Control Of Locomotor Activity Research Articles

Bimodal oscillations of cyclic nucleotide concentrations in the circadian system of the Madeira cockroach Rhyparobia maderae.

Pigment-dispersing factor (PDF) is the most important coupling factor of the circadian system in insects, comparable to its functional ortholog vasoactive intestinal polypeptide of the mammalian circadian clock. In Drosophila melanogaster, PDF signals via activation of adenylyl cyclases, controlling circadian locomotor activity rhythms at dusk and dawn. In addition, PDF mediates circadian rhythms of the visual system and is involved in entrainment to different photoperiods. We examined whether PDF daytime-dependently elevates cAMP levels in the Madeira cockroach Rhyparobia maderae and whether cAMP mimics PDF effects on locomotor activity rhythms. To determine time windows of PDF release, we searched for circadian rhythms in concentrations of cAMP and its functional opponent cGMP in the accessory medulla (AMe), the insect circadian pacemaker controlling locomotor activity rhythms, and in the optic lobes, as the major input and output area of the circadian clock. Enzyme-linked immunosorbent assays detected PDF-dependent increases of cAMP in optic lobes and daytime-dependent oscillations of cAMP and cGMP baseline levels in the AMe, both with maxima at dusk and dawn. Although these rhythms disappeared at the first day in constant conditions (DD1), cAMP but not cGMP oscillations returned at the second day in constant conditions (DD2). Whereas in light-dark cycles the cAMP baseline level remained constant in other optic lobe neuropils, it oscillated in phase with the AMe at DD2. To determine whether cAMP and cGMP mimic PDF-dependent control of locomotor activity rhythms, both cyclic nucleotides were injected at different times of the circadian day using running-wheel assays. Whereas cAMP injections generated delays at dusk and advances at dawn, cGMP only delayed locomotor activity at dusk. For the first time we found PDF-dependent phase advances at dawn in addition to previously described phase delays at dusk. Thus, we hypothesize that PDF release at dusk and dawn controls locomotor activity rhythms and visual system processing cAMP-dependently.

Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21.

The liver is a key metabolic organ that controls whole-body physiology in response to nutrient availability. Mammalian target of rapamycin (mTOR) is a nutrient-activated kinase and central controller of growth and metabolism that is negatively regulated by the tumor suppressor tuberous sclerosis complex 1 (TSC1). To investigate the role of hepatic mTOR complex 1 (mTORC1) in whole-body physiology, we generated liver-specific Tsc1 (L-Tsc1 KO) knockout mice. L-Tsc1 KO mice displayed reduced locomotor activity, body temperature, and hepatic triglyceride content in a rapamycin-sensitive manner. Ectopic activation of mTORC1 also caused depletion of hepatic and plasma glutamine, leading to peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-dependent fibroblast growth factor 21 (FGF21) expression in the liver. Injection of glutamine or knockdown of PGC-1α or FGF21 in the liver suppressed the behavioral and metabolic defects due to mTORC1 activation. Thus, mTORC1 in the liver controls whole-body physiology through PGC-1α and FGF21. Finally, mTORC1 signaling correlated with FGF21 expression in human liver tumors, suggesting that treatment of glutamine-addicted cancers with mTOR inhibitors might have beneficial effects at both the tumor and whole-body level.

Candidates for the light entrainment pathway to the circadian clock of the Madeira cockroach Rhyparobia maderae

The circadian pacemaker controlling locomotor activity rhythms in the Madeira cockroach is located at the accessory medulla (AMe). The ipsi- and contralateral compound eyes provide light input to the AMe, possibly via the γ-aminobutyric acid (GABA)-immunoreactive (-ir) distal tract, which connects the glomeruli of the AMe to the ipsilateral medulla and lamina. To identify possible light-entrainment pathways, double-label immunocytochemistry was performed employing antibodies against GABA, myoinhibitory peptide (MIP), allatotropin (AT) and orcokinin (ORC). While all antisera tested, except the anti-ORC, prominently stained the glomeruli of the AMe, colocalization with anti-GABA was detected neither in the glomeruli nor in the distal tract. However, one median neuron that colocalized GABA-, AT- and MIP-immunoreactivity appeared to connect all glomeruli of the AMe to the medulla and lamina. Furthermore, one distal-frontoventral local neuron with arborizations in all glomeruli of the AMe colocalized anti-AT- and anti-MIP immunoreactivity. As candidates for contralateral light entrainment pathways, one ventromedian and one ventral neuron colocalized MIP- and ORC immunoreactivity, projecting via posterior and anterior commissures. Both branched in the interglomerular region of the AMe, where arborizations co-labeled with anti-ORC- and anti-MIP antisera. A possible role for MIP in light entrainment is supported also by injections of Rhyparobia maderae-specific MIP-2, which generated an all-advance phase-response curve late at night. Future experiments will challenge our hypothesis that GABA-, MIP- and AT-ir neurons provide ipsilateral light entrainment to all glomeruli, while MIP- and ORC-ir neurons carry contralateral light entrainment to the AMe's interglomerular region, either delaying or advancing AMe neurons light-dependently.

Hippocampal lipoprotein lipase regulates energy balance in rodents

Brain lipid sensing is necessary to regulate energy balance. Lipoprotein lipase (LPL) may play a role in this process. We tested if hippocampal LPL regulated energy homeostasis in rodents by specifically attenuating LPL activity in the hippocampus of rats and mice, either by infusing a pharmacological inhibitor (tyloxapol), or using a genetic approach (adeno-associated virus expressing Cre-GFP injected into Lpl (lox/lox) mice). Decreased LPL activity by either method led to increased body weight gain due to decreased locomotor activity and energy expenditure, concomitant with increased parasympathetic tone (unchanged food intake). Decreased LPL activity in both models was associated with increased de novo ceramide synthesis and neurogenesis in the hippocampus, while intrahippocampal infusion of de novo ceramide synthesis inhibitor myriocin completely prevented body weight gain. We conclude that hippocampal lipid sensing might represent a core mechanism for energy homeostasis regulation through de novo ceramide synthesis.

Protein kinase G linked to dopamine D3 receptors in the dorsal striatum controls dopamine release, ΔFosB expression and locomotor activity after repeated cocaine administration

Protein kinase G (PKG) has been implicated in a variety of physiological functions including synaptic plasticity in the brain. This study investigated the involvement of dopamine D3 (D3) receptors in PKG-regulated dopamine release, long-term changes in gene expression and behavioral sensitization after repeated cocaine administration. Repeated systemic injections of cocaine (20mg/kg), once a day for seven consecutive days, increased extracellular dopamine concentrations in the dorsal striatum. Inhibition of neuronal nitric oxide synthase, cGMP or PKG, stimulation of D3 receptors, and simultaneous inhibition of each of them with D3 receptor stimulation decreased the repeated cocaine-induced increase in dopamine concentrations and locomotor activity. Similarly, inhibition of PKG and simultaneous inhibition of PKG with D3 receptor stimulation decreased ΔFosB immunoreactivity elevated by repeated cocaine administration, however stimulation of D3 receptors alone did not. These findings suggest that activation of PKG after repeated cocaine administration is more sensitive to interact with D3 receptors in the dopamine terminals than those in medium spiny neurons. This interaction may result in the development of behavioral sensitization by the upregulation of dopamine releases in the dorsal striatum.

Ritmos biológicos e fotoperíodo em peixes

Os ritmos biológicos são definidos como qualquer evento que se repete de maneira regular em um organismo, sendo um evento cíclico caracterizado por um ambiente do qual o animal pode se adaptar. Os peixes, quando submetidos ao ciclo diário de luz/escuro do fotoperíodo demonstram um padrão de atividade locomotora que os podem classificar como diurnos, noturnos e crepusculares. Este ciclo de luz/escuro tem sido considerado um dos mais importantes fatores ambientais sincronizadores do ritmo biológico, sendo o fator chave para sincronização do ritmo de atividade em peixes. O ciclo alimentar também atua como um potente sincronizador sobre o controle da atividade locomotora. Este é demonstrado através da atividade alimentar antecipatória como ritmo biológico, isto é, a capacidade em que os peixes conseguem prever com habilidade e antecipar um recorrente evento que é a alimentação. Estas respostas antecipatórias à alimentação provavelmente funcionam sob um controle endógeno, onde os peixes precisam otimizar a captura do alimento, assim como os processos digestivos e metabólicos, para poder concentrar a ingestão de alimento em um menor intervalo de tempo, melhorando, portanto, a utilização dos nutrientes. O controle do relógio biológico em peixes é considerado como um multifotorreceptor e sistema multioscilador. A existência de um oscilador circadiano tem sido sugerida através da pineal, retina e o cérebro, estando estas estruturas envolvidas na transdução do sinal fótico para estabelecer um rítmo circadiano em peixes. O acoplamento entre essas estruturas pode variar em cada indivíduo de acordo com as condições fisiológicas e ambientais, resultando em uma plasticidade no sistema circadiano de peixes teleósteos. A manipulação do fotoperíodo com objetivo de aprimorar o crescimento dos peixes tem se tornado cada vez mais frequente dentro da produção de várias espécies de interesse comercial. O fotoperíodo, dentre outros fatores ambientais, é o que apresenta maior influência sobre o relógio biológico dos peixes ao afetar o ganho de peso, a ingestão de alimento, a eficiência alimentar, o gasto de energia, a atividade locomotora, a reprodução, bem como outros parâmetros fisiológicos relacionados ao estresse. Portanto, o controle e o conhecimento fisiológico deste ritmo biológico torna-se fundamental para otimização da produção de peixes.

The evolution and comparative neurobiology of endocannabinoid signalling.

CB(1)- and CB(2)-type cannabinoid receptors mediate effects of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide in mammals. In canonical endocannabinoid-mediated synaptic plasticity, 2-AG is generated postsynaptically by diacylglycerol lipase alpha and acts via presynaptic CB(1)-type cannabinoid receptors to inhibit neurotransmitter release. Electrophysiological studies on lampreys indicate that this retrograde signalling mechanism occurs throughout the vertebrates, whereas system-level studies point to conserved roles for endocannabinoid signalling in neural mechanisms of learning and control of locomotor activity and feeding. CB(1)/CB(2)-type receptors originated in a common ancestor of extant chordates, and in the sea squirt Ciona intestinalis a CB(1)/CB(2)-type receptor is targeted to axons, indicative of an ancient role for cannabinoid receptors as axonal regulators of neuronal signalling. Although CB(1)/CB(2)-type receptors are unique to chordates, enzymes involved in biosynthesis/inactivation of endocannabinoids occur throughout the animal kingdom. Accordingly, non-CB(1)/CB(2)-mediated mechanisms of endocannabinoid signalling have been postulated. For example, there is evidence that 2-AG mediates retrograde signalling at synapses in the nervous system of the leech Hirudo medicinalis by activating presynaptic transient receptor potential vanilloid-type ion channels. Thus, postsynaptic synthesis of 2-AG or anandamide may be a phylogenetically widespread phenomenon, and a variety of proteins may have evolved as presynaptic (or postsynaptic) receptors for endocannabinoids.

Otx2 selectively controls the neurogenesis of specific neuronal subtypes of the ventral tegmental area and compensates En1-dependent neuronal loss and MPTP vulnerability

Understanding the molecular basis underlying the neurogenesis of mesencephalic–diencephalic Dopaminergic (mdDA) neurons is a major task fueled by their relevance in controlling locomotor activity and emotion and their involvement in neurodegenerative and psychiatric diseases. Increasing evidence suggests that mdDA neurons of the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) represent two main distinct neuronal populations, which, in turn, include specific neuronal subsets. Relevant studies provided important results on mdDA neurogenesis, but, nevertheless, have not yet clarified how the identity of mdDA neuronal subtypes is established and, in particular, whether neurogenic factors may direct progenitors towards the differentiation of specific mdDA neuronal subclasses. The transcription factor Otx2 is required for the neurogenesis of mesencephalic DA (mesDA) neurons and to control neuron subtype identity and sensitivity to the MPTP neurotoxin in the adult VTA. Here we studied whether Otx2 is required in mdDA progenitors for the generation of specific mdDA neuronal subtypes. We found that although expressed in virtually all mdDA progenitors, Otx2 is required selectively for the differentiation of VTA neuronal subtypes expressing Ahd2 and/or Calb but not for those co-expressing Girk2 and glyco-Dat. Moreover, mild over-expression of Otx2 in SNpc progenitors and neurons is sufficient to rescue En1 haploinsufficiency-dependent defects, such as progressive loss and increased MPTP sensitivity of SNpc neurons. Collectively, these data suggest that mdDA progenitors exhibit differential sensitivity to Otx2, which selectively influences the generation of a large and specific subset of VTA neurons. In addition, these data suggest that Otx2 and En1 may share similar properties and control survival and vulnerability to MPTP neurotoxin respectively in VTA and SNpc.

The effects of lighting conditions and food restriction paradigms on locomotor activity of common spiny mice, Acomys cahirinus.

BackgroundAn endogenous circadian clock controls locomotor activity in common spiny mice (Acomys cahirinus). However, little is known about the effects of constant light (LL) on this activity or about the existence of an additional food entrainable clock. A series of experiments were performed to investigate the effects of LL and DD on tau and activity levels.MethodsSpiny mice were housed individually and their running wheel activity monitored. One group of mice was exposed to LD, DD and several intensities of LL. Another group was exposed to a restricted feeding (RF) paradigm in light: dark (LD) during one hour before the L to D transition. Significance of rhythmicity was assessed using Lomb-Scargle periodograms.ResultsIn LD all animals exhibited nocturnal activity rhythms that persisted in DD. When animals were exposed to RF (during L), all of these animals (n = 11) demonstrated significant food anticipatory activity as well as an increase in diurnal activity. This increase in diurnal activity persisted in 4/11 animals during subsequent ad libitum conditions. Under LL conditions, the locomotor rhythms of 2/11 animals appeared to entrain to RF. When animals were exposed to sequentially increasing LL intensities, rhythmicity persisted and, while activity decreased significantly, the free-running period was relatively unaffected. In addition, the period in LL was significantly longer than the period in DD. Exposure to LL also induced long-term changes (after-effects) on period and activity when animals were again exposed to DD.ConclusionsOverall these studies demonstrate clear and robust circadian rhythms of wheel-running in A. cahirinus. In addition, LL clearly inhibited activity in this species and induced after-effects. The results also confirm the presence of a food entrainable oscillator in this species.

The ADHD-linked gene Lphn3.1 controls locomotor activity and impulsivity in zebrafish

The cover illustrates the expression pattern of the latrophilin3.1 (lphn3.1) gene in the brain of the 24-h, 48-h and 6-day-old zebrafish (central panel, dorsal views, anterior left, expression visualized in purple and black) and the behavioral effects resulting from downregulating lphn3.1 activity: top panels are traces of the swimming path of lphn3.1-invalidated (left) and wild-type control (right) zebrafish larvae at 6 days, illustrating the hyperlocomotion of manipulated animals; the bottom panel plots the swimming speed of a lphn3.1-invalidated larva over time, highlighting swimming bursts. For more information on this topic, please refer to the article by Lange et al. on pages 946–954.

Effects of leptin treatment and Western diet on wheel running in selectively bred high runner mice

The role of leptin in regulating physical activity is varied. The behavioral effects of leptin signaling depend on the type of activity and the animal's physiological state. We used mice from lines selectively bred for high voluntary wheel running to further study how leptin regulates volitional exercise. Mice from four replicate high runner (HR) lines typically run ~3-fold more revolutions per day than those from four non-selected control (C) lines. HR mice have altered dopamine function and differences from C in brain regions known to be important in leptin-mediated behavior. Furthermore, male HR mice have been found to dramatically increase running when administered Western diet, an effect possibly mediated through leptin signaling. Male mice from generation 61 (representing three HR lines and one C line) were allowed wheel access at 24days of age and given either Western diet (high in fat and with added sucrose) or standard chow. After four weeks, Western diet significantly increased circulating leptin, insulin, C-peptide, gastric inhibitory polypeptide, and inflammatory hormone resistin concentrations in HR mice (C mice not measured). Western diet increased running in HR mice, but did not significantly affect running in C mice. During the fifth week, all mice received two days of intra-peritoneal sham injections (physiological saline) followed by three days of murine recombinant leptin injections, and then another six days of sham injections. Leptin treatment significantly decreased caloric intake (adjusted for body mass) and body mass in all groups. Wheel running significantly increased with leptin injections in HR mice (fed Western or standard diet), but was unaffected in C mice. Whether Western diet and leptin treatment stimulate wheel running in HR mice through the same physiological pathways awaits future study. These results have implications for understanding the neural and endocrine systems that control locomotor activity, food consumption, and body weight, and how they may vary with genetic background.

The effect of light on melatonin secretion in the cultured pineal glands of Anolis lizards

Melatonin, a hormone produced by the pineal gland, is important for regulating circadian rhythms in many animals. Light at night causes an acute suppression of melatonin in nearly all vertebrate species. A previous study found that light failed to suppress melatonin in the lizard Anolis carolinensis. This is a surprising result given that the Anolis pineal gland is intrinsically photosensitive, is a key pacemaker controlling locomotor activity, and can be directly entrained to a light–dark cycle. To find out if the lack of photic suppression is widespread in the Anolis genus, we investigated the acute effects of light on melatonin secretion in five different species of Anolis using flow-through tissue culture. We administered a two-hour pulse of bright light to isolated pineal glands during the night. The results show photic suppression of melatonin in all five Anolis species, but the suppression is weak relative to that seen in other vertebrates. Moreover, Anolis species differ in the magnitude of the effect. These findings are discussed in the context of vertebrate pineal evolution and the ecology of Anolis lizards. Given their extensive phylogenetic and ecological divergence, Anolis lizards provide a promising system for investigating the ecology and evolution of circadian organization.

Effect of the N-methyl- d-aspartate receptor antagonist on locomotor activity and cholecystokinin-induced anorexigenic action in a goldfish model

We have previously identified that peripherally administered cholecystokinin (CCK) exerts an anorexigenic action via the vagal afferent, and subsequently the brain melanocortin- and corticotropin-releasing hormone-neuronal pathways in goldfish. N-Methyl- d-aspartate (NMDA) receptors have been shown to be involved in the regulations of locomotor activity and food intake in mammals. Although several neuropeptides and other factors exert similar effects in fish and mammals, the role of NMDA receptor in the control of locomotor activity and feeding behavior in fish is still unclear. In the present study, we examined the effect of the NMDA receptor antagonist, MK-801, on locomotor activity and food intake in the goldfish. Intraperitoneal (IP) injection of MK-801 at 0.15 nmol/g body weight (BW) increased locomotor activity, but did not affect food consumption. IP injection of MK-801 at same dose attenuated peripheral CCK (100 pmol/g BW)-induced anorexigenic, but not peripheral acyl ghrelin (10 pmol/g BW)-induced orexigenic actions. These data show for the first time that the NMDA receptor-signaling pathway is involved in the regulation of locomotor activity and feeding behavior through modulation of the peripheral CCK-induced satiety signal, but not the orexigenic effect of ghrelin.

Otx2 controls neuron subtype identity in ventral tegmental area and antagonizes vulnerability to MPTP

Mesencephalic-diencephalic dopaminergic neurons control locomotor activity and emotion and are affected in neurodegenerative and psychiatric diseases. The homeoprotein Otx2 is restricted to ventral tegmental area (VTA) neurons that are prevalently complementary to those expressing Girk2 and glycosylated active form of the dopamine transporter (Dat). High levels of glycosylated Dat mark neurons with efficient dopamine uptake and pronounced vulnerability to Parkinsonian degeneration. We found that Otx2 controls neuron subtype identity by antagonizing molecular and functional features of dorsal-lateral VTA, such as Girk2 and Dat expression. Otx2 limited the number of VTA neurons with efficient dopamine uptake and conferred resistance to the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-HCl (MPTP) neurotoxin. Ectopic Otx2 expression also provided neurons of the substantia nigra with efficient neuroprotection to MPTP. These findings indicate that Otx2 is required to specify neuron subtype identity in VTA and may antagonize vulnerability to the Parkinsonian toxin MPTP.

The investigation of locomotor activity control system in humans under the air-stepping conditions during passive and voluntary leg movements

The degree of activation of the central stepping program during passive leg movement was studied in healthy subjects under unloading conditions; the excitability of spinal motoneurons was studied during passive and voluntary stepping movements. Passive stepping movements with characteristics maximally close to those during voluntary stepping were accomplished by the experimenter. The bursts of muscular activity during voluntary and imposed stepping movements were compared. In addition, the influence on the leg movement of artificially created loading onto the foot was studied. The excitability of spinal motoneurons was estimated by the amplitude of modulation of the m. soleus H reflex. Changes in the H reflex (Hoffmann’s reflex) after fixation of the knee and hip joints were also studied. In most subjects, passive movements were accompanied by bursts of electromyographic (EMG) activity in the hip muscles (sometimes in shank muscles); the timing of the EMG burst during the step cycle coincided with the burst’s timing during voluntary stepping. In many cases, the bursts in EMG activity exceeded the activity of homonymous muscles during voluntary stepping. Simulation of foot loading influenced significantly the distal part of the moving extremity during both voluntary and passive movements, which was expressed in the appearance of movements in the ankle joint and an increase in the phasic EMG activity of the shank muscles. The excitability of motoneurons during passive movements was higher than during voluntary movements. Changes and modulation of the H reflex throughout the step cycle were similar without restriction of joint mobility and without hip joint mobility. Fixation of the knee joint was of great importance. It is supposed that imposed movements activate the same mechanisms of rhythm generation as supraspinal commands during voluntary movements. During passive movements, presynaptic inhibition depends mostly on the afferent influences from the moving leg rather than on the central commands. Under the conditions of “air-stepping,” the afferent influences from the foot pressure receptors are likely to interact actively with the central program of stepping and to determine the final activity pattern irrespective of the movement type (voluntary or passive).

Implementation of pigment‐dispersing factor‐immunoreactive neurons in a standardized atlas of the brain of the cockroach Leucophaea maderae

The cockroach Leucophaea maderae is an established model in circadian rhythm research. Its circadian clock is located in the accessory medulla of the brain. Pigment-dispersing factor-immunoreactive (PDF-ir) neurons of the accessory medulla act as circadian pacemakers controlling locomotor activity rhythms. To characterize the neuronal network of the circadian system in L. maderae, the PDF-ir neurons were implemented into a standardized three-dimensional atlas of the cockroach brain. Serial confocal images from 20 wholemount brains were used for the construction of the atlas comprising 21 neuropils. Two different standardization protocols were employed: the iterative shape averaging (ISA) procedure using an affine transformation followed by iterative non-rigid registrations, and the virtual insect brain (VIB) protocol employing local non-rigid transformations after global and local rigid transformations. Quantitative analysis of the 20 brains revealed that volumes of the accessory medulla are directly correlated with the volumes of the medulla, the protocerebral bridge, and the upper division of the central body, suggesting functional connections among these neuropils. For a standardized reconstruction of the circadian pacemaker network, the ISA protocol was used to register PDF-ir neurons in the standard cockroach brain. The registration revealed that two PDF-ir arborization areas in the brain are highly interconnected with other PDF-ir projection sites and appear to be contacted both by fibers in the posterior and the anterior optic commissures. The distances between PDF-ir branching areas show specific numerical relationships that might be physiologically relevant for temporal encoding.

Neuropeptides in theDrosophilacentral complex in modulation of locomotor behavior

The central complex is one of the most prominent neuropils in the insect brain. It has been implicated in the control of locomotor activity and is considered as a pre-motor center. Several neuropeptides are expressed in circuits of the central complex, and thus may be modulators of locomotor behavior. Here we have investigated the roles of two different neuropeptides, Drosophila tachykinin (DTK) and short neuropeptide F (sNPF), in aspects of locomotor behavior. In the Drosophila brain, DTK and sNPF are expressed in interneurons innervating the central complex. We have directed RNA interference (RNAi) towards DTK and sNPF specifically in different central complex neurons. We also expressed a temperature-sensitive dominant negative allele of the fly ortholog of dynamin called shibire(ts1), essential in membrane vesicle recycling and endocytosis, to disrupt synaptic transmission in central complex neurons. The spontaneous walking activity of the RNAi- or shibire(ts1)-expressing flies was quantified by video tracking. DTK-deficient flies displayed drastically increased center zone avoidance, suggesting that DTK is involved in the regulation of spatial orientation. In addition, DTK deficiency in other central complex neurons resulted in flies with an increased number of activity-rest bouts. Perturbations in the sNPF circuit indicated that this peptide is involved in the fine regulation of locomotor activity levels. Our findings suggest that the contribution of DTK and sNPF to locomotor behavior is circuit dependent and associated with particular neuronal substrates. Thus, peptidergic pathways in the central complex have specific roles in the fine tuning of locomotor activity of adult Drosophila.

Food-entrainable oscillator controls feeding and locomotor activity rhythms in the Japanese catfish, Plototus japonicus

Food-entrainable oscillator controls feeding and locomotor activity rhythms in the Japanese catfish, Plototus japonicus

Differential role of mu, delta and kappa opioid receptors in ethanol-mediated locomotor activation and ethanol intake in preweanling rats

The opioid system modulates ethanol intake and reinforcement in adult and preweanling rodents. While adult heterogeneous rats normally do not show ethanol-mediated locomotor stimulation, preweanling rats show it quite clearly. We recently observed that naloxone, a non-specific opioid antagonist, attenuated ethanol-induced locomotor activation in preweanling rats. In the present study we tested the role of specific opioid receptors (mu, delta and kappa) in ethanol-mediated locomotor stimulation and ethanol intake. In Experiment 1 13-day-old rats received naloxonazine (mu antagonist: 0, 7.5 or 15 mg/kg), naltrindole (delta antagonist: 0, 2 or 4 mg/kg) or nor-binaltorphimine (kappa antagonist: 0, 2, 4 or 8 mg/kg) before an intragastric administration of ethanol (0 or 2.5 g/kg), and subsequent locomotor activity assessment. In Experiment 2, the same opioid antagonists were administered on postnatal days 13 and 14 before consumption of ethanol (6%), saccharin (0.05%) or distilled water. In Experiment 1 only naloxonazine reduced ethanol-mediated locomotor stimulation. None of the opioid antagonists affected locomotor activity in water controls. In Experiment 2 naloxonazine and naltrindole suppressed ingestion of all the solutions tested. Similar to what has been reported in adult rodents, mu-opioid receptors seem to modulate ethanol-activating effects during early ontogeny. Hence, there seems to be a partial overlap of neurochemical mechanisms involved in the rewarding and stimulating effects of ethanol in preweanling rats. Mu-receptor antagonists reduced both ethanol-induced activity and ethanol intake, but it is unclear whether the latter effect is specific to ethanol or only a reflection of an effect on consummatory behavior generally, since mu and delta receptor antagonists also suppressed ingestion of water and sacccharin.

Identification of Surrogate Agonists and Antagonists for Orphan G-Protein-Coupled Receptor GPR139

GPR139 is an orphan G-protein-coupled receptor (GPCR) that is expressed nearly exclusively in the central nervous system and may play a role in the control of locomotor activity. The signal transduction pathway and pharmacological function of GPR139, however, are still controversial due to the lack of natural or synthetic ligands. The authors report the characterization of human GPR139 signaling pathway and identification of surrogate agonists and antagonists. In both transient and stable transfections of HEK293F cells, overexpression of GPR139 increased basal intracellular cAMP concentrations compared to control cells. Furthermore, forskolin and isoproterenol-stimulated cAMP responses were enhanced in GPR139-expressing cells, suggesting that GPR139 is predominantly coupled to Galpha(s). The authors screened a large library of small molecules for compounds that increase cAMP levels in GPR139-expressing cells and identified a compound with GPR139 agonist activity. This compound increased cAMP production specifically in cells expressing GPR139 but not in cells expressing its highly homologous receptor GPR142. Furthermore, this compound did not induce calcium mobilization in GPR139 cells, indicating no Galpha(q)-mediated response. In addition, antagonist screening with the identified agonist yielded 2 classes of compounds as antagonists. The identification of surrogate agonists and antagonists of human GPR139 provides important tools for further study of this orphan GPCR.