Inhibition Of Motor Activity Research Articles

Why do we sleep?

According to a simple behavioral definition, sleep is a reversible behavioral state of perceptual disengagement from and unresponsiveness to the environment. Sleep is dividing into two states: Non-rapid eye movement (NREM) sleep which is subdivided into three stages (N1, N2, N3); and rapid eye movement (REM) sleep characterized by rapid eye movements, muscle atonia and desynchronized EEG. Mammalian sleep and wake states are regulated by multiple neuronal systems located in the brainstem, diencephalon, and telencephalon. Wakefulness is maintained by activation of the ascending reticular activating system involving several neurotransmitters including glutamate, acetylcholine and the monoamines. NREM sleep onset is associated with a reduction in activation of the ascending reticular activating system and an increase in neural activity within the ventrolateral preoptic area, anterior hypothalamus and basal forebrain. REM sleep is triggered by activation of cholinergic neurons in the laterodorsal and pedunculopontine tegmental nuclei. The suppression of motor activity in REM sleep is generated by glutamate-mediated activation of descending medullary reticular formation. The two-process model postulates that a homeostatic process rises during waking and declines during sleep and interacts with a circadian process that is not directly dependent of sleep and waking. Sleep function remains controversial. Sleep is thought to be restorative, conservative, adaptive, thermoregulatory and memory consolidative functions. Sleep also serves host-defense mechanisms and conserves caloric expenditures. Emerging evidences indicated that sleep replenishes brain energy stores and that sleep serves a glymphatic function by removing toxic byproducts of waking activity. Finally, there is experimental evidence that connectivity changes with sleep, sleep loss, and with changing afferent input, and that those changes are linked to sleep regulatory mechanisms. Sleep medicine as a medical specialty has existed for more than 30 years. The study on over 90 kinds of sleep disorders has shed light on the understanding to the mechanisms of sleep. For example, the finding of the role of hypocretin/orexin in the patho-physiology of narcolepsy led to the reveal of hypocretin/orexin as a major wakefulness promoting substance. The evolution of the field will help us recognize the impact of sleep disorders on society as well as the nature of sleep itself.

Experimental pharmacological research regarding some newly synthesized benzamides on central nervous system functions

Three newly synthesized benzamides by the Department of Pharmaceutical Chemistry of the Faculty of pharmacy from the University of Medicine and Pharmacy „Carol Davila” Bucharest were tested in order to determine whether these new molecules have similar effects on the central nervous system as those already in therapeutic use belonging to the same chemical group, such as tiapride (neuroleptic) or lidocaine (local anaesthetic). Tests were carried out on NMRI mice which were given new compounds, conventionally named I5C, I14C, and II5C in a dose of 1/20 of the lethal dose 50% (LD50), as previously determined. They received this treatment daily for 21 days. The evasive–investigating capacity of mice was determined using the platform test, and the motor activity using an Activity cage device. The results have shown that compounds I5C and II5C decrease the investigation capacity of the mice; and compound I5C inhibits motor activity, while II5C stimulates it. Thus we concluded that only compounds I5C and II5C have a neuroleptic potential that might be investigated further.

Effect of Zbtb33 gene knockout and bacterial lipopolysaccharide on home cage behavior in mice

The Zbtb33 gene encodes the bimodal transcriptional repressor Kaiso, which causes epigenetic repression of genes by binding to methylated mCpG islets in the promoters of the genes. Despite the fact that Kaiso is intensively expressed in the central nervous system, its participation in the regulation of behavior is still poorly understood. Only the participation of Kaiso in the regulation of the behavioral response to emotional stress in the open field and forced swimming tests has been shown. The aim of this study is to elucidate the role that Kaiso plays in regulating daily activity, as well as the behavioral response to stimulation of nonspecific immunity. Experiments were performed on adult male mice with Zbtb33 gene knockout (KO) and animals of the C57BL/6 line (wild type, WT). All animals were 11 weeks old, weighed 26 ± 1 g and had SPF (specific pathogen free) status throughout the experiment. The animals of each genotype were divided into three weighted groups of 8 animals each. Initially, the daily dynamics of motor activity, sleep, food and water intake of intact animals was measured using the PhenoMaster software-hardware complex. The animals of each group were then injected with saline (control), 0.1 or 1.0 mg/kg of bacterial lipopolysaccharide (LPS) dissolved in saline, and again measured for their daily activity, food and water intake. Intact KO and WT mice did not differ in the average daily motor activity and sleep duration. However, intact KO mice were less active in the dark time, and also consumed less food and water as compared to intact WT animals. LPS at both doses suppressed motor activity, prolonged sleep duration and caused anorexia in mice of both genotypes. However, the effect of low dose of LPS (0.1 mg/kg) on the food and water intake was more pronounced in KO mice than in WT animals. The results shed light on the biological significance of the Kaiso gene and serve as a justification for the necessity of the normal functioning of this gene in natural populations.

Влияние острой гипоксии в позднем пренатальном периоде на проявление нейротоксического эффекта толуола у взрослых белых крыс

The aim of the present investigation is to estimate the role of prenatal hypoxia in toluene neurotoxic effect in adult rats. Toluene-induced behavioral and electroencephalographic manifestations were investigated in animals with normal and abnormal embryonic development. To simulate prenatal hypoxia, we gave subcutaneous injections of sodium nitrite to pregnant female rats in a dose of 50mg/kg on the 18–19th day of gestation. At the age of 3months the males from the offspring were exposed to toluene inhalation (560mg/m3, 4w eeks, 4h/day, 5days/week). After toluene inhalation exposure we estimated rats’ individual behavior by plus maze test and visual and auditory evoked potentials (VEPs and AEPs). Toluene reduced P2N2 interpeak amplitude of VEPs compared with control rats without any latency change. We found out that toluene exposure of rats with acute prenatal hypoxia in late gestation had led to inhibition of motor activity and a statistically significant increase in latency of VEP’s N1, AEP’s P3 and N1P2 interpeak amplitude of AEP in comparison with all remained groups. Thus, these results show that prenatal hypoxic damage to the central nervous system is an aggravating factor in toluene intoxication in rats.

A Neural Mechanism for Surprise-related Interruptions of Visuospatial Working Memory.

Surprising perceptual events recruit a fronto-basal ganglia mechanism for inhibition, which suppresses motor activity following surprise. A recent study found that this inhibitory mechanism also disrupts the maintenance of verbal working memory (WM) after surprising tones. However, it is unclear whether this same mechanism also relates to surprise-related interruptions of non-verbal WM. We tested this hypothesis using a change-detection task, in which surprising tones impaired visuospatial WM. Participants also performed a stop-signal task (SST). We used independent component analysis and single-trial scalp-electroencephalogram to test whether the same inhibitory mechanism that reflects motor inhibition in the SST relates to surprise-related visuospatial WM decrements, as was the case for verbal WM. As expected, surprising tones elicited activity of the inhibitory mechanism, and this activity correlated strongly with the trial-by-trial level of surprise. However, unlike for verbal WM, the activity of this mechanism was unrelated to visuospatial WM accuracy. Instead, inhibition-independent activity that immediately succeeded the inhibitory mechanism was increased when visuospatial WM was disrupted. This shows that surprise-related interruptions of visuospatial WM are not effected by the same inhibitory mechanism that interrupts verbal WM, and instead provides evidence for a 2-stage model of distraction.

Gestational exposure to perfluorooctanoic acid (PFOA): Alterations in motor related behaviors

Perfluoroalkyl and polyfluoroalkyl substances are used in commercial applications and developmental exposure has been implicated in alterations in neurobehavioral functioning. While associations between developmental perfluorooctanoic acid (PFOA) exposure and human outcomes have been inconsistent, studies in experimental animals suggest alterations in motor related behaviors. To examine a dose-response pattern of neurobehavioral effects following gestational exposure to PFOA, pregnant CD-1 mice received PFOA (0, 0.1, 0.3, 1.0mg/kg/day) via oral gavage from gestational day 1–17 and the male offspring examined. Motor activity assessments on postnatal day (PND)18, 19, and 20 indicated a shift in the developmental pattern with an elevated activity level observed in the 1.0mg/kg/day dose group on PND18. In the adult, no alterations were observed in body weights, activity levels, diurnal pattern of running wheel activity, startle response, or pre-pulse startle inhibition. In response to a subcutaneous injection of saline or nicotine (80μg/kg), all animals displayed a transient increase in activity likely associated with handling with no differences observed across dose groups. Inhibition of motor activity over 18days of 400μg/kg nicotine injection was not significantly different across dose groups. Hyperactivity induced by 2mg/kg (+)-methamphetamine hydrochloride intraperitoneal injection was significantly lower in the 1.0mg/kg/day PFOA dose group as compared to controls. Taken together, these data suggest that the effects on motor-related behaviors with gestational PFOA exposure do not mimic those reported for acute postnatal exposure. Changes were not observed at dose levels under 1.0mg/kg/day PFOA. Further examination of pathways associated with methamphetamine-induced activity is warranted.

Surprise disrupts cognition via a fronto-basal ganglia suppressive mechanism.

Surprising events markedly affect behaviour and cognition, yet the underlying mechanism is unclear. Surprise recruits a brain mechanism that globally suppresses motor activity, ostensibly via the subthalamic nucleus (STN) of the basal ganglia. Here, we tested whether this suppressive mechanism extends beyond skeletomotor suppression and also affects cognition (here, verbal working memory, WM). We recorded scalp-EEG (electrophysiology) in healthy participants and STN local field potentials in Parkinson's patients during a task in which surprise disrupted WM. For scalp-EEG, surprising events engage the same independent neural signal component that indexes action stopping in a stop-signal task. Importantly, the degree of this recruitment mediates surprise-related WM decrements. Intracranially, STN activity is also increased post surprise, especially when WM is interrupted. These results suggest that surprise interrupts cognition via the same fronto-basal ganglia mechanism that interrupts action. This motivates a new neural theory of how cognition is interrupted, and how distraction arises after surprising events.

Inhibition of Cortical Activity and Apoptosis Caused by Ethanol in Neonatal Rats In Vivo.

Alcohol consumption during pregnancy causes fetal alcohol spectrum disorder, which includes neuroapoptosis and neurobehavioral deficits. The neuroapoptotic effects of alcohol have been hypothesized to involve suppression of brain activity. However, in vitro studies suggest that ethanol acts as a potent stimulant of cortical activity. We explored the effects of alcohol (1-6 g/kg) on electrical activity in the rat somatosensory cortex in vivo at postnatal days P1-23 and compared them with its apoptotic actions. At P4-7, when the peak of alcohol-induced apoptosis was observed, alcohol strongly suppressed spontaneous gamma and spindle-bursts and almost completely silenced neurons in a dose-dependent manner. The dose-dependence of suppression of neuronal activity strongly correlated with the alcohol-induced neuroapoptosis. Alcohol also profoundly inhibited sensory-evoked bursts and suppressed motor activity, a physiological trigger of cortical activity bursts in newborns. The suppressive effects of ethanol on neuronal activity waned during the second and third postnatal weeks, when instead of silencing the cortex, alcohol evoked delta-wave electrographic activity. Thus, the effects of alcohol on brain activity are strongly age-dependent, and during the first postnatal week alcohol profoundly inhibits brain activity. Our findings suggest that the adverse effects of alcohol in the developing brain involve suppression of neuronal activity.

Structure-activity relationships of IKM-159: Diverted synthesis and biological evaluation of a series of C5-oxy analogs.

Ligands for neuronal receptors are important for understanding the biological functions as well as for treatment of neuronal diseases associated with. Here, we report diverted synthesis and biological evaluation of four C-ring analogs of IKM-159, a subtype-selective inhibitor for (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA)-type ionotropic glutamate receptor. Starting from iodinated 7-oxanorbornene 7, those analogs 3-6 were successfully synthesized in 7.0-33% yields over 8-11 steps via a common intermediate 13. Intracerebroventricular injection of those analogs on mice showed that introduction of oxo group on the C-ring (analogs 4, 5) or cleavage of the C-ring (analog 6) caused significant loss of the activity, while the ether analog 3 still retain the suppressed motor activity, indicating the importance of the C-ring in the neuronal activity of IKM-159.

A Group of Segmental Premotor Interneurons Regulates the Speed of Axial Locomotion in Drosophila Larvae

Animals control the speed of motion to meet behavioral demands. Yet, the underlying neuronal mechanisms remain poorly understood. Here we show that a class of segmentally arrayed local interneurons (period-positive median segmental interneurons, or PMSIs) regulates the speed of peristaltic locomotion in Drosophila larvae. PMSIs formed glutamatergic synapses on motor neurons and, when optogenetically activated, inhibited motor activity, indicating that they are inhibitory premotor interneurons. Calcium imaging showed that PMSIs are rhythmically active during peristalsis with a short time delay in relation to motor neurons. Optogenetic silencing of these neurons elongated the duration of motor bursting and greatly reduced the speed of larval locomotion. Our results suggest that PMSIs control the speed of axial locomotion by limiting, via inhibition, the duration of motor outputs in each segment. Similar mechanisms are found in the regulation of mammalian limb locomotion, suggesting that common strategies may be used to control the speed of animal movements in a diversity of species.

Morphofunctional Studies of the Involvement of the Serotoninergic System in the Control of Postural and Locomotor Functions

Various transmitter systems, including the serotoninergic, influence the locomotor behavior of animals. Studies have shown that the spinal cord, deprived of supraspinal control, has mechanisms able to induce locomotor activity in the hindlimbs and that the afferent system can trigger these mechanisms. Behavioral experiments on rats with complete transection of the spinal cord showed that pharmacological suppression of the serotoninergic system leads to suppression of motor activity associated with activation of support reactions (locomotor training). Histological studies did not identify any effect of activating support reactions on neuron survival or the distribution of synaptic contacts in spinal cord segments L2–L4. However, suppression of the serotoninergic system has been shown to lead to changes in cells in laminae 1–3 of the dorsal horns and in Rexed lamina 7, along with redistribution of synaptic contacts in Rexed laminae 1–4 in the dorsal horns of the spinal cord.

Silver nanoparticles augment releasing of pyrogenic factors by blood cells stimulated with LPS

Abstract Silver nanoparticles (AgNPs) have cytotoxic properties via generation of reactive oxygen species which are involved in the generalized sickness behavior of the host, including fever and lethargy among others. The aim of the present study was to investigate the impact of AgNPs on the ability of rat peripheral blood mononuclear cells (PBMCs) to release fever mediating factors after stimulation with lipopolysaccharide (LPS). Body temperature and motor activity of the Wistar rats were measured by biotelemetry system. Rat PBMCs were stimulated with LPS and after that the cells were washed and incubated alone or with AgNPs. The final supernatants were injected intraperitoneally. The levels of endogenous pyrogens such as interleukin-1β (IL−1β), IL-6 and tumor necrosis factor-α (TNF-α) released from the PBMCs into the final supernatants were also estimated. The results indicated that injection of the supernatants from the cells stimulated with LPS induced fever and inhibited motor activity. These effects were potentiated by the presence of AgNPs during the final incubation. The presence of the AgNPs also resulted in significant increases in levels of endogenous pyrogens. The augmentation of fever in the rats by the AgNPs treatment of the cultures seemed to be primarily associated with the changes in interleukin-1β levels.

Effect of activated peripheral κ-opioid receptors on the action of nicotine and its withdrawal in nicotine-dependent rats.

We studied the possibilities of modulating the effects of nicotine and its withdrawal in nicotine-dependent rats by peripheral injection of κ-opioid receptor agonist ICI 204,448. Injection of nicotine to rats previously treated with nicotine for 14 days reduced motor activity, suppressed metabolism, and increased food intake. In rats receiving ICI 204,448 after chronic administration of nicotine, food intake did not differ from that in control animals receiving isotonic NaCl solution. ICI 204,448 had virtually no effect on suppression of motor activity and metabolism. The rats receiving the last injection of nicotine 24 h prior to the experiment demonstrated an increase in metabolism, locomotor activity, and food intake. In these animals, ICI 204,448 completely abolished the effects of nicotine withdrawal. It was found that peripheral administration of compound ICI 204,448 did not significantly inhibit the effect of nicotine in nicotine-dependent rats, but abolished symptoms of nicotine withdrawal. It can be hypothesized that nicotine withdrawal syndrome is related to inhibition of dopamine release in the nucleus accumbens probably caused by enhanced κ-opioid activity in presynaptic terminals. Activation of peripheral κ-opioid receptors apparently suppressed (via vagal afferent pathways) central κ-opioid activity and reduced nicotine withdrawal symptoms in nicotine-dependent subjects.

Carbachol excites sublaterodorsal nucleus neurons projecting to the spinal cord

Considerable electrophysiological and pharmacological evidence has long suggested an important role for acetylcholine in the regulation of rapid-eye-movement (REM) sleep. For example, injection of the cholinergic agonist carbachol into the dorsomedial pons produces an REM sleep-like state with muscle atonia and cortical activation, both of which are cardinal features of REM sleep. Located within this region of the pons is the sublaterodorsal nucleus (SLD), a structure thought to be both necessary and sufficient for generating REM sleep muscle atonia. Subsets of glutamatergic SLD neurons potently contribute to motor inhibition during REM sleep through descending projections to motor-related glycinergic/GABAergic neurons in the spinal cord and ventromedial medulla. Prior electrophysiological and pharmacological studies examining the effects of acetylcholine on SLD neurons have, however, produced conflicting results. In the present study, we sought to clarify how acetylcholine influences the activity of spinally projecting SLD (SLDsp) neurons. We used retrograde tracing in combination with patch-clamp recordings and recorded pre- and postsynaptic effects of carbachol on SLDsp neurons. Carbachol acted presynaptically by increasing the frequency of glutamatergic miniature excitatory postsynaptic currents. We also found that carbachol directly excited SLDsp neurons by activating an Na(+)-Ca(2+) exchanger. Both pre- and postsynaptic effects were mediated by co-activation of M1 and M3 muscarinic receptors. These observations suggest that acetylcholine produces synergistic, excitatory pre- and postsynaptic responses on SLDsp neurons that, in turn, probably serve to promote muscle atonia during REM sleep.

Acute administration of GLP-1 receptor agonists induces hypolocomotion but not anxiety in mice.

Krass M, Rünkorg K, Vasar E, Volke V. Acute administration of GLP-1 receptor agonists induces hypolocomotion but not anxiety in mice.Objective: The aim of this study was to compare the behavioural and hormonal effects of systemic (subcutaneous) treatment with glucaemically equipotent doses of exenatide and liraglutide in mice.Methods: The effects of glucagon-like peptide-1 (GLP-1) receptor agonists were determined on anxiety level in the light–dark compartment test, the motor activity in automated activity cages and finally the forced swimming test was performed.Results: Both exenatide (1–20 µg/kg) and liraglutide (200–1200 µg/kg) decreased the glucose levels up to 30% in freely fed animals. In glucaemically equipotent doses the drugs induced very similar behavioural and hormonal effects: there was no change on anxiety level or immobility time, however, both drugs suppressed motor activity and increased corticosterone levels.Conclusion: We conclude that the two clinically approved GLP-1 receptor agonists induce very similar suppression of motor activity and stimulation of corticosterone release in mice.

Dopamine D4 receptor stimulation in GABAergic projections of the globus pallidus to the reticular thalamic nucleus and the substantia nigra reticulata of the rat decreases locomotor activity

Dopamine D4 receptors are localized in the GABAergic projections that globus pallidus (GP) neurons send to the reticular nucleus of the thalamus (RTN), the substantia nigra reticulata (SNr) and the subthalamic nucleus (STN). Deficient D4 function in this network could lead to hyperactivity and thus be important in generating some of the symptoms of ADHD (attention deficit hyperactivity disorder), a condition associated with polymorphisms of dopamine D4 receptors. It is then, unexpected that systemic injections of D4 ligands have no significant effects on the motor activity of normal rats. We further examined this issue by microinjecting D4 ligands and psychostimulant drugs in relevant structures. Interstitial dopamine overflow in the RTN was increased by reverse microdialysis of both methylphenidate and methamphetamine. Intranuclear injections in the RTN of methylphenidate, methamphetamine and the selective D4 agonist PD 168,077 reduced motor activity. Intraperitoneal injection of the D4 antagonist L 745,870 blocked the effects of these intranuclear injections. Similarly, intranuclear injections of PD 168,077 in the SNr inhibited motor activity, an effect that was also blocked by intraperitoneal L 745,870. In rats with 6-OHDA induced hemiparkinsonism, intraperitoneal PD 168,077 produced ipsilateral turning behavior that was blocked by L 745,870. Our results suggest that diminished D4 signaling in GP projections could lead to increased traffic through the relay nuclei of the thalamus and hyperactivity. Hence this basal-ganglia–thalamus network may be one of the targets of the beneficial effects that psychostimulant drugs have in disorders associated with D4 receptor abnormalities. This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.

Changes in Contractile Activity of the Duodenum, Jejunum, and Ileum under Conditions of Psychogenic Stress in Rabbits

Psychogenic stress in rabbits caused by fixation of the animal to a frame was accompanied by an increase in duodenal contractile activity. In the jejunum, initial inhibition of motor activity gave way to activation more pronounced in the proximal part. In both parts of the ileum, inhibition of contractile activity was noted. A proximodistal gradient of the excitatory and inhibitory effects on the motility of the small intestine was demonstrated.

Fetal neurobehavioral effects of exposure to methadone or buprenorphine

As part of a double-blind study of medication treatment for opioid dependence during pregnancy, 17 opioid-dependent pregnant women maintained on either buprenorphine or methadone underwent fetal monitoring at 24, 28, 32, and 36 weeks gestation. Maternal demographic information and infant outcomes did not significantly differ by medication group. Earlier in gestation (24 and 28 weeks), buprenorphine-exposed fetuses had higher levels of fetal heart rate variability, more accelerations in fetal heart rate and greater coupling between fetal heart rate and fetal movement than the methadone-exposed group (all ps < .05). Later in gestation (32 and 36 weeks), buprenorphine-exposed fetuses displayed less suppression of motor activity and longer duration of movements than the methadone-exposed group (all ps < .05). These results may have implications for the optimal treatment of the opioid-dependent pregnant woman.

Pharmacological profile and antiparkinsonian properties of the novel nociceptin/orphanin FQ receptor antagonist 1-[1-cyclooctylmethyl-5-(1-hydroxy-1-methyl-ethyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-ethyl-1,3-dihydro-benzoimidazol-2-one (GF-4)

In this study we provided a pharmacological characterization of the recently synthesized nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) antagonist 1-[1-Cyclooctylmethyl-5-(1-hydroxy-1-methyl-ethyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-ethyl-1,3-dihydro-benzoimidazol-2-one (GF-4) and investigated its antiparkinsonian properties. GF-4 inhibited N/OFQ binding to CHO hNOP cell membranes (p K i 7.46), and antagonized N/OFQ effects in a calcium mobilization assay and electrically stimulated isolated tissues (p K B 7.27–7.82), showing a ∼5-fold selectivity over classical opioid receptors. In vivo, GF-4 dually modulated stepping activity in wild-type mice, causing facilitation in the 0.01–10 mg/kg dose range and inhibition at 30 mg/kg. These effects were mediated by NOP receptors since GF-4 was ineffective in NOP receptor knock-out mice. Antiparkinsonian properties of GF-4 were investigated in 6-hydroxydopamine hemilesioned rats. GF-4 ameliorated akinesia, bradykinesia and overall gait ability in the 0.1–10 mg/kg dose range, but inhibited motor activity at 30 mg/kg. To investigate the circuitry underlying motor facilitating and inhibitory effects of GF-4, microdialysis coupled to behavioral testing (akinesia test) was performed. An anti-akinetic dose of GF-4 (1 mg/kg) reduced glutamate (GLU) and enhanced GABA release in SNr, while the pro-akinetic dose of GF-4 (30 mg/kg) evoked opposite effects. Moreover, the anti-akinetic dose of GF-4 reduced GABA and increased GLU release in ventro-medial thalamus, the pro-akinetic dose decreasing GABA without affecting GLU release in this area. We conclude that GF-4 is an effective NOP receptor antagonist able to attenuate parkinsonian-like symptoms in vivo via inhibition of the nigro-thalamic pathway.

Individual differences in the effects of cannabinoids on motor activity, dopaminergic activity and DARPP-32 phosphorylation in distinct regions of the brain

This study explored the behavioural, neurochemical and molecular effects of Delta9-tetrahydrocannabinol (Delta9-THC) and WIN55,212-2, in two rat phenotypes, distinguished on the basis of their vertical activity upon exposure to a novel environment, as high responders (HR) and low responders (LR). Motor effects were assessed under habituated vs. non-habituated conditions. Dopaminergic activity and DARPP-32 phosphorylation were measured in the dorsal striatum, nucleus accumbens, prefrontal cortex and amygdala. These cannabinoids influenced motor activity in a biphasic manner, i.e. low doses stimulated, whereas high doses suppressed motor activity. Dopamine (DA) biosynthesis was increased in most brain regions studied following Delta9-THC administration mainly in HR rats, and low-dose WIN55,212-2 increased DA biosynthesis in HR rats only. Both high and low doses of Delta9-THC increased DARPP-32 phosphorylation in most brain regions studied in both phenotypes, an effect that was also observed following high-dose WIN55,212-2 administration only in the striatum. The present results provide further support for a key role of cannabinoids in the regulation of motoric responses and elements of dopaminergic neurotransmission and reveal their complex differential effects in distinct rat phenotypes, as seen with other drugs of abuse.