Sympathectomy improves skin blood flow at the thermoregulatory but not the nutritive level

These results indicate that in case of lower limb ischemia, sympathectomy improves skin blood flow at the thermoregulatory but not the nutritive level of skin microcirculation. This may be related to the fact that the thermoregulatory vessels are mainly sympathetically controlled, whereas the nutritive capillaries are mainly controlled by local (nonneural) factors.

François M.H. van Dielen¹, Harrie A.J.M. Kurvers¹, Ruben Dammers¹, Mirjam G.A. oude Egbrink², Dick W. Slaaf³, Jan H.M. Tordoir¹ and Peter J.E.H.M. Kitslaar¹

(1)	Department of General Surgery, Cardiovascular Research Institute Maastricht and University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands, NL

(2)	Department of Physiology, Cardiovascular Research Institute Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands, NL

(3)	Department of Biophysics, Cardiovascular Research Institute Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands, NL World Journal of Surgery Volume 22, Number 8 / August, 1998

Imbalance of regional cerebral blood flow

Imbalance of regional cerebral blood flow and oxygen consumption: effect of vascular alpha adrenoceptor blockade.

Neuropharmacology. 1993 Mar;32(3):297-302.
Weiss HR, Sinha AK.

Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway 08854-5635.

the regulation of cerebrovascular tone

Brain perfusion is tightly coupled to neuronal activity, is commonly used to monitor normal or pathological brain function, and is a direct reflection of the interactions that occur between neuronal signals and blood vessels. Cerebral blood vessels at the surface and within the brain are surrounded by nerve fibers that originate, respectively, from peripheral nerve ganglia and intrinsic brain neurons. Although of different origin and targeting distinct vascular beds, these "perivascular nerves" fulfill similar roles related to cerebrovascular functions, a major one being to regulate their tone and, therein, brain perfusion. This utmost function, which underlies the signals used in functional neuroimaging techniques and which can be jeopardized in pathologies such as Alzheimer's disease, stroke, and migraine headache, is thus regulated at several levels. Recently, new insights into our understanding of how neural input regulate cerebrovascular tone resulted in the rediscovery of the functional "neurovascular unit." These remarkable advances suggest that neuron-driven changes in vascular tone result from interactions that involve all components of the neurovascular unit, transducing neuronal signals into vasomotor responses not only through direct interaction between neurons and vessels but also indirectly via the perivascular astrocytes. Neurovascular coupling is thus determined by chemical signals released from activated perivascular nerves and astrocytes that alter vascular tone to locally adjust perfusion to the spatial and temporal changes in brain activity.
Edith Hamel

Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada

J Appl Physiol 100: 1059-1064, 2006; doi:10.1152/japplphysiol.00954.2005

Dopaminergic regulation of cerebral cortical microcirculation

Nature Neuroscience 1, 286 - 289 (1998)
doi:10.1038/1099
Leonid S. Krimer¹, E. Christopher Muly III², Graham V. Williams¹ & Patricia S. Goldman-Rakic¹

¹ Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA

² Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06510, USU

Functional variations in cerebral cortical activity are accompanied by local changes in blood flow, but the mechanisms underlying this physiological coupling are not well understood. Here we report that dopamine, a neurotransmitter normally associated with neuromodulatory actions, may directly affect local cortical blood flow. Using light and electron-microscopic immunocytochemistry, we show that dopaminergic axons innervate the intraparenchymal microvessels. We also provide evidence in an in vitro slice preparation that dopamine produces vasomotor responses in the cortical vasculature. These anatomical and physiological observations reveal a previously unknown source of regulation of the microvasculature by dopamine. The findings may be relevant to the mechanisms underlying changes in blood flow observed in circulatory and neuropsychiatric disorders.

Disturbance of sympathetic cardiovascular regulation is involved in CFS

Wyller VB, Saul JP, Walloe L, Thaulow E "...our results suggest that CFS patients suffer from a more comprehensive disturbance of sympathetic cardiovascular regulation than previously acknowledged, supporting the hypothesis that dysautonomia may be a central etiologic component of CFS (Freeman and Komaroff 1997). Specifically, the sympathetic nervous system is more activated at rest, and seems to have an enhanced response to orthostatic stress, but has a reduced response to the addition of isometric exercise. These abnormalities may account for the high prevalence of orthostatic symptoms among CFS patients.

recent reports have linked cerebral hypoperfusion to abnormalities in cholinergic metabolism

Dr Faisel Khan, Vascular Diseases Research Unit,
University Department of Medicine, Ninewells
Hospital and Medical School, Dundee DD1 9SY, UK

accepted 30 April 2003

Although the aetiology of chronic fatigue syndrome (CFS) is unknown, there have
been a number of reports of blood flow abnormalities within the cerebral circulation
and systemic blood pressure defects manifesting as orthostatic intolerance. Neither
of these phenomena has been explained adequately, but recent reports have linked
cerebral hypoperfusion to abnormalities in cholinergic metabolism. Our group has
previously reported enhanced skin vasodilatation in response to cumulative doses of
transdermally applied acetylcholine (ACh), implying an alteration of peripheral
cholinergic function. To investigate this further, we studied the time course of ACh-
induced vasodilatation following a single dose of ACh in 30 patients with CFS and
30 age- and gender-matched healthy control subjects. No differences in peak blood
flow was seen between patients and controls, but the time taken for the ACh
response to recover to baseline was significantly longer in the CFS patients than in
control subjects. The time taken to decay to 75% of the peak response in patients and
controls was 13Æ7 ± 11Æ3 versus 8Æ9 ± 3Æ7 min (P
1⁄4 0Æ03), respectively, and time
taken to decay to 50% of the peak response was 24Æ5 ± 18Æ8 versus 15Æ1 ± 8Æ9 min
(P
1⁄4 0Æ03), respectively. Prolongation of ACh-induced vasodilatation is suggestive
of a disturbance to cholinergic pathways, perhaps within the vascular endothelium
of patients with CFS, and might be related to some of the unusual vascular
symptoms, such as hypotension and orthostatic intolerance, which are characteristic
of the condition.

Regional temperature rises within the CNS can lead to alteration of membrane properties.

Regional temperature rises within the
CNS can lead to an alteration of mem-
brane properties. For example, enzyme
activity – ornithine decarboxylase – is in-
creased when calcium flows into the cell
via a temperature-sensitive mechanism.
Interestingly, one study observed an acti-
vation of this enzyme after EMF exposure,
subsequently resulting in a temporary per-
meability increase of the BBB.

On the other hand, also a tempo-
rary blood pressure rise could cause an
increase of BBB permeability.

Privatdozent Dr. med. Florian Stögbauer,
University of Münster

Hyperpigmentation after sympathectomy

Hyperpigmentation after sympathectomy

• CLAIRE SAMUEL,**Departments of Surgery, Royal Infirmary, Bristol BS2 8HW
• D.R. BIRD¹¹Departments of Dermatology, Royal Infirmary, Bristol BS2 8HW AND
• J.L. BURTON¹¹Departments of Dermatology, Royal Infirmary, Bristol BS2 8HW

• ¹Departments of Dermatology, Royal Infirmary, Bristol BS2 8HW *Departments of Surgery, Royal Infirmary, Bristol BS2 8HW

• Clinical and Experimental Dermatology

  Volume 5 Issue 3 Page 349-350, September 1980

Avoidance learning

Chemical sympathectomy and two-way escape and avoidance learning in the rat.

Six experiments are reported on the effects of 2,4,5-trihydroxyphenylethyl-amine (6-hydroxydopamine) on two-way escape and avoidance learning. Rats were tested on either escape or avoidance learning at 80 days of age after chemical sympathectomy at birth or 40 or 80 days of age. Neonatal and chronic sympathectomy (at 40 days), but not acute sympathectomy (at 80 days), resulted in depressed escape learning. Avoidance learning was affected by neonatal sympathectomy and partially by acute sympathectomy. The results have implications for the role of the autonomic nervous system in escape-avoidance learning.
Lord BJ, King MG, Pfister HP
J Comp Physiol Psychol 1976; 90:303-16.

alteration of carbohydrate and lipid metabolism following sympathectomy

Recent Adv Stud Cardiac Struct Metab 1976; 9:259-67.
Imbach A

These results indicate an important alteration of carbohydrate and lipid metabolism after chemical sympathectomy, thus supporting a role of the sympathetic nervous system in their regulation.

sympathectomy on insulin receptors and insulin action

Insulin receptors and effects of insulin on lipolysis, lipogenesis and glucose transport were investigated in fat cells obtained from rats chemically sympathectomized with 6-hydroxydopamine. Four days after a single injection of 6-hydroxydopamine (50 mg/kg), the norepinephrine content of the epididymal adipose tissue was reduced by 97.5%. The number of high-affinity insulin binding sites was increased moderately (16%). In parallel, the sensitivity to insulin of the isoprenaline-stimulated lipolysis was increased as judged from insulin concentrations yielding half-maximal inhibition which were lower (40%) in the treated group. Glucose metabolism, however, was inhibited by chemical sympathectomy: the glucose transport rate was significantly reduced and fatty acid synthesis was nearly totally abolished. Insulin was still effective in stimulating both parameters but failed to restore normal levels. The results suggest that the sympathetic innervation of adipose tissue may exert an inhibitory effect on the number of high-affinity insulin receptors as well as on the sensitivity of the lipolysis to insulin, as both parameters were increased by sympathectomy. To explain the inhibitory effect of 6-hydroxydopamine treatment on glucose transport and fatty acid synthesis, a possible trophic effect of the sympathetic innervation is discussed as well as indirect mechanism counteracting the effects of the chemical sympathectomy.

Effects of chemical sympathectomy on insulin receptors and insulin action in isolated rat adipocytes.
Joost HG, Quentin SH J Pharmacol Exp Ther 1984; 229:839-44.

relevant to the pathogenesis of human dysautonomias.

Brimijoin, S, Lennon, V A

Systemic injection of monoclonal antibodies to neural acetylcholinesterase in adult rats caused a syndrome with permanent, complement-mediated destruction of presynaptic fibers in sympathetic ganglia and adrenal medulla. Ptosis, hypotension, bradycardia, and postural syncope ensued. In sympathetic ganglia, acetylcholinesterase activity disappeared from neuropil but not from nerve cell bodies. Choline acetyltransferase activity and ultrastructurally defined synapses were also lost. Electrical stimulation of presynaptic fibers to the superior cervical ganglion ceased to evoke end-organ responses. On the other hand, direct ganglionic stimulation remained effective, and the postganglionic adrenergic system appeared intact. Motor performance and the choline acetyltransferase content of skeletal muscle were preserved, as was parasympathetic (vagal) function. This model of selective cholinergic autoimmunity represents another tool for autonomic physiology and may be relevant to the pathogenesis of human dysautonomias.

Norepinephrine depletion commonly is the desired effect, other neurotransmitters (eg ATP, NPY and enkephalins) are depleted by sympathectomy

The term Sympathectomy used in this discussion refers mainly to the lesioning of postganglionic noradrenergic (NA) neurons and fibers except where noted. Although norepinephrine depletion commonly is the desired effect, other costored neurotransmitters (eg ATP, NPY and enkephalins) are depleted by sympathetic denervation. The multitude of research studying the effects of sympathetic loss is made possible by the morphologically defined anatomy of the postganglionic sympathetic chains, the sensitivity of postganglionic NA neurons to nerve growth factor (NGF) deprivation, and the phenotypic specialty of these neurons that allows for the selective uptake of neurotoxins.

Primer on the Autonomic Nervous System

By David Robertson
Published 2004

Serum Dopamine-β -Hydroxylase: Decrease after Chemical Sympathectomy

Dopamine-β -hydroxylase is an enzyme that is localized to catecholamine-containing vesicles in sympathetic nerves and the adrenal medulla, and is also found in the serum. Treatment of rats with 6-hydroxydopamine, a drug which destroys sympathetic nerve terminals, leads to a decrease in serum dopamine-β -hydroxylase activity.

		Weinshilboum, Richard; Axelrod, Julius
Publication:		Science, Volume 173, Issue 4000, pp. 931-934
Publication Date:		09/1971
Origin:		JSTOR

In the adrenal medulla, AChE-rich presynaptic fibers disappeared within 3 days

In the adrenal medulla, AChE-rich presynaptic fibers disappeared within 3 days
Autoimmune Preganglionic Sympathectomy Induced by Acetylcholinesterase Antibodies
Stephen Brimijoin and Vanda A. Lennon
Proceedings of the National Academy of Sciences of the United States of America, Vol. 87, No. 24 (Dec., 1990), pp. 9630-9634 (article consists of 5 pages)
Published by: National Academy of Sciences
• 
  

intact adrenal medulla was essential for SHR groups to achieve many of the adaptations associated with training.

Responses of SHR to combinations of chemical sympathectomy, adrenal demedullation, and training

C. M. Tipton, M. S. Sturek, R. A. Oppliger, R. D. Matthes, J. M. Overton and J. G. Edwards

The single and combined influences of exercise training, chemical sympathectomy (SYMX), and surgical adrenal demedullation (D) were examined in four separate spontaneously hypertensive rat (SHR) groups. SYMX was accomplished by subcutaneous injections of antinerve growth factor (ANGF) over a 5-day period after birth followed by 20 separate injections of guanethidine sulfate during a 27-day period. Measurements of urine, plasma, or tissue levels of catecholamines indicated that these experimental procedures were effective. The animals were exercise trained (T) for 10 wk or longer at 40-60% of their VO2max capacity, and all T groups exhibited longer run times or higher muscle cytochrome oxidase activity; however, only the SHR + T subgroup had a significantly higher VO2max value than its control (NT). Training lowered resting systolic blood pressure (SBP) in the SHR subgroup but normalization of SBP occurred only with SYMX. Interestingly, only the SYMX + T subgroup with intact adrenal glands also had lower SBP values than the NT. The SHR + T and SYMX + T subgroups but not the SYMX + D + T had less cardiac acceleration after ip injections of atropine than their controls. Heavier heart weights were observed only in the SHR + T subgroup; SYMX was associated with lighter heart weights regardless of whether the rats had been T or D. These collective findings demonstrated again the importance of the sympathetic nervous system to an exercise response, suggesting that an intact adrenal medulla was essential for SHR groups to achieve many of the adaptations associated with training.
Am J Physiol Heart Circ Physiol 247: H109-H118, 1984;
0363-6135/84 $5.00

no one has examined the effects of sympathectomy, adrenergic blockade, or adrenal demedulation

Thus, until proven otherwise, we suggest that many, if not all, of the anti-inflammatory effects associated with efferent vagal stimulation are due to the concurrent activation of the adrenal medulla and the sympathetic nervous system. It is surprising that no one has examined the effects of sympathectomy, adrenergic blockade, or adrenal demedulation on the inhibition of TNF-� and inflammation produced by efferent vagal stimulation.

PubMed articles by:
Autonomic Innervation and Regulation of the Immune System
(1987-2007)
Dwight M. Nance and Virginia M. Sanders
Brain Behav Immun. 2007 August; 21(6): 736–745.


Madden KS, Felten SY, Felten DL, Sundaresan PR, Livnat S.
Sympathetic neural modulation of the immune system. I.
Depression of T cell immunity in vivo and in vitro following chemical sympathectomy. Brain Behav.Immun.
1989;3:72–89. [PubMed]

HYPOTHALAMUS:

RECENT STUDIES ON THE HYPOTHALAMUS:
K. E. COOPER
TEMPERATURE REGULATION AND THE HYPOTHALAMUS
Br. Med. Bull., September 1966; 22: 238 - 242.
......pathway is necessary for the complete febrile response in cats was shown by Knkston (1935), who found that complete bilateral sympathectomy greatly reduced the pyrogenic response, and by Douglas (1954), who showed the importance of ear vasoconstriction in the......

Role of Dopamine

Dopamine has moved from being an insignificant intermediary in the formation of noradrenaline in 1957 to its present-day position as a major neurotransmitter in the brain. This neurotransmitter is involved in the control of movement and Parkinson's disease, the neurobiology and symptoms of schizophrenia and attention deficit hyperactivity disorder. It is also considered an essential element in the brain reward system and in the action of many drugs of abuse. This evolution reflects the ability of several famous names in neuropharmacology, neurology and psychiatry to apply new techniques to ask and answer the right questions. There is now excellent knowledge about the metabolism of dopamine, dopamine receptor systems and the structural organisation of dopamine pathways in the brain. Less is known about the function of the different receptors and how the various dopamine pathways are organised to produce normal behaviour, which exhibits disruption in the disease states mentioned. In particular, we have very limited information as to why and how the dopamine system dies or becomes abnormal in Parkinson's disease or a neurodevelopmental disorder such as schizophrenia. Dopamine neurones account for less than 1% of the total neuronal population of the brain, but have a profound effect on function. The future challenge is to understand how dopamine is involved in the integration of information to produce a relevant response rather than to study dopamine in isolation from other transmission systems. This integrated approach should lead to greater understanding and improved treatment of diseases involving dopamine.
Charles A Marsden
1
School of Biomedical Sciences, Institute of Neuroscience, Medical School, Queen's Medical Centre, University of
Nottingham, Nottingham NG7 2UH

mental stress is abolished by sympathectomy

AUTONOMIC NERVOUS SYSTEM:
C. LOVATT EVANS
SWEATING IN RELATION TO SYMPATHETIC INNERVATION
Br. Med. Bull., September 1957; 13: 197 - 201.
*......or to mental stress is abolished by sympathectomy, but apocrine emotional sweating in...axilla is stated not to be abolished by sympathectomy (Shelley & Hurley, 1952). 4. The Sympathetic...according to the results of operations for sympathectomy, there are sudomotor as well as pilomotor......

bizarre phenomena

AUTONOMIC NERVOUS SYSTEM:
J. G. MURRAY and J. W. THOMPSON
COLLATERAL SPROUTING IN RESPONSE TO INJURY OF THE AUTONOMIC NERVOUS SYSTEM, AND ITS CONSEQUENCES
Br. Med. Bull., September 1957; 13: 213 - 219.
......after sympathec- tomy, e.g., surgical sympathectomy of thoracicolumbar region and upper...syndrome (Haxton, 1948; Young, 1956) Post-sympathectomy pain (Tracy & Cockett, 1957) After...reflex autonomic function after surgical sympathectomy, and (ii) bizarre phenomena. The operation......

Autonomic innervation of the heart and vasculature

As shown in the following table, activation of sympathetic efferent nerves to the heart increases heart rate (positive chronotropy), contractility (positive inotropy), rate of relaxation (increased lusitropy), and conduction velocity (positive dromotropy). Parasympathetic effects are opposite. Parasympathetic effects on inotropy are weak in the ventricle, but relatively strong in the atria. Physiologically, whenever the body activates the sympathetic system, it down regulates parasympathetic activity, and visa versa, so that the activities of these two branches of the autonomic nervous system respond reciprocally.

In blood vessels, sympathetic activation constricts arteries and arterioles (resistance vessels), which increases resistance and decreases distal blood flow. Sympathetic-induced constriction of veins (capacitance vessels) decreases venous compliance and blood volume, and thereby increases venous pressure. Most blood vessels in the body do not have parasympathetic innervation. However, parasympathetic nerves do innervate salivary glands, gastrointestinal glands, and genital erectile tissue where they cause vasodilation.

The overall effect of sympathetic activation is to increase cardiac output, systemic vascular resistance (both arteries and veins), and arterial blood pressure. Enhanced sympathetic activity is particularly important during exercise, emotional stress, and during hemorrhagic shock.

Cardiac function is altered by neural activation. Sympathetic stimulation increases heart rate (positive chronotropy), inotropy and conduction velocity (positive dromotropy), whereas parasympathetic stimulation of the heart has opposite effects. Sympathetic and parasympathetic effects on heart function are mediated by beta-adrenoceptors and muscarinic receptors, respectively.

Sympathetic adrenergic nerves travel along arteries and nerves and are found in the adventitia (outer wall of a blood vessel). Varicosities, which are small enlargements along the nerve fibers, are the site of neurotransmitter release. Capillaries receive no innervation. Activation of vascular sympathetic nerves causes vasoconstriction of arteries and veins mediated by alpha-adrenoceptors.

Richard E. Klabunde, Ph.D.

loss of myocardial sympathetic-nerve terminals

"The classification of dysautonomias has been confusing, and the pathophysiology obscure. We examined sympathetic innervation of the heart in patients with acquired, idiopathic dysautonomias using thoracic positron-emission tomography and assessments of the entry rate of the sympathetic neurotransmitter norepinephrine into the cardiac venous drainage (cardiac norepinephrine spillover). We related the laboratory findings to signs of sympathetic neurocirculatory failure (orthostatic hypotension and abnormal blood-pressure responses associated with the Valsalva maneuver), central neural degeneration, and responsiveness to treatment with levodopa–carbidopa (Sinemet)."

"The results of 6-[¹⁸F]fluorodopamine positron-emission tomography and neurochemical analyses support a new clinical pathophysiologic classification of dysautonomias, based on the occurrence of sympathetic neurocirculatory failure, signs of central neurodegeneration, and responsiveness to levodopa–carbidopa."

Sympathetic Cardioneuropathy in Dysautonomias

David S. Goldstein, M.D., Ph.D., Courtney Holmes, C.M.T., Richard O. Cannon, M.D., Graeme Eisenhofer, Ph.D., and Irwin J. Kopin, M.D.

The New England Journal of Medicine , March 6, 1997

Clinical Investiation

To validate the method, healthy volunteers underwent 6-¹⁸F-fluorodopamine scanning of the head, thorax, and abdomen, with or without treatment with desipramine to block sympathoneural uptake of catecholamines. ¹³N-Ammonia scanning was used to address possible group differences in 6-¹⁸F-fluorodopamine delivery by blood perfusion. Results: Desipramine treatment was associated with decreased 6-¹⁸F-fluorodopamine–derived radioactivity in the heart, renal cortex, and thyroid gland but not in the liver, spleen, renal pelvis, or salivary glands. Both the PD+OH group and the PAF group had decreased 6-¹⁸F-fluorodopamine–derived radioactivity in the heart (P <> (P = 0.02 and P = 0.005, respectively). The PD+OH group also had decreased radioactivity in the thyroid gland (P = 0.01). Neither group had decreased radioactivity in the other organs, after correction for ¹³N-ammonia–derived radioactivity. Conclusion: 6-¹⁸F-Fluorodopamine scanning visualizes sympathetic innervation in the heart, renal cortex, and thyroid gland. Both PD+OH and PAF involve decreased noradrenergic innervation that is most prominent in the heart but is also detectable in extracardiac organs.
Dnyanesh N. Tipre, MPharm, PhD and David S. Goldstein, MD, PhD

Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

JNM 2005 46

Heterogenous cardiac sympathetic innervation - cause of sudden cardiac death

Recently, a colony of German shepherd dogs with inherited spontaneous cardiac arrhythmias and associated sudden death has been developed and characterized. Due to the median age of onset of the arrhythmia (4.5 months), the tendency for the arrhythmia to occur during REM sleep or after exercise, and the absence of structural heart disease, we hypothesized a developmental abnormality of the sympathetic innervation to the heart. METHODS AND RESULTS: We studied 11 dogs from this colony, ranging in age from 6 months to 6 years, and four 7-month-old German shepherd dogs unrelated to the colony as controls. We imaged the distribution of functional myocardial sympathetic innervation and perfusion with [123I]metaiodobenzylguanidine (MIBG) and 201Tl, respectively. Sympathetic nerve distribution was evaluated morphologically by immunocytochemical localization of tyrosine hydroxylase. All of the hearts showed evidence of a regional decrease in MIBG uptake, ranging from 5.3% to 53.4% of the myocardium, whereas control dogs showed homogeneous MIBG uptake. Immunocytochemical studies on sections from regions with decreased MIBG uptake showed a striking paucity of nerves compared with regions with normal MIBG uptake, confirming denervation. When the dogs were grouped into those with (n=6) and without (n=5) evidence of ventricular tachycardia on ambulatory ECG, the group with ventricular tachycardia showed 35+/-16.5% denervation, whereas the group without ventricular tachycardia showed 12+/-5.6% denervation (P<.02). CONCLUSIONS: Abnormal heterogeneous sympathetic innervation exists in these dogs with inherited ventricular arrhythmia and sudden cardiac death. Mechanisms relating the presence and extent of regional denervation to the incidence of ventricular arrhythmia remain to be defined.

Loss of sympathetic innervation to the eye

Loss of sympathetic innervation caused a significant increase in steady state mRNA levels of fibronectin and a 15% increase in laminin-ß1 mRNA 3 weeks after surgical sympathectomy. Protein expression also increased at this point. In addition, capillary basement membrane thickness increased significantly. NG2 proteoglycan staining decreased significantly in pericytes in the sympathectomized rat retina. Steady state mRNA for PDGF-BB decreased significantly 6 weeks after surgery.
Sympathetic nerves may be compromised in diabetes, and these findings suggest that they may regulate some complications of diabetic retinopathy. Gene expression levels of fibronectin and laminin-ß1 changed between 1 and 3 weeks. These data are supported by electron microscopy, which showed the increase in basement membrane thickness in vivo. Loss of sympathetic innervation to the eye also caused a decrease in the number of pericytes. Steady state mRNA expression of PDGF-BB was reduced, suggesting a mechanism for the loss of pericytes in the sympathectomized retina. Overall, these results suggest that sympathetic nerve alterations may function in some complications observed in diabetic retinopathy, and this may be a suitable model to investigate therapies for this disorder.
(Investigative Ophthalmology and Visual Science. 2005;46:744-748.)
© 2005 by The Association for Research in Vision and Ophthalmology, Inc.
DOI: 10.1167/iovs.04-1023

Coronary artery calcification

Ludman et al. have reported the prevalence of coronary artery calcification in heart transplant recipients and examined risk factors for calcifi- cation[1]. The authors noted that in some patients calcification was present despite angiographically trivial disease. One possible explanation to consider is that in cardiac transplant recipients, the usual close correlation between coronary artery calcification
and atheroma may not hold true.
Specifically, denervation might result in calcification of the media of coronary vessels. Medial calcification cannot easily be distinguished from intimal calcification with electron beam CT scanning.
Autopsy studies of unselected patients show that coronary calcification is atherosclerosis-related and intimal and this is the basis for using the calcification score as a proxy foratheroma burden. However, calcification of the media in in peripheral vessels is commonin diabetic patients in whom it is closely related to autonomic neuropathy and there are case reports of medial calcification in coronary vessels of diabetic patients.
Lumbar sympathectomy can also result in medial calcification
of peripheral vessels. Thus given that the transplanted heart is denervated
it is at least possible that some of the calcification detected
by Ludman et al is medial.
H.M. COLHOUN
Circ 1994; 90: 1786–93.

Clinical Lecturer in
Epidemiology and Public Health,
University College,
London, U.K.

Ablation of the sympathetic nervous system by chemical sympathectomy is a standard model for the study of sympathetic nervous system regulation of imm

Ablation of the sympathetic nervous system by chemical sympathectomy is a standard model for the study of sympathetic nervous system regulation of immune function. We have previously documented that chemical denervation results in enhanced antigen-specific, but suppressed mitogen-induced, cytokine production by spleen cells. In our investigation into the mechanisms of sympathectomy-induced immune alterations, we first evaluated the peritoneal environment into which the protein antigen keyhole limpet hemocyanin is administered. Denervation resulted in increased production of tumor necrosis factor- by peritoneal exudate cells and these cells appeared to have enhanced antigen presenting capability. We hypothesized that nerve terminal destruction may be inducing an inflammatory response by monocyte/macrophages and other cell types throughout the periphery that could differentially alter subsequent mitogen versus antigen-specific responses. However, no evidence of sympathectomy-induced systemic or local splenic inflammatory responses was observed, as indicated by measuring the proinflammatory cytokines tumor necrosis factor- and interleukin-1. These experiments indicate that an inflammatory response is not likely to be responsible for sympathectomy-induced immune alterations, eliminating a potential confounding factor in interpreting sympathectomy studies. Copyright 2001 Elsevier Science (USA).

Authors: Callahan T.A.^{1, 2}; Moynihan J.A.^{1, 2, 3, 4, 5}

Source: Brain, Behavior, and Immunity, Volume 16, Number 1, February 2002 , pp. 33-45(13)

Effects of antidepressants on cytokine production and actions

There are intriguing analogies between many features of depression and physiological and behavioral responses to infection, which are mediated by the brain effects of cytokines. These observations suggest that depression can be considered as a psychoneuroimmunological disorder where a central increase of pro-inflammatory cytokines, may have adverse consequences on the functional activity of the neurochemical and neuroendocrine systems implicated in the symptoms of the disorder. According to this hypothesis, the therapeutic effects of antidepressants should be at least partly exerted by attenuating the brain expression and/or actions of pro-inflammatory cytokines. Despite their inherent limitations, animal models of depression that are based on behavioral and pharmacological analogies with the symptoms observed in humans, represent the best available tool to test this hypothesis and to investigate the action mechanisms of the immune effects of antidepressants. Treatment with different classes of antidepressants indeed conferred protection against cytokine-induced depressive-like biological and behavioral changes. This ‘anti-inflammatory’ profile may be due to alterations of the pro-/anti-inflammatory cytokine balance. The mechanisms underlying these effects of antidepressants are presently unknown, but the available literature suggests several possibilities, including actions on different molecules representing potential mediators of mood disorders induced by cytokines. The studies summarized in this review have opened up new vistas in both the pathophysiology of depression and the pharmacology of antidepressants. Whether their demonstrated immune effects are a side effect or a significant part of their clinical activity still remains to be elucidated.

Nathalie Castanon^{, , a}, Brian E. Leonard^b, Pierre J. Neveu^a and Raz Yirmiya^c

^a INRA-INSERM U394, Neurobiologie Integrative, Institut François Magendie, Rue Camille Saint-Saëns, Bordeaux Cedex 33077, France

^b Pharmacology Department, National University of Ireland, Galway, Ireland

^c Department of Psychology, The Hebrew University, Mount Scopus, Jerusalem 91905, Israel

Received 9 July 2001.

Available online 1 October 2002.

In 1965, Schildkraut postulated that noradrenaline may play a pivotal role in the aetiology of depression. In favour of this hypothesis was the observ

In 1965, Schildkraut postulated that noradrenaline may play a pivotal role in the aetiology of depression. In favour of this hypothesis was the observation that the antihypertensive drug reserpine, which depletes central and peripheral vesicular stores of catecholamines such as noradrenaline, can precipitate depression in patients in remission. The experimental drug -methyl-paratyrosine that blocks the synthesis of noradrenaline and dopamine by inhibiting the rate-limiting enzyme tyrosine hydroxylase also precipitates depression in patients during remission. Such findings are only indirect indicators that noradrenaline plays an important role in human behaviour, and may be defective in depression – more direct evidence is needed to substantiate the hypothesis.
In depression, it should be emphasised that the reduced growth hormone response to clonidine cannot be accounted for by the drug treatment, age or gender of the patient, which supports the view that the noradrenergic system is dysregulated. Lastly, determination of the urine or plasma concentrations of MHPG (an indicator of central noradrenergic activity), suggests that central noradrenergic function is sub-optimal in depression. Taken together, these results suggest that central noradrenergic function is decreased in depression, an event leading to an increase in the density of the post-synaptic ß-adrenoceptors (Leonard, 1986; Dinan, 1994).
The role of serotonin (5-hydroxytryptamine, 5-HT) has also been extensively studied in patients with depression. Whereas the overall psychophysiological effects of noradrenaline in the central nervous system appear to be linked to drive and motivation, 5-HT is primarily involved in the expression of mood (see Charney et al, 1991). The main 5-HT metabolite, 5-hydroxyindole acetic acid (5-HIAA), is reduced in the cerebrospinal fluid (CSF) of patients with severe depression, as are 5-HT and 5-HIAA in the limbic regions of the brain of suicide victims (Agren, 1980). Serotonin receptor function is also abnormal in depression with an increase in the density of cortical 5-HT_2a receptors in the brains of suicide victims and also on the platelet membrane of patients with depression.
Dopaminergic function
Studies on platelets, lymphocytes, changes in cerebrospinal fluid metabolites of brain monoamines and post-mortem studies suggest that a major abnormality in both noradrenergic and serotonergic function occurs in depression, and that such changes could be causally related to the disease process.
Less attention has been paid to the possible involvement of dopamine in this disorder. However, anhedonia is a characteristic feature of major depression, and a defect in dopaminergic function is thought to be causally involved in this symptom (Willner, 1983). The concentration of the main dopamine metabolite, homovanillic acid (HVA), is decreased in the CSF of patients with depression, particularly those with psychomotor retardation.

Advances in Psychiatric Treatment (2000) 6: 178-186
© 2000 The Royal College of Psychiatrists

Clinical implications of mechanisms of action of antidepressants

Brian Leonard

Sympathetic innervation of white adipose tissue and its regulation of fat cell number

White adipose tissue (WAT) is innervated by the sympathetic nervous system (SNS), and the central origins of this innervation have been demonstrated for inguinal and epididymal WAT (iWAT and eWAT, respectively) using a viral transneuronal tract tracer, the pseudorabies virus (PRV). Although the more established role of this sympathetic innervation of WAT is as a major stimulator of lipid mobilization, this innervation also inhibits WAT fat cell number (FCN); thus, local denervation of WAT leads to marked increases in WAT mass and FCN. The purpose of this study was to extend our understanding of the SNS regulation of FCN using neuroanatomical and functional analyses. Therefore, we injected PRV into retroperitoneal WAT (rWAT) to compare the SNS outflow to this pad from what already is known for iWAT and eWAT. In addition, we tested the ability of local unilateral denervation of rWAT or iWAT to promote increases in WAT mass and FCN vs. their contralateral neurally intact counterparts. Although the overall pattern of innervation was more similar than different for rWAT vs. iWAT or eWAT, its SNS outflow appeared to involve more neurons in the suprachiasmatic and solitary tract nuclei. Denervation produced significant increases in WAT mass and FCN for both iWAT and rWAT, but FCN was increased significantly more in iWAT than in rWAT. These data suggest differences in origins of the sympathetic outflow to WAT and functional differences in the WAT SNS innervation that could contribute to the differential propensity for fat cell proliferation across WAT depots in vivo.
Robert R. Bowers,^1,* William T. L. Festuccia,^2,* C. Kay Song,³ Haifei Shi,³ Renato H. Migliorini,² and Timothy J. Bartness³

¹Molecular and Cellular Biology and Pathobiology Program, Medical University of South Carolina, Charleston, South Carolina 29425; ²Department of Physiology, School of Medicine, University of São Paulo, Ribeirão Preto-SP, 14049-900 Brazil; and ³Department of Biology and Center for Behavioral Neuroscience, Georgia State University, Atlanta, Georgia 30303

Submitted 29 September 2003 ; accepted in final form 17 February 2004

Cross-talk between sympathetic neurons and adipocytes in coculture.

L C Turtzo, R Marx, M D Lane

Departments of Biological Chemistry and Neuroscience, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.

White adipose tissue plays an integral role in energy metabolism and is governed by endocrine, autocrine, and neural signals. Neural control of adipose metabolism is mediated by sympathetic neurons that innervate the tissue. To investigate the effects of this innervation, an ex vivo system was developed in which 3T3-L1 adipocytes are cocultured with sympathetic neurons isolated from the superior cervical ganglia of newborn rats. In coculture, both adipocytes and neurons exhibit appropriate morphology, express cell-type-specific markers, and modulate key metabolic processes in one another. Lipolysis (stimulated by beta-adrenergic agents) and leptin secretion by adipocytes are down-regulated by neurons in coculture, effects apparently mediated by neuropeptide Y (NPY). Secretion of NPY by neurons is up-regulated dramatically by the presence of adipocytes in coculture and appears to be mediated by an adipocyte-derived soluble factor. Insulin, an antilipolytic agent, down-regulates NPY secretion. Our findings suggest that an adipocyte-derived factor(s) up-regulates the secretion of NPY by sympathetic neurons, which, in turn, attenuates lipolytic energy mobilization by adipocytes.

Proc Natl Acad Sci U S A. 2001 Oct 23;98 (22):12385-90 11606782 (P,S,E,B) Cited:1

Completing the Loop: Neuron-Adipocyte Interactions and the Control of Energy Homeostasis

Control of energy homeostasis requires communication between the brain and adipose tissue. The sympathetic nervous system plays an integral role in relaying information during this process. Recent investigations indicate that the contributions of the sympathetic nervous system to the regulation of adipose tissue are greater than initially appreciated. A recently developed co-culture system provides evidence that a local feedback loop may exist between sympathetic neurons and adipose tissue. The co-culture approach may prove useful in further investigations of the interaction between sympathetic neurons and adipocytes, and might be adapted to study interactions between other types of neurons and adipose tissue.

L. C. Turtzo¹, M. D. Lane^{1 1} Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Horm Metab Res 2002; 34: 607-615
DOI: 10.1055/s-2002-38245

The effect of splanchnic nerve section on the sensitivity of the adrenal cortex to adrenocorticotrophin in the calf

J Physiol. 1987 September; 390: 23–31. A V Edwards and C T Jones Physiological Laboratory, University of Cambridge. 1. Adrenal cortical responses to adrenocorticotrophin (ACTH) in conscious 2-6-week-old calves, in which both splanchnic nerves had been cut at least 7 days previously, were compared with those of normal calves of the same age in order to discover whether splanchnic nerve section affects the sensitivity of the adrenal cortex to the trophin. 2. In one series of experiments an increase in the release of endogenous ACTH was elicited by an i.v. infusion of noradrenaline (333 ng min-1 kg-1 for 10 min) and in another the concentration of ACTH in the plasma was artificially increased by infusing synthetic ACTH1-24 intravenously at either 5 or 10 ng min-1 kg-1 for 10 min. 3. In all groups mean plasma ACTH was linearly related to mean plasma cortisol and the sensitivity of the adrenal steroidogenic response to ACTH was found to be substantially reduced 7 or more days after section of both splanchnic nerves.

The effect of splanchnic nerve section on the sensitivity of the adrenal cortex to adrenocorticotrophin in the calf

1. Adrenal cortical responses to adrenocorticotrophin (ACTH) in conscious 2-6-week-old calves, in which both splanchnic nerves had been cut at least 7 days previously, were compared with those of normal calves of the same age in order to discover whether splanchnic nerve section affects the sensitivity of the adrenal cortex to the trophin. 2. In one series of experiments an increase in the release of endogenous ACTH was elicited by an i.v. infusion of noradrenaline (333 ng min-1 kg-1 for 10 min) and in another the concentration of ACTH in the plasma was artificially increased by infusing synthetic ACTH1-24 intravenously at either 5 or 10 ng min-1 kg-1 for 10 min. 3. In all groups mean plasma ACTH was linearly related to mean plasma cortisol and the sensitivity of the adrenal steroidogenic response to ACTH was found to be substantially reduced 7 or more days after section of both splanchnic nerves.

A V Edwards and C T Jones

Physiological Laboratory, University of Cambridge.

Limbic-cortical dysregulation: a proposed model of depression

J Neuropsychiatry Clin Neurosci 1997; 9:471-481
Copyright © 1997 by American Neuropsychiatric Association

REGULAR ARTICLES

HS Mayberg
Department of Medicine (Neurology), University of Texas Health Science Center at San Antonio 78284-6240, USA. mayberg@uthscsa.edu

A working model of depression implicating failure of the coordinated interactions of a distributed network of limbic-cortical pathways is proposed. Resting state patterns of regional glucose metabolism in idiopathic depressed patients, changes in metabolism with antidepressant treatment, and blood flow changes with induced sadness in healthy subjects were used to test and refine this hypothesis. Dorsal neocortical decreases and ventral paralimbic increases characterize both healthy sadness and depressive illness; concurrent inhibition of overactive paralimbic regions and normalization of hypofunctioning dorsal cortical sites characterize disease remission. Normal functioning of the rostral anterior cingulate, with its direct connections to these dorsal and ventral areas, is postulated to be additionally required for the observed reciprocal compensatory changes, since pretreatment metabolism in this region uniquely predicts antidepressant treatment response. This model is offered as an adaptable framework to facilitate continued integration of clinical imaging findings with complementary neuroanatomical, neurochemical, and electrophysiological studies in the investigation of the pathogenesis of affective disorders.

Causes of Changes in Brain Noradrenaline Systems and Later Effects on Responses to Social Stressors in Rhesus Monkeys: The Cascade Hypothesis

Disruption of social attachments in social primates produces a protest-despair response. In rhesus monkeys, the response is probably adaptive in the feral environment, although the despair stage resembles human depression in many respects. The severity of the response varies between individuals and is affected by deprivation of certain classes of social stimuli during development. Social deprivation is associated with differences in the concentrations of noradrenaline (NA) in cerebrospinal fluid and in responses to agents that affect catecholamine systems. Thus, early rearing conditions and pre-existing genetic or perinatal differences between monkeys can have long-term effects on the response to social separation, and NA system release and/or receptor mechanisms are involved.

NA systems appear to mediate adaptation to the environment from the level of perception to reorganization of neural tissue. Adaptation to the social environment may involve a cascade of changes that begins with behavioural coping attempts and terminates in structural reorganization of regions of the cerebral cortex. Processes at each level occur within environmentally appropriate but neurobiologically constrained time-frames. The cerebral NA system may be an adaptive mechanism that can fail or be damaged. Behavioural changes caused by such damage or failure would be manifested by inappropriate responses to environmental contingencies and inability to change behaviour to adapt to the prevailing environment. These features of NA system disorder could be common to depression and several other forms of human psychopathology.

Chapter Author: Gary W. Kraemer

Series: Novartis Foundation Symposia

Noradrenaline in basic models of depression.

This review reports anatomical studies evaluating central and peripheral alpha 2- and beta-adrenoceptors. The results suggest abnormalities exist in the noradrenergic system in depressed patients. Most animal models involve the use of stress to simulate depression in man. All models that have been developed lead to differential changes in noradrenergic function. We have assessed the effects of reboxetine, a novel, selective noradrenaline-reuptake inhibitor (NARI) in olfactory bulbectomised rats, a procedure that induces significant changes in amygdala function. Reboxetine is an effective antidepressant in the forced swim test and open field test in bulbectomised rats. Unlike the tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), reboxetine is ineffective in the 8-OH-DPAT hypothermia test, indicating that reboxetine is selective for the noradrenergic system. Owing to the abnormalities that occur in depression, it would seem sensible to target the noradrenergic system for treatment of this condition.
Leonard BE.
Department of Pharmacology, University College, Galway, Ireland.

Do noradrenaline and serotonin differentially affect social motivation and behaviour?

Dubini A, Bosc M, Polin V.

Pharmacia and Upjohn Clinical Development, Milan, Italy.

In a placebo-controlled 8-week study comparing the selective noradrenaline re-uptake inhibitor (NARI), reboxetine, with the selective serotonin reuptake inhibitor (SSRI), fluoxetine, in major depression, patient social motivation and behaviour were investigated through a newly developed 21-item self-rating scale, the Social Adaptation Self-evaluation Scale (SASS). At last assessment the mean SASS total score was significantly superior on both reboxetine (n = 103) and fluoxetine (n = 100) compared with on placebo (n = 99). In addition, the SASS total score in the reboxetine group was significantly higher compared with the fluoxetine group. At point-biserial correlation analysis, all but one item discriminated reboxetine from placebo, while only 12 items discriminated fluoxetine from placebo. In the reboxetine-fluoxetine comparison, nine items showed a positive association with reboxetine, while the opposite was never seen; the association was maximal in the area of negative self perception and lack of motivation towards action. These results support, at social functioning level, a differential effect of selective manipulation of the noradrenergic or serotonergic system in keeping with the long-debated hypothesis on the specific involvement of serotonin in regulating mood and of noradrenaline in sustaining drive.

Galanin induces a hyperpolarization of norepinephrine-containing locus coeruleus neurons

Pieribone V A, Xu ZQ, Zhang X, Grillner S, Bartfei T and Hökfelt T (1995) Galanin induces a hyperpolarization of norepinephrine-containing locus coeruleus neurons in the brainstem slice. Neuroscience 64, 861-874.

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Serum dopamine-p-hydroxylase: Decrease after chemical sympathectomy

Drugs as Tools in Neurotransmitter Research

By Alan A.

Effects of locus coeruleus lesions on vigilance and attentive behaviour

Delagrange P, Canu MH, Rougeul A, Buser P, Bouyer JJ.

Département de Neurophysiologie comparée, CNRS-UPMC, Paris, France.

Previous data have suggested that in the cat, expectancy behaviour (waiting for a target to appear) and associated electrocortical, focal, synchronized activity ('mu' rhythms) are modulated by a noradrenergic system possibly originating from the locus coeruleus (LC). To test the latter hypothesis, we have examined the behavioural and ECoG changes induced after bilateral LC lesions. Our results demonstrated that destruction of the anterior 3/4th of the LC (A6 noradrenergic cell group) resulted in a considerable increase of mu rhythms and expectancy behaviour, without episodes of drowsiness that normally occur. Destruction of the posterior fourth of LC (A4 noradrenergic group) only increased the duration of slow sleep. Extending the A6 lesion to include the dorsal ascending noradrenergic bundle also increased the expectancy behaviour and mu rhythms. Finally, when the nucleus subcoeruleus was also involved, the duration of slow sleep and the frequency of paradoxical sleep episodes increased. These findings indicate that the LC exerts an inhibitory effect on structures involved in the induction and persistence of expectancy behaviour with accompanying mu rhythms.

Behav Brain Res. 1993 Feb 26;53(1-2):155-65.

Compensatory increase in tyrosine hydroxylase activity

... INCREASE IN ACTIVITY AFTER CHEMICAL SYMPATHECTOMY, SCIENCE 163: 468 (1969). ... IN NEURONS OF NUCLEUS LOCUS COERULEUS DURING RETROGRADE REACTION, ...
www.sciencemag.org/cgi/content/refs/207/4430/537 - Similar pages - Note this

Peripheral, autonomic regulation of locus coeruleus noradrenergic neurons in brain: putative implications for psychiatry and psychopharmacology

the new data seem to allow a better understanding of how autonomic vulnerability or visceral dysfunction may precipitate or aggravate mental symptoms and disorder.

T. H. Svensson¹

(1)	Department of Pharmacology, Karolinska Institute, Box 60 400, S-104 01 Stockholm, Sweden

Received: 20 June 1986 Revised: 25 November 1986
Psychopharmacology

Sympathetic nervous system mediates cold stress-induced suppression of natural killer cytotoxicity

The aim of the present study is to investigate the mechanisms of suppression of splenic natural killer (NK) cytotoxicity caused by cold stress, using 6-hydroxydopamine (6-OHDA) as chemical sympathectomy. The NK activity was measured by ⁵¹chromium release assay. Central sympathectomy with intracerebroventricular injection of 6-OHDA significantly reduced the elevation of the plasma corticosterone level, the expression of Fos in hypothalamic paraventricular nucleus and in locus coeruleus, as well as the suppression of NK activity induced by cold stress at 4 °C for 4 h. Peripheral sympathectomy with intraperitoneal (i.p.) injection of 6-OHDA and blockade of β-adrenergic receptor with i.p. injection of propranolol also reversed the cold stress-induced suppression of NK cytotoxicity, but without significant effect on Fos expression in the brain. The results suggest that the activation of the hypothalamic-pituitary-adrenal axis induced by cold stress might be mediated, at least partially, by the central noradrenergic system, and that the cold stress-induced suppression of NK cytotoxicity might be mediated by the activation of the peripheral sympathetic nerve.

JIANG Xing-Hong ^{(1 2)} ; GUO Shi-Yu ^{(1 2)} ; SHUANG XU ^{(1 2)} ; YIN Qi-Zhang ⁽²⁾ ; OHSHITA Yusuke ⁽¹⁾ ; NAITOH Michiko ⁽¹⁾ ; HORIBE Yuzo ⁽¹⁾ ; HISAMITSU Tadashi ⁽¹⁾ ;
2004, vol. 358, n^o1, pp. 1-4 [ Neuroscience letters ISSN 0304-3940

Depletion of noradrenaline in the brain has been shown to cause a decrease in drive and motivation, and may be linked to depression.

A small area in the brainstem consisting of a pair of identical nuclei (clusters of neurons) in the pons from which all brain connections using noradrenaline arise. It appears to be involved in attention and mental focus.
A catecholamine neurotransmitter (catecholamine means that a substance belongs to a group of compounds containing ceratin structural characteristics, such as a catechol nucleus and an amine group), like dopamine. Cell bodies that contain noradrenaline are found in the pons and medulla, and these project neurons to the hypothalamus, thalamus, limbic system and cerebral cortex. These neurons are particularly important in controlling sleep patterns. Depletion of noradrenaline in the brain has been shown to cause a decrease in drive and motivation, and may be linked to depression.

locus coeruleus after guanethidine sympathectomy

Cytochemical study of the neurocytes of the rat locus coeruleus after guanethidine sympathectomy

Altan G, Iarygin VN, Grigor'eva AV.

The histone localization, template activity of chromatin and epinephrine fluorescence in L. Coeruleus (LC) neurons of normal a. guanethidine sympathectomized (GS) rats (15 mg/kg during 3, 8 or 14 days after birth) were studied. The absence of chromatin rearrangements connected with genome reprogramming under sympathectomy was documented by the fact that maximal doses of guanethidine gives no changes in ammoniacal silver staining pattern. However GS caused the decrease in nuclear and extranuclear template activity and in epinephrine fluorescence proportionally with GS. It is obvious that LC cells tend to form discrete classes according to their transcription levels.

Biull Eksp Biol Med. 1989 Feb;107(2):242-5.

Role of noradrenaline in sustaining drive

In a placebo-controlled 8-week study comparing the selective noradrenaline re-uptake inhibitor (NARI), reboxetine, with the selective serotonin reuptake inhibitor (SSRI), fluoxetine, in major depression, patient social motivation and behaviour were investigated through a newly developed 21-item self-rating scale, the Social Adaptation Self-evaluation Scale (SASS). At last assessment the mean SASS total score was significantly superior on both reboxetine (n = 103) and fluoxetine (n = 100) compared with on placebo (n = 99). In addition, the SASS total score in the reboxetine group was significantly higher compared with the fluoxetine group. At point-biserial correlation analysis, all but one item discriminated reboxetine from placebo, while only 12 items discriminated fluoxetine from placebo. In the reboxetine-fluoxetine comparison, nine items showed a positive association with reboxetine, while the opposite was never seen; the association was maximal in the area of negative self perception and lack of motivation towards action. These results support, at social functioning level, a differential effect of selective manipulation of the noradrenergic or serotonergic system in keeping with the long-debated hypothesis on the specific involvement of serotonin in regulating mood and of noradrenaline in sustaining drive.

Dubini A, Bosc M, Polin V.
Pharmacia and Upjohn Clinical Development, Milan, Italy.antidepressant therapy: differential effects on social [J Psychopharmacol. 1997]

The importance of noradrenaline in depression is supported by its association with clinical parameters such as vigilance and drive

The need for new and better antidepressants: reboxetine a new option.

Neuropsychiatry Unit, Institute of Clinical Neurosciences, Sahlgrenska University Hospital, Goteborg, Sweden.

The selective serotonin reuptake inhibitors (SSRIs) have obtained global attention but have not demonstrated superior efficacy in major depression compared with older tricyclic antidepressants. From a pharmacological viewpoint the noradrenergic system in the brain appears to have a central role in neurotransmitter organization. The importance of noradrenaline in depression is supported by its association with clinical parameters such as vigilance and drive. Reboxetine is a selective noradrenaline reuptake inhibitor--the first in its class to be marketed. In both preclinical and clinical studies reboxetine has been found to be an effective and safe antidepressant. Furthermore, reboxetine restores a patients' social functioning, producing a better quality of remission than fluoxetine.

Acta Psychiatr Scand Suppl. 2000;402:6-11.

The role of noradrenaline and selective noradrenaline reuptake inhibition in depression

Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Modena, Italy. brunello.nicoletta@unimo.it

Depression is a common disorder that impacts on all aspects of a person's life. For the past 10 years, clinicians have focused on serotonin in their treatment of depression. This is largely due to the growing acceptance of the efficacy and safety of the selective serotonin reuptake inhibitors (SSRIs) in comparison with older tricyclic antidepressants (TCAs). However, evidence for a role of noradrenaline in depression has been accumulating for some time, beginning with the discovery that drugs which either caused or alleviated depression acted to alter noradrenaline metabolism. Until recently, the role of noradrenaline in depression was predicted from clinical experience with noradrenergic TCAs (desipramine, nortriptyline and protriptyline) and selective serotonin and noradrenaline reuptake inhibitors (venlafaxine, milnacipran). The licensing of reboxetine, a selective noradrenaline reuptake inhibitor now allows the role of noradrenaline in depression to be investigated directly. This review presents key data from the literature that support a role for noradrenaline in depression taking into account neurophysiology, psychopharmacology and clinical trial data.

Brunello N, Mendlewicz J, Kasper S, Leonard B, Montgomery S, Nelson J, Paykel E, Versiani M, Racagni G.

Noradrenaline in basic models of depression

This review reports anatomical studies evaluating central and peripheral alpha 2- and beta-adrenoceptors. The results suggest abnormalities exist in the noradrenergic system in depressed patients. Most animal models involve the use of stress to simulate depression in man. All models that have been developed lead to differential changes in noradrenergic function. We have assessed the effects of reboxetine, a novel, selective noradrenaline-reuptake inhibitor (NARI) in olfactory bulbectomised rats, a procedure that induces significant changes in amygdala function. Reboxetine is an effective antidepressant in the forced swim test and open field test in bulbectomised rats. Unlike the tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), reboxetine is ineffective in the 8-OH-DPAT hypothermia test, indicating that reboxetine is selective for the noradrenergic system. Owing to the abnormalities that occur in depression, it would seem sensible to target the noradrenergic system for treatment of this condition.
Eur Neuropsychopharmacol. 1997 Apr;7 Suppl 1:S11-6; discussion S71-3.

Psychopathology of depression

[My paper] Brian E Leonard

This review assesses some of the important advances that have been made in our understanding of the psychopathology of depression. While the monoamine theory, that postulates dysfunctional noradrenergic and serotonergic systems as the underlying cause of depression, has been valuable in the development of conventional antidepressants that are thought to act by reversing these dysfunctional states, recent clinical and experimental studies have questioned this reductionist view of depression. This has led to an assessment of the role of dysfunctional endocrine and immune systems in the aetiology of depression. In addition to explaining the link between defective neurotransmitter function and the symptoms of depression, changes in the endocrine and immune axes also help to explain the link between major depression and physical ill health. In addition, experimental and clinical studies have extended the possible involvement of neurotransmitters to include the glutamate and GABA systems. Such approaches may stimulate the development of new types of antidepressants that hopefully will combine increased efficacy with shorter speed of onset and improved side effect profiles.

Drugs Today (Barc). 2007 Oct ;43 (10):705-16 17987223 (P,S,E,B,D)