice were the least active and slowest to habituate. Robust strain-dependent differences in sensitivity to MK-801 were found, but not to saline. NIHS, C57BL6/J and BALB/C were more active in response to MK-801, exhibiting more rapid, robust and long-lasting increases in LMA than CD-1 or MF1 mice. Total concentrations of MK-801 in the brain did not differ across the strains. We found no correlation between the LMA stimulated by novelty and MK-801. NIHS, C57BL6/J and BALB/C appeared significantly more sensitive to MK-801 than CD-1 and MF1 and can be strains of choice in evaluating the effect of antipsychotic compounds in this model.

A role for corticosterone and food restriction in the fledging of nestling White storks

Fledging is a critical period in the life of a bird, notably because at this stage under-development and lack of experience in searching for food may impair survival. The behavioral changes that accompany nest departure are therefore expected to be finely tuned to body condition and growth by endocrine processes. This study examines the possible involvement of corticosterone (CORT) in the stimulation of fledging in White storks through measurement of the changes in its plasma levels in relation to growth, nutritional status and the hatching rank of nestlings. For the first time in nest-bound chicks, we show that fledging is preceded by a marked and progressive 4 fold increase in baseline plasma CORT levels concomitant with an increase in locomotor activity (wing flapping) at the nest. Data on changes in body size, body mass, plasma metabolites and feeding frequency support the view that the increase in plasma CORT was induced by food restriction rather than being endogenously programmed. The timing and intensity of plasma CORT increase was dependent on the hatching rank within a brood, this increase being blunted in the less developed chicks possibly to avoid the impairment of final wing growth. These results show that an increase in plasma CORT as a result of food restriction and through the stimulation of locomotor activity is involved in the control of fledging in White storks. Moreover the CORT increase is adjusted to the hatching rank-related growth status of nestlings.

Diurnal changes in the synthesis of 7α-hydroxypregnenolone stimulating locomotor activity in the avian brain

Diurnal changes in the synthesis of 7α-hydroxypregnenolone stimulating locomotor activity in the avian brain