Noradrenergic Mechanisms Research Articles

Noradrenergic mechanism involved in the nociceptive modulation of nociceptive-related neurons in the caudate putamen

Norepinephrine (NE) participates in pain modulation of the central nervous system. The caudate putamen (CPu) is one region of the basal ganglia that has been demonstrated to be involved in nociceptive perception. Our previous work has shown that microinjection of different doses of norepinephrine into the CPu produces opposing effects in the tail-flick latency (TFL) of rats. However, the mechanism of action of NE on the pain-related neurons in the CPu remains unclear. The present study examined the effects of NE and the alpha-adrenoceptor antagonist phentolamine on the pain-evoked response of pain-excitation neurons (PENs) and pain-inhibition neurons (PINs) in the CPu of rats. Trains of electric impulses were used for noxious stimulation, and were applied to the sciatic nerve. The electrical activities of pain-related neurons in the CPu were recorded by a glass microelectrode. The results revealed that intra-CPu microinjection of NE (8 μg/2 μl) increased evoked firing frequency of PEN and shortened the firing latency, but decreased the evoked firing frequency of PIN and prolonged the inhibitory duration (ID). Intra-CPu administration of phentolamine (4 μg/2 μl) showed the opposite effects. The above results suggest that NE in the CPu modulates nociception by affecting the baseline firing rates of PENs and PINs.

Duloxetine May Improve Some Symptoms of Attention-Deficit/Hyperactivity Disorder

Duloxetine May Improve Some Symptoms of Attention-Deficit/Hyperactivity Disorder

Is there a delay in the activation of non‐noradrenergic vasoconstriction during cold exposure in human skin?

This study tested the hypothesis that cutaneous vasoconstriction during brief cold exposure occurs entirely through noradrenergic mechanisms. In 6 subjects, 2 microdialysis (MD) fibers were placed in the forearm skin. A control fiber received lactated ringers and the other received 5mM yohimbine (α‐adrenergic blockade). Skin blood flow was assessed at each site (laser‐Doppler flowmetry) and cutaneous vascular conductance (CVC) was calculated (red blood cell flux/mean arterial pressure). Subjects were exposed to 10 min of cold stress (water‐perfused suit). CVC was reduced by 64 ± 9 % in the control site (P<0.05 vs. baseline) but unchanged in the yohimbine site during cold stress. In a follow‐up protocol (n=3) we added a third MD site with yohimbine + 1mM propranolol and extended the cold stress to 30 min. CVC was reduced in the control site throughout cold stress, but showed vasoconstriction during only the second half of the cold stress in both yohimbine and yohimbine + propranolol sites. Thus, short duration cold exposure can elicit cutaneous vasoconstriction mediated solely through noradrenergic mechanisms, whereas more prolonged cold stress also activates non‐noradrenergic vasoconstriction. Supported by the Evonuk and ACSM Foundations

Cold-induced vasoconstriction at forearm and hand skin sites: the effect of age

During mild cold exposure, elderly are at risk of hypothermia. In humans, glabrous skin at the hands is well adapted as a heat exchanger. Evidence exists that elderly show equal vasoconstriction due to local cooling at the ventral forearm, yet no age effects on vasoconstriction at hand skin have been studied. Here, we tested the hypotheses that at hand sites (a) elderly show equal vasoconstriction due to local cooling and (b) elderly show reduced response to noradrenergic stimuli. Skin perfusion and mean arterial pressure were measured in 16 young adults (Y: 18–28 years) and 16 elderly (E: 68–78 years). To study the effect of local vasoconstriction mechanisms local sympathetic nerve terminals were blocked by bretylium (BR). Baseline local skin temperature was clamped at 33°C. Next, local temperature was reduced to 24°C. After 15 min of local cooling, noradrenalin (NA) was administered to study the effect of neural vasoconstriction mechanisms. No significant age effect was observed in vasoconstriction due to local cooling at BR sites. After NA, vasoconstriction at the forearm showed a significant age effect; however, no significant age effect was found at the hand sites. [Change in CVC (% from baseline): Forearm Y: −76 ± 3 vs. E: −60 ± 5 (P < 0.01), dorsal hand Y: −74 ± 4 vs. E: −72 ± 4 (n.s.), ventral hand Y: −80 ± 7 vs. E: −70 ± 11 (n.s.)]. In conclusion, in contrast to results from the ventral forearm, elderly did not show a blunted response to local cooling and noradrenalin at hand skin sites. This indicates that at hand skin the noradrenergic mechanism of vasoconstriction is maintained with age.

Investigating the role of protein kinase-G in the antidepressant-like response of sildenafil in combination with muscarinic acetylcholine receptor antagonism

The cGMP/PK-G pathway plays a crucial role in neuroprotection and neurotrophin support, and is possibly involved in antidepressant action. Recently we reported on a novel antidepressant-like response following simultaneous administration of sildenafil (phosphodiesterase 5 (PDE5) inhibitor, thereby increasing cGMP levels), and atropine (muscarinic acetylcholine receptor antagonist) in the rat forced swim test (FST). However, it is unclear whether the antidepressant-like activity of sildenafil + atropine is mediated via the activation of PK-G, an important down-stream effector for cGMP, and whether this may target known pathways in antidepressant action. We investigated whether the antidepressant-like response of sildenafil ± atropine could be reversed by Rp-8-Br-PET-cGMP, a PK-G inhibitor, and also whether a combination of 8-Br-cGMP (PK-G activator) ± atropine would likewise be active in the FST, and whether this combination could be attenuated by a PK-G inhibitor. 8-Br-cGMP alone, but not sildenafil alone, reduced immobility and selectively increased swimming in the FST. The antidepressant-like action of sildenafil was only evident following co-administration of atropine, and selectively increased climbing behaviour. Importantly, PK-G inhibition prevented the antidepressant-like effects of both 8-Br-cGMP and the sildenafil/atropine combination. These results confirm cholinergic-cGMP–PK-G interactions in the antidepressant-like effects of sildenafil, putatively acting via noradrenergic mechanisms, whereas direct PK-G activation induces antidepressant-like effects that are associated with enhancement of serotonergic neurotransmission.

Pupil dilation betrays the timing of decisions

The notion of “mind-reading” by carefully observing another individual's physiological responses has recently become commonplace in popular culture, particularly in the context of brain imaging. The question remains, however, whether outwardly accessible physiological signals indeed betray a decision before a person voluntarily reports it. In one experiment we asked observers to push a button at any time during a 10-s period (“immediate overt response”). In a series of three additional experiments observers were asked to select one number from five sequentially presented digits but concealed their decision until the trial's end (“covert choice”). In these experiments observers either had to choose the digit themselves under conditions of reward and no reward, or were instructed which digit to select via an external cue provided at the time of the digit presentation. In all cases pupil dilation alone predicted the choice (timing of button response or chosen digit, respectively). Consideration of the average pupil-dilation responses, across all experiments, showed that this prediction of timing was distinct from a general arousal or reward-anticipation response. Furthermore, the pupil dilation appeared to reflect the post-decisional consolidation of the selected outcome rather than the pre-decisional cognitive appraisal component of the decision. Given the tight link between pupil dilation and norepinephrine levels during constant illumination, our results have implications beyond the tantalizing mind-reading speculations. These findings suggest that similar noradrenergic mechanisms may underlie the consolidation of both overt and covert decisions.

Deep Brain Stimulation Reveals Emotional Impact Processing in Ventromedial Prefrontal Cortex

We tested the hypothesis that modulation of monoaminergic tone with deep-brain stimulation (DBS) of subthalamic nucleus would reveal a site of reactivity in the ventromedial prefrontal cortex that we previously identified by modulating serotonergic and noradrenergic mechanisms by blocking serotonin-noradrenaline reuptake sites. We tested the hypothesis in patients with Parkinson's disease in whom we had measured the changes of blood flow everywhere in the brain associated with the deep brain stimulation of the subthalamic nucleus. We determined the emotional reactivity of the patients as the average impact of emotive images rated by the patients off the DBS. We then searched for sites in the brain that had significant correlation of the changes of blood flow with the emotional impact rated by the patients. The results indicate a significant link between the emotional impact when patients are not stimulated and the change of blood flow associated with the DBS. In subjects with a low emotional impact, activity measured as blood flow rose when the electrode was turned on, while in subjects of high impact, the activity at this site in the ventromedial prefrontal cortex declined when the electrode was turned on. We conclude that changes of neurotransmission in the ventromedial prefrontal cortex had an effect on the tissue that depends on changes of monoamine concentration interacting with specific combinations of inhibitory and excitatory monoamine receptors.

Noradrenergic Modulation of Cortical Networks Engaged in Visuomotor Processing

Both animal and human data suggest that stimulation of the noradrenergic system may influence neuronal excitability in regions engaged in sensory processing and visuospatial attention. We tested the hypothesis that the neural mechanisms subserving motor performance in tasks relying on the visuomotor control of goal-directed hand movements might be modulated by noradrenergic influences. Healthy subjects were stimulated using the selective noradrenaline reuptake inhibitor reboxetine (RBX) in a placebo-controlled crossover design. Functional magnetic resonance imaging and dynamic causal modeling (DCM) were used to assess drug-related changes in blood oxygen level-dependent activity and interregional connectivity while subjects performed a joystick task requiring goal-directed movements. Improved task performance under RBX was associated with increased activity in right visual, intraparietal and superior frontal cortex (premotor/frontal eye field). DCM revealed that the neuronal coupling among these regions was significantly enhanced when subjects were stimulated with RBX. Concurrently, right intraparietal cortex and right superior frontal cortex exerted a stronger driving influence on visuomotor areas of the left hemisphere, including SMA and M1. These effects were independent from task difficulty. The data suggest that stimulating noradrenergic mechanisms may rearrange the functional network architecture within and across the hemispheres, for example, by synaptic gating, thereby optimizing motor behavior.

Evidence for a noradrenergic mechanism causing hypertension and abnormal glucose metabolism in rats with relative deficiency of γ‐melanocyte‐stimulating hormone

A close association between salt-sensitive hypertension and insulin resistance has been recognized for more than two decades, although the mechanism(s) underlying this relationship have not been elucidated. Recent data in mice with genetic disruption of the gamma-melanocyte-stimulating hormone (gamma-MSH) system suggest that this system plays a role in the pathophysiological relationship between hypertension and altered glucose metabolism during ingestion of a high-sodium diet (8% NaCl, HSD). We tested the hypothesis that these two consequences of interrupted gamma-MSH signalling were the result of sympathetic activation by studying rats treated with the dopaminergic agonist bromocriptine (5 mg kg(-1) i.p., daily for 1 week; Bromo) to cause relative gamma-MSH deficiency. Bromo-treated rats fed the HSD developed hypertension and also exhibited fasting hyperglycaemia (P < 0.005) and hyperinsulinaemia (P < 0.025). Furthermore, Bromo-treated rats on the HSD had impaired glucose tolerance and blunted insulin-mediated glucose disposal. Intravenous infusion of gamma(2)-MSH, or of the alpha-adrenergic receptor antagonist phentolamine, to Bromo-HSD rats lowered both mean arterial pressure (MAP) and blood glucose to normal after 15 min (P < 0.001 versus control), but had no effect in rats receiving vehicle and fed the HSD; gamma(2)-MSH infusion also reduced the elevated plasma noradrenaline to control levels in parallel with the reductions in MAP and blood glucose concentration. Infusion of hydralazine to Bromo-HSD rats lowered MAP but had only a trivial effect on blood glucose. We conclude that rats with relative gamma-MSH deficiency develop abnormal glucose metabolism, with features of insulin resistance, in association with hypertension when ingesting the HSD. Elevated plasma noradrenaline concentration in Bromo-HSD rats is normalized by gamma(2)-MSH infusion, suggesting that an adrenergic mechanism may link the salt-sensitive hypertension and the impaired glucose metabolism of relative gamma-MSH deficiency.

Adrenaline, noradrenaline and dopamine level estimation in depression: Does it help?

Background: Abnormalities of catecholaminergic function have been hypothesised in causation of depressive illness. Electroconvulsive therapy (ECT) is postulated to have noradrenergic mechanism of action. We studied the clinical utility of estimating catecholamines level changes after ECT. Methods: Plasma adrenaline, noradrenaline and dopamine in healthy controls and depressed patients were estimated by high performance liquid chromatography with electrochemical detection method before and after ECT. Result: Mean ± standard deviation of plasma adrenaline, noradrenaline and dopamine in controls was 36.7 ± 13.2, 209.3 ± 76, 21.8 ± 9.5 ng/L respectively, while in depressed patients before and after ECT it was found to be 32.5 ± 12.0, 419.3 ± 167.7, 22.1 ± 16 and 37.2 ± 19.6, 386.1 ± 168.4, 22.3 ± 15.5ng/L respectively. Correlation of adrenaline, noradrenaline and dopamine concentration with scores of Beck Depression Inventory, Suicidal Ideation Scale and Melancholia Inventory was positive but statistically not significant and poor. Based on the cut off values of noradrenaline, only 62% cases could be categorized as abnormal, which after ECT reduced to 50% , whereas post ECT psychiatric ratings was normal in about 78% cases. Conclusion: There is no clinical significance of estimating adrenaline, noradrenaline and dopamine in depressed patients.

Cardiovascular effects of noradrenaline injected into the Medial Nucleus of Amígdala (MeA) of unanesthetized rats.

IntroductionThe MeA, is involved with physiological and behavioral processes modulation, as well as regulation of the autonomic nervous system. Some evidences indicating that electrical rats MeA stimulation is able to evoke cardiovascular response. The noradrenaline (NA) is a neurotransmitter involved in the control of cardiovascular responses into the several structures in the central nervous system. The MeA received noradrenergic innervations of the A6 neurons and locus coeruleus (LC). Moreover, binding studies demonstrate noradrenergic receptors in this area.ObjectiveThe aim of the present work is characterize the cardiovascular responses evoked by local administration of NA in the MeA.Methods and ResultsMale Wistar rats were used. Cannulaes was implanted in the MeA using a stereotaxic apparatus. A catheter was implanted into the femoral artery for blood pressure and heart rate (HR) recording. Injecting different doses of NA (3, 9, 27 or 45 nmol/100 nL) into the MeA of normotensive rats (baseline MAP=100±2 mmHg and HR=369 ± 4bpm, n=25) caused dose‐related pressor responses and HR decrease. Nonlinear regression analysis indicated a significant correlation between doses and cardiovascular responses.ConclusionOur results reinforce the idea that noradrenergic mechanisms into the MeA are involved in cardiovascular control.Financial SupportsFAPESP, CNPQ and FAEPA.

Opposite effects of opioid blockade on the blood pressure–pain relationship in depressed and non-depressed participants

The effect of the opioid antagonist naltrexone on the relationship between blood pressure and pain was examined in 24 participants with major depressive disorder and 31 non-depressed controls, before and after 25 min of stressful mental arithmetic. Pain was induced by immersing the non-dominant foot in 2 °C ice-water for as long as possible or until 4 min had elapsed (the cold pressor test). Blood pressure was measured before each cold pressor test, and at 2-min intervals during mental arithmetic. In the group as a whole, neither depression nor naltrexone influenced blood pressure at any stage of the experiment. However, naltrexone disrupted an association between elevated resting blood pressure and low levels of pain in non-depressed controls, suggesting that endogenous opioid peptides are involved in blood pressure-mediated analgesia. Effects were similar when expressed in relation to blood pressure during psychological stress. In contrast to controls, blood pressure was unrelated to pain in depressed participants in the placebo condition. However, naltrexone unmasked an association between blood pressure and pain – those with highest blood pressure reported least cold-induced pain. Thus, endogenous opioids apparently masked an analgesic mechanism linking elevated blood pressure with reduced sensitivity to pain in participants with major depressive disorder. Noradrenergic mechanisms involved in active coping, stress-induced analgesia and baroreflexes might account for these findings.

Postgraduate corner: Continuing medical education: Psychopharmacology

Byline: Chittaranjan. Andrade CME Questions A) Fibromyalgia is a poorly understod syndrome that is characterized by chronic, widespread musculoskeletal and joint pain. There are often multiple tender nodules present in specific anatomical loci, such as over the shoulders and back. Common accompanying symptoms include stiffness, fatigue, mood disturbance, and insomnia. Affected patients suffer from pain-related disability and impaired functioning in everyday life. With this background, mark True or False against each of the following statements: *Escitalopram is an approved treatment for fibromyalgia. *Duloxetine 120mg/day is more effective than duloxetine 60mg/day in the treatment of fibromyalgia. *An adequate trial of duloxetine for fibromyalgia should last at least 4-6 months. *In addition to attenuating measures of pain, duloxetine improves functional outcomes in fibromyalgia. *Fibromyalgia treatments have demonstrated efficacy in long-term as well as short-term management. B) Tamoxifen is prescribed for various indications to women with estrogen receptor-positive breast cancer. These women may require antidepressant medication for concurrent depression; or for the treatment of hot flushes and other symptoms of artificial menopause. With this background, mark True or False against each of the following statements: *Tamoxifen is metabolized by CYP3A4. *Mirtazapine should be preferred to duloxetine over depressed women who are receiving tamoxifen. C) Benzodiazepines have anxiolytic and anticonvulsant properties and are cross-tolerant with alcohol. They are therefore prescribed during alcohol withdrawal to reduce the severity of the withdrawal syndrome and to reduce the risk of withdrawal seizures. Diazepam and chlordiazepoxide are traditionally preferred for this indication because both have long half-lives of approximately 1-2 days, each; their levels in blood therefore tend to remain uniform across the course of the day, and drug withdrawal difficulties are fewer. However, they are metabolized by demethylation and hydroxylation and have active metabolites; as a result of these pharmacokinetic properties, they may accumulate, and mask or even precipitate hepatic encephalopathy in patients with alcoholic liver disease. With this background, mark True or False against each of the following statements: *For important theoretical reasons, if alcoholic liver disease is present or suspected, lorazepam should be avoided in patients who are being withdrawn from alcohol. *Clinical data exist to suggest that lorazepam may be effective in the management of uncomplicated alcohol withdrawal. View Answer CME Answers A) Fibromyalgia Answers: 1. False; 2. False; 3. False. 4. True; 5. True. *Citalopram appears ineffective in patients with fibromyalgia[sup] [1],[2] and, to judge from a PubMed search conducted on June 14, 2009, escitalopram has not been studied for this indication. Pregabalin,[sup] [3],[4] duloxetine[sup] [5],[6] and milnacipran[sup] [7],[8] are USA Food and Drug Administration-approved treatments for fibromyalgia. However, as serotonergic and noradrenergic mechanisms have both been described to mediate pain relief,[sup] [9] it is likely that most antidepressants, especially dual-acting drugs such as the tricyclic antidepressants, could be effective treatments for fibromyalgia. In other words, antidepressant efficacy against fibromyalgia could be a class action. *Short-term, randomized, double-blind, placebo-controlled clinical trials of duloxetine (60 or 120mg/day) in patients with fibromyalgia found that the 120mg/day dose was not better than the 60mg/day dose.[sup] [10],[11] A 1-year randomized controlled study also found no advantage with the higher dose.[sup] [12] For the majority of patients, therefore, 60mg/day is likely an adequate dose; whereas some patients may indeed require a higher dose, it should be kept in mind that the higher dose could increase the adverse effect burden. …

Dopamine vs Noradrenaline: Inverted-U Effects and ADHD Theories

The aim of the present study was to review the dopamine theory of attention-deficit-hyperactivity disorder (ADHD), in light of recent use of noradrenergic therapies. A historical review of pharmacological theories of ADHD was conducted, including inverted-U, spatial working memory and neural circuit aspects. Pharmacological advances, including animal and human studies of dopaminergic and noradrenergic mechanisms at the prefrontal cortex (PFC), indicate that alpha-2A adrenoreceptor stimulation results in increased dendritic firing during delay periods for preferred directions, while moderate levels of D1 receptor stimulation result in reduction of delay-related firing to non-preferred directions, allowing representational control in the PFC. Recent studies of the COMT val/met gene and stimulant medication response may help explain variation in inverted-U responses in individuals. Further studies utilizing delay-related firing paradigms should be useful in the investigation of attentional syndromes, and responses to newer pharmacological treatments.

Novelty Determines the Effects of Olfactory Enrichment on Memory and Neurogenesis Through Noradrenergic Mechanisms

Commonly used experimental paradigms of environmental enrichment combine increased social interactions and sensory inputs and renewal of the objects present in the environment. However, the specific contribution of novelty to the effects of enrichment is unclear. Here, we show that repeated daily exposure to single novel odorants and not to an enriched but stable olfactory environment improves short-term olfactory memory and neurogenesis in the mouse olfactory bulb. In addition, these positive effects are mediated by noradrenalin as they are blocked by a noradrenergic receptor antagonist. These data suggest that novelty recognition and noradrenergic mechanisms are crucial in mediating neural plasticity induced by olfactory enrichment.

Extract fromAcanthopanax senticosusHarms (Siberian Ginseng) Activates NTS and SON/PVN in the Rat Brain

The extract of the stem bark of Siberian ginseng, Acanthopanax senticosus Harms (ASH), is believed to play a body-coping role in stress through a brain noradrenergic mechanism. The present study was carried out to investigate the effect of ASH on the neuronal activation patterns of c-Fos expression in the rat brain. With ASH administration, c-Fos accumulated in both the supraoptic nuclei (SON) and paraventricular nuclei (PVN), which regulate stress response. Only the caudal regions in the nucleus of the solitary tract (NTS), a locus innervating both the SON and PVN, were activated. Such a neuro-anatomical pattern associated with ASH suggests the possible involvement of these stress-related brain loci.

Multiplicative interactions to enhance gabapentin to treat neuropathic pain

We previously reported that gabapentin activates the bulbospinal-spinal noradrenergic–cholinergic pathway to produce analgesia in rats after nerve injury. Also, gabapentin interacts synergistically with a cholinesterase inhibitor donepezil to produce analgesia. Duloxetine, a serotonin/noradrenaline re-uptake inhibitor, has been used for the treatment of neuropathic pain and should amplify the noradrenergic mechanisms recruited by gabapentin. In the present study, we determined the interaction between duloxetine and gabapentin with and without donepezil when administered by the clinically preferred oral route in rats after spinal nerve ligation. The ED 50 value of gabapentin, donepezil, and duloxetine to reduce mechanical hypersensitivity after nerve injury was 45, 3.7, and 32 mg/kg, respectively. In the examination of two drug combinations, oral duloxetine with either gabapentin or donepezil were additive to reduce hypersensitivity. The combination of all three drugs yielded a synergistic interaction with an observed ED 50 at 1/4th the predicted dose of additivity, likely due to the gabapentin–donepezil interaction. This three drug combination did not affect motor coordination or show signs of sedation in the rotarod test. Analgesia by the combination of these three drugs was reversed by intrathecal injection either of the α 2-adrenoceptor antagonist idazoxan or by the muscarinic receptor antagonist atropine. These results suggest that the combination of these drugs, which stimulate and augment the bulbospinal-spinal noradrenergic–cholinergic pathway, lowers the dose requirement for each drug to reduce hypersensitivity after nerve injury without sedative effects. The current study provides the rationale for clinical study of the combination of gabapentin, donepezil and duloxetine to treat neuropathic pain.

Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities

Mutations in SLITRK1 are found in patients with Tourette's syndrome and trichotillomania. SLITRK1 encodes a transmembrane protein containing leucine-rich repeats that is produced predominantly in the nervous system. However, the role of this protein is largely unknown, except that it can modulate neurite outgrowth in vitro. To clarify the role of Slitrk1 in vivo, we developed Slitrk1-knockout mice and analyzed their behavioral and neurochemical phenotypes. Slitrk1-deficient mice exhibited elevated anxiety-like behavior in the elevated plus-maze test as well as increased immobility time in forced swimming and tail suspension tests. Neurochemical analysis revealed that Slitrk1-knockout mice had increased levels of norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylglycol. Administration of clonidine, an alpha2-adrenergic agonist that is frequently used to treat patients with Tourette's syndrome, attenuated the anxiety-like behavior of Slitrk1-deficient mice in the elevated plus-maze test. These results lead us to conclude that noradrenergic mechanisms are involved in the behavioral abnormalities of Slitrk1-deficient mice. Elevated anxiety due to Slitrk1 dysfunction may contribute to the pathogenesis of neuropsychiatric diseases such as Tourette's syndrome and trichotillomania.

Methylphenidate amplifies long-term plasticity in the hippocampus via noradrenergic mechanisms

Methylphenidate treatment is used for Attention Deficit Hyperactivity Disorder and can improve learning and memory. Previously, improvements were considered a by-product of increased attention; however, we hypothesize that methylphenidate directly alters mechanisms underlying learning and memory, and therefore examined its effects on hippocampal long-term potentiation and long-term depression. Methylphenidate enhanced both mechanisms in the absence of presynaptic changes and in a noradrenalin beta-receptor-dependent manner. These findings can explain both the improved learning and memory and decreased learning selectivity found with methylphenidate treatment and constitute the first demonstration of direct actions of methylphenidate on mechanisms implicated in cognition.

Effects of Localized Intraspinal Injections of a Noradrenergic Blocker on Locomotion of High Decerebrate Cats

Previous studies demonstrated that neuronal networks located in midlumbar segments (L3-L4) are critical for the expression of locomotion in cats following complete spinalization. In the present study the importance of several thoracolumbar segments (T8-L7) for the generation of spontaneous hindlimb locomotion in decerebrate cats was evaluated. Experiments were performed in high decerebrate cats (n = 18) walking spontaneously. Yohimbine, an alpha2-noradrenergic antagonist, was microinjected intraspinally in various thoracolumbar segments. Locomotor performance was evaluated with kinematics and electromyographic (EMG) recordings before and after each injection. When and if spontaneous locomotion (SL) was abolished, skin or perineal stimuli (exteroceptive stimuli) were used to trigger locomotion (exteroceptive-induced locomotion [EL]). Yohimbine injections at L3 or L4 completely inhibited SL and EL. In contrast, injections at T8 did not interfere with SL or EL. Injections at T10, T11, T12, L5, L6, and L7 inhibited SL but EL could still be evoked. Injections at T13, L1, and L2 had similar effects except that the quality of locomotion evoked by exteroceptive stimulation declined. Combined injections at T13, L1, and L2 abolished SL and EL, in contrast to injections restricted to the same individual segments. Simultaneous injections at L5, L6, and L7 also abolished SL but EL could still be induced. These results suggest that noradrenergic mechanisms in L3-L4 segments are involved in the expression of locomotion in decerebrate cats, whereas antagonizing noradrenergic inputs in individual rostral or caudal segments may alter the expression and overall quality of the locomotor pattern without abolishing locomotion.