Noradrenergic Enhancement of Motor Learning,Attention, and Working Memory in Humans

BackgroundNoradrenaline has an important role as a neuromodulator of the central nervous system. Noradrenergic enhancement was recently shown to enhance glutamate-dependent cortical facilitation and long term potentiation-like plasticity. As cortical excitability and plasticity are closely linked to various cognitive processes, here we aimed to explore whether these alterations are associated with respective cognitive performance changes. Specifically, we assessed the impact of noradrenergic enhancement on motor learning (serial reaction time task), attentional processes (Stroop interference task), and working memory performance (n-back letter task).MethodsThe study was conducted in a cross-over design. Twenty-five healthy humans performed the respective cognitive tasks after a single dose of the noradrenaline reuptake inhibitor reboxetine or placebo administration.ResultsThe results show that motor learning, attentional processes, and working memory performance in healthy participants were improved by reboxetine application compared with placebo.ConclusionsThe results of the present study thus suggest that noradrenergic enhancement can improve memory formation and executive functions in healthy humans. The respective changes are in line with related effects of noradrenaline on cortical excitability and plasticity.     

The effects of noradrenergic re-uptake inhibition on memory encoding in man

RATIONALE: Animal and human evidence implicate the central noradrenergic system in the process of memory modulation for emotional material. Blockade of the beta-adrenergic system in humans has been shown to result in decreased recall and recognition memory performance, relative to placebo, for the emotional elements of a series of slides accompanied by a narrative. Stimulation of the noradrenergic system with yohimbine has also been shown to result in increased recall and recognition performance relative to placebo for the same stimulus materials. OBJECTIVES: The present study tested the hypothesis that stimulating the central noradrenergic system using the new noradrenaline re-uptake inhibitor reboxetine would result in a dose-dependent enhancement of memory for emotional material in man. METHODS: The central noradrenergic system was manipulated using reboxetine in a double-blind, randomised between-group, placebo-controlled design with 36 healthy adult subjects in each of three groups (placebo, 4 and 8 mg reboxetine). Free recall and recognition memory performance were assessed in a 'surprise' memory test following a 7-day interval. RESULTS: We found no memory enhancing effect of reboxetine. In contrast we observed a dose-dependent effect on memory opposite to the predicted direction. There were no significant differences between groups in self-rated stress and arousal scores or self-rated emotional reactions to the stimuli. All groups showed the expected increased memory performance for the middle 'emotive' phase of the story. CONCLUSION: Selective stimulation of the central noradrenergic system at encoding did not result in enhanced long-term memory for emotional material in man.     

Reversal of ethanol intoxication in humans: An assessment of the efficacy of l-dopa,aminophylline, and ephedrine

The effect of postethanol treatment with l-Dopa, aminophylline and/or ephedrine was investigated. In one experiment, healthy, male, moderate drinkers ingested ethanol (0.8 g/kg) and then either l-Dopa (1.5 g), or placebo. In a second experiment, subjects ingested ethanol followed by aminophylline (200 mg), ephedrine (50 mg), aminophylline (200 mg) plus ephedrine (50 mg), or placebo. Double-blind, within-subjects, crossover designs were employed. Treatment with l-Dopa significantly reduced ethanol's effect on the electroencephalogram, motor coordination, and divided attention performance (t-test for paired data). Treatment with aminophylline and/or ephedrine also significantly reduced ethanol's effects on the electroencephalogram and motor coordination. The ethanol-antagonism may result from central noradrenergic stimulation.     

Serotonergic and Noradrenergic Modulation of Emotion Processing by Single Dose Antidepressants

Serotonergic and noradrenergic pathways are the main targets of antidepressants. Their differential effects on emotion processing-related brain activation are, however, to be further characterized. We aimed at elucidating the neural sites of action of an acute differential serotonergic and noradrenergic influence on an emotion-processing task, which was earlier shown to be associated with depressiveness. In a single-blind pseudo-randomized crossover study, 21 healthy subjects (16 subjects finally included in the analysis) participated to ingest a single dose at three time points of either 40 mg citalopram, a selective serotonin-reuptake inhibitor, 8 mg reboxetine, a selective noradrenaline-reuptake inhibitor, or placebo 2–3 h before functional magnetic resonance imaging (fMRI). During fMRI, subjects performed a task comprising the anticipation and perception of pictures of either ‘known'' (positive, negative, neutral) or ‘unknown'' valence (randomly 50% positive or negative). In direct comparison with citalopram and with placebo, reboxetine increased brain activity in the medial thalamus. Citalopram modulated certain prefrontal and insular areas more prominently. Other frontal and parieto-occipital areas were modulated by both drugs. In conclusion, the functional network involved in emotional information processing could be modulated by the acute application of selective noradrenergic and serotonergic drugs revealing a noradrenergic effect in thalamic and frontal areas, and a prefrontal and insular focus of serotonergic modulation. These findings could have implications for future selection criteria concerning personalized antidepressant medication in depression.     

Differential modulation of emotion processing brain regions by noradrenergic and serotonergic antidepressants

Rationale

Most widely used antidepressant drugs affect the serotonergic and noradrenergic pathways. However, there are currently no neurobiological criteria for selecting between these targets and predicting the treatment response in individual depressed patients.

Objectives

The current study is aimed at differentiating brain regions known to be pathophysiologically and functionally involved in depression-related emotion processing with respect to their susceptibility to serotonergic and noradrenergic modulation.

Methods

In a single-blind pseudo-randomized crossover study, 16 healthy subjects (out of 21 enrolled) were included in analysis after ingesting a single dose of citalopram (a selective serotonin-reuptake inhibitor, 40?mg), reboxetine (a selective noradrenaline-reuptake inhibitor, 8?mg), or placebo at three time points prior to functional magnetic resonance imaging (fMRI). During fMRI, subjects anticipated and subsequently viewed emotional pictures. Effects of serotonergic and noradrenergic modulation versus placebo on brain activity during the perception of negative pictures were analyzed with a repeated measures ANOVA in the whole brain and in specific regions of interest relevant to depression.

Results

Noradrenergic modulation by reboxetine increased brain activity in the thalamus, right dorsolateral prefrontal cortex and occipital regions during the perception of negative emotional stimuli. Citalopram primarily affected the ventrolateral prefrontal cortical regions.

Conclusion

The brain regions involved in the processing of negative emotional stimuli were differentially modulated by selective noradrenergic and serotonergic drugs: thalamic activity was increased by reboxetine, whereas citalopram primarily affected ventrolateral prefrontal regions. Thus, dysfunction in these regions, which could be identified in depressed patients, may predict treatment responses to either noradrenergic or serotonergic antidepressants.     

Neuroplasticity in Depressed Individuals Compared with Healthy Controls

Several lines of evidence suggest that neuroplasticity is impaired in depression. This study aimed to compare neuroplasticity in 23 subjects with DSM-IV major depressive episode and 23 age- and gender-matched healthy controls, using an objective test that is independent of subject effort and motivation. Neuroplasticity was assessed in the motor cortex using a brain stimulation paradigm known as paired associative stimulation (PAS), which induces transient changes in motor cortical function. Motor cortical excitability was assessed before and after PAS using single-pulse transcranial magnetic stimulation (TMS) to induce motor evoked potentials (MEPs) in a hand muscle. After PAS, MEP amplitudes significantly increased in healthy controls compared with depressed subjects (P=0.002). The functional significance of motor cortical changes was assessed using a motor learning task—a computerized version of the rotor pursuit task. Healthy controls also performed better on motor learning (P=0.02). BDNF blood levels and genotype were assayed to determine any relationship with motor cortical plasticity. However, PAS results did not correlate with motor learning, nor appear to be related to BDNF measures. The significance of these findings is that it provides one of the first direct demonstrations of reduced neuroplasticity in depressed subjects, using an objective test.     

Erotic Stimulus Processing under Amisulpride and Reboxetine: A Placebo-Controlled fMRI Study in Healthy Subjects

Background:

Impaired sexual function is increasingly recognized as a side effect of psychopharmacological treatment. However, underlying mechanisms of action of the different drugs on sexual processing are still to be explored. Using functional magnetic resonance imaging, we previously investigated effects of serotonergic (paroxetine) and dopaminergic (bupropion) antidepressants on sexual functioning (Abler et al., 2011). Here, we studied the impact of noradrenergic and antidopaminergic medication on neural correlates of visual sexual stimulation in a new sample of subjects.

Methods:

Nineteen healthy heterosexual males (mean age 24 years, SD 3.1) under subchronic intake (7 days) of the noradrenergic agent reboxetine (4mg/d), the antidopaminergic agent amisulpride (200mg/d), and placebo were included and studied with functional magnetic resonance imaging within a randomized, double-blind, placebo-controlled, within-subjects design during an established erotic video-clip task. Subjective sexual functioning was assessed using the Massachusetts General Hospital-Sexual Functioning Questionnaire.

Results:

Relative to placebo, subjective sexual functioning was attenuated under reboxetine along with diminished neural activations within the caudate nucleus. Altered neural activations correlated with decreased sexual interest. Under amisulpride, neural activations and subjective sexual functioning remained unchanged.

Conclusions:

In line with previous interpretations of the role of the caudate nucleus in the context of primary reward processing, attenuated caudate activation may reflect detrimental effects on motivational aspects of erotic stimulus processing under noradrenergic agents.     

Intracortical excitability is modulated by a norepinephrine-reuptake inhibitor as measured with paired-pulse transcranial magnetic stimulation

Abstract Objective. Paired-pulse transcranial magnetic stimulation (ppTMS) of the motor cortex can be used to measure intracortical inhibition and facilitation of evoked motor potentials dependent on different interstimulus intervals (ISI). The reuptake-inhibition of norepinephrine, known as an excitatory neuromodulator and neurotransmitter, was postulated to enhance cortical excitability through increased facilitation and reduced inhibition as measured with ppTMS. Methods. Eight healthy subjects were examined with ppTMS at ISIs of 2, 3, 4, 5, 6, 7, 8, 10, 15 and 20 ms before and approximately 1.5 h after ingestion of 8 mg reboxetine. The group effects at the different ISIs pre/post reboxetine intake were analysed. Results. Post-reboxetine ppTMS showed an enhanced intracortical facilitation effect at ISIs of 8, 10, 15 and 20 ms. A decreased inhibition was found at an ISI of 3 ms. Conclusions. Reboxetine-induced higher postsynaptic norepinephrine level enhances intracortical excitability as measured with ppTMS. This finding provides new perspectives for evaluating neurophysiological properties of antidepressive medication and for investigating the pathophysiology of depression. Electronic Publication     

Effects of reboxetine,a selective norepinephrine reuptake inhibitor,on sympathetic and parasympathetic outflow to the heart: preliminary data

RATIONALE: Antidepressants exert distinct effects on cardiac autonomic nervous system (ANS) function, depending on their receptor profile. Reboxetine is a selective norepinephrine (NE) reuptake inhibitor and shows only low affinity for adrenergic and muscarinic receptors. Data on reboxetine's effects on ANS function in patients with major depression (MD) are sparse. OBJECTIVE: This study evaluates the effects of reboxetine on cardiac ANS function assessed by standardized measurements of heart rate variability (HRV). METHODS: Twenty-five MD patients (DSM-III-R) underwent serial ANS function tests ( n = 94) including conventional electrocardiograms and standardized measurements of HRV and blood pressure prior to reboxetine treatment as well as on days 2, 10 and 21 during reboxetine therapy. The starting dose was 4 mg; on day 10, reboxetine was increased to 8 mg/day. The effects of reboxetine on ANS function were evaluated using the paired Wilcoxon test. RESULTS: Reboxetine treatment was associated with 1) a significant decrease in absolute and relative low-frequency power as well as in mean arterial pressure on day 2, and 2) a significant decrease in the average low- to high-frequency ratio on days 2 and 10. No significant changes in any of the vagally mediated HRV indices occurred. CONCLUSION: These preliminary findings are compatible with the hypothesis that inhibition of brain NE reuptake by reboxetine resulted in an inhibition of central noradrenergic activity via a local increase of NE concentration at inhibitory alpha(2)-autoreceptors. Long-term treatment (21 days) may cause desensitization and down-regulation of alpha(2)-autoreceptors, so that attenuation of the inhibitory restraint on sympathetic outflow results.     

Effects of acute and chronic reboxetine treatment on stress-induced monoamine efflux in the rat frontal cortex.

Reboxetine is a selective noradrenergic reuptake inhibitor that displays an antidepressant profile in both animal tests and in clinical trials. The present study examined the ability of reboxetine to alter stress-induced increases in norepinephrine, serotonin and dopamine efflux in the frontal cortex in awake behaving rats. Acute systemic administration of reboxetine (0.3-20.0 mg/kg) dose-dependently increased extracellular norepinephrine in the frontal cortex while having no effect on extracellular serotonin. At 20 mg/kg, reboxetine also increased extracellular dopamine. Application of a 20-min tailpinch stress increased extracellular norepinephrine. This effect was greatly potentiated in rats pretreated with reboxetine. Tailpinch did not elicit increases in dopamine in saline treated animals but this stimulus increased dopamine levels following reboxetine pretreatment. Furthermore, chronic administration of reboxetine for 14 days resulted in elevated basal concentrations of extracellular norepinephrine and dopamine and a greater net increase of extracellular norepinephrine and dopamine, but not serotonin, in response to tailpinch compared with vehicle control animals. Taken together, these data support the view that the noradrenergic and dopaminergic systems are modified by reboxetine treatment and may be important factors in the mechanism of action of antidepressant compounds.     

Pronounced cognitive deficits following an intravenous L-tryptophan challenge in first-degree relatives of bipolar patients compared to healthy controls.

Cognitive impairment has repeatedly been described in bipolar disorders (BD). Serotonin (5-hydroxytryptophan; 5-HT) is possibly involved in these cognitive processes, more particularly in executive functions, learning, memory, and attention. The aim of this study was to investigate serotonergic vulnerability and its relation to cognitive functioning in healthy first-degree relatives of BD patients. We investigated the effects of an intravenous (i.v.) tryptophan (Trp) challenge and placebo on cognitive performance in 30 healthy first-degree relatives of bipolar patients (FH) and 15 matched controls in a double-blind crossover design. A distinction was made between relatives of type I BD patients (FH I) and type II BD patients (FH II). Performances on planning, memory, attention, and psychomotor tasks were assessed 3 h after Trp infusion. After Trp, planning and attention were impaired in FH subjects but not in controls. Independent of Trp, FH subjects showed cognitive deficits on memory, focused and divided attention, and psychomotor performance. FH I subjects showed more pronounced cognitive impairments then FH II and controls. In all groups, Trp impaired memory and psychomotor performance significantly. In conclusions, cognitive deficits in FH following Trp may reflect a central 5-HT vulnerability in frontal brain areas. Independent of Trp, cognitive deficits in FH provide evidence for a trait marker for BD.     

Reboxetine in a neuroendocrine challenge paradigm: evidence for high cortisol responses in healthy volunteers scoring high on subclinical depression

This paper investigates if the highly selective norepinephrine reuptake inhibitor reboxetine leads to a dose-dependent cortisol release and if this response depends on personality dimensions related to clinical depression in healthy volunteers. Twenty-four male subjects received placebo, 2 mg, or 4 mg reboxetine in a balanced, randomized cross-over study. Cortisol was measured in saliva at six different time-points according to the kinetics of the drug. Furthermore, several measurements of cardiovascular parameters, emotional states, and possible side-effects were obtained. Subjects were divided into two groups scoring above or below the median of a depressiveness questionnaire scale [n = 11, low (D-); n = 13, high (D+)]. Results clearly demonstrated, that reboxetine stimulates cortisol release. Whereas blood pressure was not affected, heart rate increased after 2 and 4 mg but not dose dependently. Subjects reported more non-specific arousal while the dimensions of tiredness-wakefulness and positive-negative emotional states were not affected by the drug. Somatic complaints were low and only non-specific complaints were statistically elevated but of negligible amount. Subjects classified as D+ can be characterized as high responders to the drug. This is especially true not only for cortisol increases but also for changes in heart rate and some ratings on physical complaints. Hot flushes, sweating and a throbbing sensation in blood vessels in the head were observed in D+ but only with the 4 mg dose. The results clearly demonstrate that reboxetine stimulates cortisol release and heart rate and that this is particularly pronounced in subjects scoring high on depression-related personality dimensions. Reboxetine, therefore, is a promising tool for investigating neuroendocrine response to noradrenergic challenge tests. The question whether increased responses in D+ are due to an up-regulation of receptor sensitivity as a consequence of low norepinephrine supply is discussed.     

Norepinephrine and impulsivity: effects of acute yohimbine

Rationale

Rapid-response impulsivity, characterized by inability to withhold response to a stimulus until it is adequately appraised, is associated with risky behavior and may be increased in a state-dependent manner by norepinephrine.

Objective

We assessed effects of yohimbine, which increases norepinephrine release by blocking alpha-2 noradrenergic receptors, on plasma catecholamine metabolites, blood pressure, subjective symptoms, and laboratory-measured rapid-response impulsivity.

Methods

Subjects were 23 healthy controls recruited from the community, with normal physical examination and ECG, and negative history for hypertension, cardiovascular illness, and axis I or II disorder. Blood pressure, pulse, and behavioral measures were obtained before and periodically after 0.4 mg/kg oral yohimbine or placebo in a randomized, counterbalanced design. Metabolites of norepinephrine [3-methoxy-4-hydroxyphenylglycol (MHPG) and vanillylmandelic acid (VMA)] and dopamine [homovanillic acid (HVA)] were measured by high-pressure liquid chromatography with electrochemical detection. Rapid-response impulsivity was measured by commission errors and reaction times on the immediate memory task (IMT), a continuous performance test designed to measure impulsivity and attention.

Results

Yohimbine increased plasma MHPG and VMA but not HVA. Yohimbine increased systolic and diastolic blood pressure and pulse rate. On the IMT, yohimbine increased impulsive errors and impulsive response bias and accelerated reaction times. Yohimbine-associated increase in plasma MHPG correlated with increased impulsive response rates. Time courses varied; effects on blood pressure generally preceded those on metabolites and test performance.

Conclusions

These effects are consistent with increased rapid-response impulsivity after pharmacological noradrenergic stimulation in healthy controls. Labile noradrenergic responses, or increased sensitivity to norepinephrine, may increase risk for impulsive behavior.     

Reboxetine,a selective noradrenaline reuptake inhibitor,is non-sedative and does not impair psychomotor performance in healthy subjects

A double-blind, randomized, four-way crossover study was performed to assess the CNS effects of reboxetine, a unique selective noradrenaline reuptake inhibitor (NRI). Eighteen volunteers received reboxetine (1 or 3 mg), imipramine (75 mg) or placebo at weekly intervals. Pharmaco-electroencephalography was recorded under high- and low-vigilance conditions and spectral difference index, total power and alpha slow-wave index (ASI) were calculated. In addition, skilled performance on psychometric tests and well-being were assessed. Absolute and relative power were relatively unaffected by reboxetine but increased by imipramine. Total power and ASI were unaffected or slightly increased by reboxetine, but reduced by imipramine. Reboxetine and imipramine decreased fronto-central θ and fast β power. In pharmaco-electroencephalography, imipramine showed a left shift in the occipito-temporal lead, with an increase in δ and θ and a decrease in α power. Reboxetine increased α power. Following reboxetine administration, the results in performance tests either did not differ from placebo or were better (Pegboard test). After imipramine, a deterioration in the Steadiness and Pauli test occurred. Critical flicker fusion and Vienna test results were unaltered by either drug. In summary, reboxetine, unlike the tricyclic antidepressant imipramine, has no sedative effects of electroencephalography or on any behavioural variable indicative of a decline in vigilance. Furthermore, reboxetine showed a vigilance-enhancing effect. © 1998 John Wiley & Sons, Ltd.     

Sex differences in cortisol response to reboxetine

This study examined the cortisol response to reboxetine in a sample of healthy men and women. Forty healthy volunteers were randomly allocated to one of two treatment groups: placebo or 4 mg reboxetine under double-blind conditions. Saliva cortisol was measured pre, 1 and 1.5 h post-treatment. Mood and side-effects were also measured. A single oral dose of 4 mg reboxetine did not affect positive or negative mood but did produce some side-effects. It was also sufficient to increase cortisol release 1.5 h post-treatment compared to placebo. In addition, reboxetine lead to a significantly increased cortisol release in male compared to female volunteers. The results suggest that healthy male volunteers are more responsive to challenge with a noradrenergic compound than females.     

Reboxetine versus paroxetine versus placebo: effects on cognitive functioning in depressed patients

Impaired cognitive functioning is often associated with major depressive disorder (MDD). Moreover, a number of agents used to treat MDD are known to have negative effects on cognitive functioning. We report an assessment of the effects of the selective norepinephrine reuptake inhibitor reboxetine, the selective serotonin reuptake inhibitor paroxetine, and placebo on a variety of measures of cognitive functioning in patients with MDD. Cognitive functioning in 74 adult patients (aged 18-65 years) with a confirmed diagnosis of MDD (DSM-IV) was assessed as part of two identical, randomized, double-blind, placebo- and active-treatment-controlled, fixed/flexible dose comparisons of 8 weeks of treatment with reboxetine (8-10 mg/day), paroxetine (20-40 mg/day) and placebo. Cognitive function was assessed at baseline, day 14 and day 56 using a selection of tasks from the Cognitive Drug Research computerized assessment system, including Simple Reaction Time, Digit Vigilance, Choice Reaction Time, Numeric Working Memory, Word Recognition and Critical Flicker Frequency. The results in the 74 patients (reboxetine n = 25, paroxetine n = 23, placebo n = 26) showed that reboxetine significantly improved the ability to sustain attention at day 56 compared with baseline (P = 0.023). In addition, patients who received reboxetine experienced significant improvements in their speed of cognitive functioning when tested at day 56 compared to baseline (P = 0.024). No significant changes or trends in this direction were seen among patients who received either placebo or paroxetine. The results of the present study provide objective data to support the possibility that reboxetine favourably affects cognitive processes in depressed patients.     

Antagonism of the stress-induced increase in cortical norepinephrine output by the selective norepinephrine reuptake inhibitor reboxetine

We have previously shown that long-term treatment of rats with antidepressant drugs that affect the activity of noradrenergic and serotonergic neurons by different mechanisms, inhibits the increase in cortical norepinephrine output induced by stress. With the use of microdialysis, we have now evaluated the effects of reboxetine, an antidepressant drug that selectively inhibits norepinephrine reuptake, on the increase in cortical norepinephrine output elicited in rats by exposure to foot-shock stress or by the acute administration of N-methyl-beta-carboline-3-carboxamide (FG 7142) (20 mg/kg, i.p.). Foot-shock stress and FG 7142 each induced a marked increase in the cortical extracellular concentration of norepinephrine (+200 and +90%, respectively) in control rats. Long-term treatment with reboxetine (10 mg/kg, i.p., once a day for 21 days) reduced the effect of foot-shock stress and completely antagonized the effect of FG 7142 on cortical norepinephrine output. Our results suggest that changes in the activity of noradrenergic neurons in the cortex might be relevant to the anxiolytic and antidepressant effects of reboxetine.     

Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation

Serotonin (5-hydroxytryptamine; 5-HT) circuits may play a role in cognitive performance, particularly in learning and memory. Cognitive impairment is often seen in depressed patients, in whom 5-HT turnover in the brain is thought to be lowered. A possible human pharmacological model to study the involvement of the serotonergic system in cognitive impairment is to reduce central 5-HT synthesis through L-tryptophan depletion in healthy subjects. In this study, the cognitive effects of tryptophan depletion were assessed and whether genetically or developmentally determined vulnerability factors were predictive of the cognitive impairment induced by tryptophan depletion. Sixteen healthy volunteers with a positive family history of depression and 11 without were given 100 g of an amino acid mixture with or without tryptophan, according to a double-blind, cross-over design. Tryptophan depletion specifically impaired long-term memory performance in all subjects: delayed recall performance, recognition sensitivity, and recognition reaction times were significantly impaired after tryptophan depletion relative to placebo. Short-term memory and perceptual and psychomotor functions were unchanged. There were no differences between groups with a positive and a negative family history for depression. On the basis of these results, it is concluded that tryptophan depletion specifically impairs long-term memory formation, presumably as a result of an acute decrease in 5-HT turnover in the brain. Received: 13 February 1998 / Final version: 8 July 1998     

Morris water maze performance deficit produced by intermittent swim stress is partially mediated by norepinephrine

Intermittent swim stress (ISS) exposes a rat to cold water and the effects of the procedure produce detrimental results on activity measures 24 h later. The ISS model can be used with the Morris water maze (MWM) to investigate the impact of stress on a spatial learning and memory task, known to involve the hippocampus. We investigated if the ISS model produced performance deficits in the MWM (experiments 1 and 2). We also investigated the role of norepinephrine by using an alpha-2 adrenergic agonist (i.e., clonidine) to exacerbate ISS-induced deficits (experiment 3), and using antidepressants (i.e., desipramine and reboxetine) that enhance the synaptic availability of norepinephrine to reduce ISS-induced deficits (experiments 4 and 5). Results indicated a main effect for stress in all experiments, with the exception of experiment 2, as ISS did induce performance deficits in the MWM. Clonidine enhanced ISS-induced deficits only in the learning trials, while desipramine and reboxetine reduced ISS-induced deficits in the learning trials. Additionally, only reboxetine reduced memory deficits in the MWM. These findings provide evidence that norepinephrine may act as a partial mediator of ISS-induced deficits in MWM performance.     

Acute noradrenergic effects of desipramine in depression

As a probe of the noradrenergic system in depression, single oral doses of the tricyclic antidepressant desipramine (100 mg) and placebo were administered to unipolar and bipolar depressed patients and healthy volunteers. Plasma concentrations of norepinephrine (NE) were determined 2-3 hours after dosing, with subjects in supine and upright positions. On the placebo day plasma NE was low in a subset of bipolar patients; both groups of depressives demonstrated an exaggerated increase in plasma NE upon standing. After desipramine dosing, the orthostatic procedure resulted in even greater relative increments in plasma NE in both patient groups, with no change in volunteers. These data are consistent with noradrenergic dysregulation in depression.