Noradrenaline Neurons Research Articles

The Auditory Cortex in Schizophrenia

The Auditory Cortex in Schizophrenia

The organic cation transporters (OCT1, OCT2, EMT) and the plasma membrane monoamine transporter (PMAT) show differential distribution and cyclic expression pattern in human endometrium and early pregnancy decidua

The non-neuronal monoamine transporters (OCT1, OCT2, EMT, and PMAT) play a key role in the clearance of monoamines from extracellular compartments. In a previous report we described endometrial distribution and cyclic variation of the vesicular monoamine transporter (VMAT2) mRNA and the neuronal norepinephrine transporter (NET) mRNA. In the present study we used in situ hybridization, real-time PCR and immunohistochemistry to reveal tissue distribution and cyclic variation of mRNA for the non-neuronal monoamine transporters in the human endometrium and early pregnancy decidua. We found that non-neuronal monoamine transporters are predominantly expressed in the stroma. The plasma membrane monoamine transporter (PMAT) mRNA expression peaked in the proliferative phase, whereas the extra-neuronal monoamine transporter (EMT) mRNA expression peaked in the secretory phase. The organic cation transporter 2 (OCT2) mRNA expression was exclusively detected in few scattered stromal cells and OCT1 mRNA was not detected at all. Our present results demonstrate that PMAT, EMT, and OCT2 transporters are expressed in the endometrial stroma and can potentially regulate reuptake of monoamines in general and histamine in particular. Taken together with our previous finding of VMAT2 mRNA in epithelial cells, we suggest a paracrine interaction between stromal and epithelial cells, which may modulate certain steps of the reproductive process.

Tracemetals, neuromelanin and neurodegeneration: An interesting area for research

Byline: T. Sathyanarayana Rao, Luigi. Zecca, K. Rao International Scenario The understanding of cellular neurodegeneration in brain disease is today's major challenge. The mapping of region-specific changes in the brain during neurodegeneration is a thrust area in neuroscience. Bipolar disorders are classical neuropsychiatric disorders where crosstalk between environmental factors and genetics plays an important role in the etiology of these disorders. Locus coeruleus (LC) is the main brain region containing norepinephrine neurons. The rostral projections from these neurons seem to be involved in the modulation of neuronal activity, metabolism and memory[sup] [1],[2] whereas the spinal cord projections are known to modulate spinal motoneuron function.[sup] [3],[4] Neuronal loss in LC occurs in Parkinson's disease (PD) and Alzheimer's disease and Down's syndrome[sup] [5],[6] in the midbrain regions. In Alzheimer's disease and Down's syndrome, it is not clear whether neuronal loss in LC is a primary event or a consequence of retrograde degeneration of cortically projecting cells due to the loss of cortical synapses. In PD, results have showed neuronal loss in substania nigra (SN) compared to LC.[sup] [5],[6],[7],[8] However, a recent study reported extensive impairment of LC neurons in PD.[sup] [9] SN and LC share anatomical and biochemical similarities, both being pigmented because of neuromelanin (NM) and both composed of catecholaminergic neurons. The relationship of factors like iron, ferritins and NM[sup] [10],[11],[12],[13],[14] to aging has been analyzed in previous studies. These factors may influence neuronal viability and undergo dramatic changes in PD. As aging is an important risk factor for PD, it would be relevant to establish the age-related changes in elements involved in oxidative stress like iron, copper and related molecules, all of which have been implicated as putative pathogenic factors. Due to their role in peroxidation, changes in iron, copper, their major storage proteins ferritin and ceruloplasmin (CP), together with the enzymes manganese-superoxide dismutase (SOD) and copper/zinc-SOD were determined in human SN and LC at various ages. Being a strong chelator of iron and other toxic metals,[sup] [14] NM has been shown to be a strong modulator of their cellular effects.[sup] [15],[16],[17] Luigi from the Italian group did a comparative analysis of metal-related neuronal vulnerability in two brainstem nuclei, the locus coeruleus (LC) and substantia nigra (SN), which are known targets of the etiological noxae in PD and related disorders. LC and SN pars compacta neurons both degenerate in PD and other Parkinsonisms although LC neurons are comparatively less affected with a variable degree of involvement. In this study, iron, copper and their major molecular forms like ferritins, ceruloplasmin, neuromelanin (NM), manganese-superoxide dismutase (SOD) and copper/zinc-SOD were measured in LC and SN of normal subjects at different ages. Iron content in LC was much lower than that in SN and the ratio of heavy chain ferritin / iron in LC was higher than in SN. The NM concentrations were similar in LC and SN although the iron content in NM of LC was much lower than in SN. In both regions, heavy and light chain ferritins were present only in glia and were not detectable in neurons. This data suggests that iron mobilization and toxicity are lower in LC neurons than in SN and are efficiently buffered by NM. The greater damage occuring in SN could be related to the higher content of iron. Ferritins accomplish the same function of buffering iron in glial cells. Ceruloplasmin levels were similar in LC and SN although copper content was higher in LC. However, the copper content in NM of LC was higher than that of SN, indicating a higher copper mobilization in LC neurons. Manganese-SOD and copper / zinc-SOD had similar age-related trends in LC and SN. These results may explain some of the underlying lower vulnerability of LC compared to SN in Parkinsonian syndromes. …

Lack of significant toxicity after mirtazapine overdose: A five-year review of cases admitted to a regional toxicology unit

Introduction. Mirtazapine is a comparatively new antidepressant that selectively blocks central α2-adrenergic autoreceptors and postsynaptic 5-HT2 and 5-HT3 receptors, causing reduced neuronal norepinephrine and serotonin reuptake. The prevalence of mirtazapine prescribing has steadily risen; however, comparatively little information is available regarding the clinical features associated with mirtazapine overdose. Aims. To characterize the toxic features that result from mirtazapine overdose. Methods. We performed a retrospective case analysis of patients admitted to the Toxicology Unit of the Royal Infirmary of Edinburgh between January 2000 and December 2004 after stated mirtazapine overdose. Casenotes were examined for clinical, laboratory, and electrocardiographic safety data. Results. There were 117 mirtazapine cases where the median (interquartile range) stated dose ingested was 450 mg (240–785 mg). Conscious level was reduced in 27.2% of patients and there was a higher incidence of tachycardia (30.4%) than predicted from normal reference range values (p < 0.001). There was no evidence of any other significant clinical, laboratory, or electrocardiographic abnormality. Conclusions. Severe toxic features could be attributed to other co-ingested drugs or alcohol. The adverse clinical effects attributable to mirtazapine overdose appeared mild and predictable. Mirtazapine overdose appears to be associated with fewer features of severe toxicity than previously reported for other antidepressants.

Novel localization of norepinephrine transporter in sensory nerve endings in heart

The cardiac neuronal norepinephrine transporter (NET) is responsible for uptake of NE from the neuroeffector junction. There is ample evidence of reduced function of NET in hypertension, heart failure, and orthostatic intolerance. Studies on the localization of cardiac NET are limited, and suggest that NET is found in sympathetic fibers and intrinsic cardiac adrenergic cells. We hypothesized that NET would also be present in sensory terminals that innervate the heart. Histology and RT-PCR were used. Fixed atria and mesenteric vessels from normal, adult rats were stained for tyrosine hyrdoxylase (TH) and NET to confirm localization of NET to cardiac sympathetic nerve fibers (n=1). NET and TH were colocalized in the majority of fibers. However, there are NET-positive fibers that were TH-negative and presumably non-sympathetic. In these nerve fibers NET colocalized with calcitonin gene related peptide (CGRP), a marker of sensory neurons (n=1). The pattern of NET staining was the same in mesenteric blood vessels (n=1), suggesting that NET and CGRP colocalization is not unique to the heart. Dorsal root ganglion cell bodies, which receive sensory afferents from heart and mesentery, are positive for NET protein and express NET mRNA (n=4). In conclusion, sensory neurons are a source of NET in the heart that should be considered when assessing dysfunction of cardiac NET in disease. This is the first report of NET mRNA and protein in cardiac sensory nerves. Funding: AHA predoctoral fellowship and PO1HL70687.

The importance of serotonin and noradrenaline in anxiety

The therapeutics of obsessive-compulsive disorder (OCD) involves the serotonergic system in the brain; the selective serotonin reuptake inhibitors (SSRIs) are the only class of drugs to be consistently effective for this disorder. Preclinical studies in the orbito-frontal cortex – a brain area known to be involved in mediation of OCD symptoms – show that sustained administration of SSRI for 2 months leads to enhanced 5-HT release. Initially, raised 5-HT levels, resulting from serotonin (5-HT) reuptake inhibition, over-activates the cell body 5-HT1A autoreceptor, which has an inhibitory effect on the neuronal firing rate. However, after long-term administration of SSRIs, these 5-HT1A autoreceptors become desensitized to the raised extracellular 5-HT levels, and increase 5-HT transmission. The recovery of neuronal firing rate is faster with escitalopram (the active S-enantiomer of citalopram) than with citalopram, which may be due to different mechanisms of action. The 5-HT system has reciprocal interactions with the noradrenaline (NA) system. Although not a major mediator in the treatment of OCD symptomatology, patients with anxiety disorders such as panic disorder have increased NA reactivity and/or tone. Long-term SSRI administration reduces the firing rate of NA neurones, unlike 5-HT neurones. Evidence indicates that accrued 5-HT levels have an inhibitory modulatory effect on NA transmission, thus indicating the clinical relevance of SSRI treatment for anxiety disorders. The different effectiveness of the SSRIs escitalopram and citalopram in enhancing synaptic 5-HT levels may be due to the inhibitory action of the R-enantiomer in racemic citalopram on S-enantiomer binding to the 5-HT transporter. This allows escitalopram to produce higher extracellular 5-HT levels than can be achieved by the equivalent S-enantiomer dose of citalopram. Escitalopram is therefore a viable front-line treatment option for people with anxiety disorders, and possibly for those who have failed to respond to conventional SSRI therapies.

Locus Ceruleus Regulates Sensory Encoding by Neurons and Networks in Waking Animals

Substantial evidence indicates that the locus ceruleus (LC)-norepinephrine (NE) projection system regulates behavioral state and state-dependent processing of sensory information. Tonic LC discharge (0.1-5.0 Hz) is correlated with levels of arousal and demonstrates an optimal firing rate during good performance in a sustained attention task. In addition, studies have shown that locally applied NE or LC stimulation can modulate the responsiveness of neurons, including those in the thalamus, to nonmonoaminergic synaptic inputs. Many recent investigations further indicate that within sensory relay circuits of the thalamus both general and specific features of sensory information are represented within the collective firing patterns of like-modality neurons. However, no studies have examined the impact of NE or LC output on the discharge properties of ensembles of functionally related cells in intact, conscious animals. Here, we provide evidence linking LC neuronal discharge and NE efflux with LC-mediated modulation of single-neuron and neuronal ensemble representations of sensory stimuli in the ventral posteriomedial thalamus of waking rats. As such, the current study provides evidence that output from the LC across a physiologic range modulates single thalamic neuron responsiveness to synaptic input and representation of sensory information across ensembles of thalamic neurons in a manner that is consistent with the well documented actions of LC output on cognition.

Neurokinin 1 receptor antagonism requires norepinephrine to increase serotonin function

The present studies examined the role of norepinephrine (NE) system in mediating the enhancement of 5-HT function produced by neurokinin (NK)1 receptor antagonism. Dorsal raphe 5-HT and locus coeruleus NE neurons were recorded in vivo in mice lacking NK1 receptors in wildtype mice pretreated with the NK1 antagonist RP67580 and its inactive enantiomer RP 68651. RP67580 and RP68651 were also tested on 5-HT neurons of mice lacking the 5-HT 1A receptor. RP67580 increased the firing rate of 5-HT neurons in wildtype mice and in 5-HT 1A null mutant mice to the same degree, thus indicating that the mechanism by which NK1 antagonists enhances 5-HT firing is independent of 5-HT 1A receptors. NE neuronal burst activity was increased in NK1 null mutant and wildtype mice given RP67580, but not with RP68651. After NE depletion, RP67580 was ineffective in increasing 5-HT neuronal firing activity in NK1 wildtype mice, and the enhancement of 5-HT neuronal firing observed in NK1 null mutant mice was abolished. In conclusion, NE neurons are essential for the action of NK1 antagonists on 5-HT neurons. In addition, the desensitization of 5-HT 1A autoreceptors produced by NK1 receptor antagonism is not critical for enhancing 5-HT neuronal firing.

In Vitro Continuous Amperometry with a Diamond Microelectrode Coupled with Video Microscopy for Simultaneously Monitoring Endogenous Norepinephrine and Its Effect on the Contractile Response of a Rat Mesenteric Artery

Continuous amperometry with a diamond microelectrode and video microscopy were used to record (in vitro) endogenous norepinephrine release simultaneously with the evoked contractile response of a mesenteric artery from a healthy Sprague Dawley rat. Norepinephrine (NE) is a vasoconstricting neurotransmitter released from sympathetic nerves that innervate the smooth muscle cell layers surrounding arteries and veins. Using these two techniques along with several drugs, the NE released at sympathetic neuroeffector junctions nearby the microelectrode was measured as an oxidation current. Key to the amperometric measurement was the use of a diamond microelectrode because of the response sensitivity, reproducibility, and stability it provided. NE release was elicited by electrical stimulation at frequencies between 1 and 60 Hz, with a maximum response seen at 20 Hz. Confirmation that the oxidation current was, in fact, associated with endogenous NE came from the results of several drugs. Tetrodotoxin (TTX, 0.3 microM), a voltage-dependent sodium channel antagonist that blocks nerve conduction, abolished both the oxidation current and the arterial constriction. The alpha(2)-adrenergic autoreceptor antagonist, yohimbine (1.0 microM), caused an increase in the oxidation current and the corresponding constriction. The addition of cocaine (10 microM), an antagonist that inhibits neuronal NE reuptake, caused both the oxidation current and the contractile response to increase. These results, combined with the fact that the hydrodynamic voltammetric E(1/2) for endogenous NE was identical to that for a standard solution, confirmed that the oxidation current was due to NE and that this compound caused, at least in part, the contractile response. The results demonstrate that continuous amperometric monitoring of NE with a diamond microelectrode and video imaging of vascular tone allow real time local measurement of the temporal relationship between nerve-stimulated NE release and arterial constriction.

Hindbrain catecholamine neurons control multiple glucoregulatory responses

Reduced brain glucose availability evokes an integrated constellation of responses that protect and restore the brain's glucose supply. These include increased food intake, adrenal medullary secretion, corticosterone secretion and suppression of estrous cycles. Our research has focused on mechanisms and neural circuitry underlying these systemic glucoregulatory responses. Using microinjection techniques, we found that localized glucoprivation of hindbrain but not hypothalamic sites, elicited key glucoregulatory responses, indicating that glucoreceptor cells controlling these responses are located in the hindbrain. Selective destruction of hindbrain catecholamine neurons using the retrogradely transported immunotoxin, anti-dopamine beta-hydroxylase conjugated to saporin (DSAP), revealed that spinally-projecting epinephrine (E) or norepinephrine (NE) neurons are required for the adrenal medullary response to glucoprivation, while E/NE neurons with hypothalamic projections are required for feeding, corticosterone and reproductive responses. We also found that E/NE neurons are required for both consummatory and appetitive phases of glucoprivic feeding, suggesting that multilevel collateral projections of these neurons coordinate various components of the behavioral response. Epinephrine or NE neurons co-expressing neuropeptide Y (NPY) may be the neuronal phenotype required for glucoprivic feeding: they increase NPY mRNA expression in response to glucoprivation and are nearly eliminated by DSAP injections that abolish glucoprivic feeding. In contrast, lesion of arcuate nucleus NPY neurons, using the toxin, NPY–saporin, does not impair glucoprivic feeding or hyperglycemic responses. Thus, hindbrain E/NE neurons orchestrate multiple concurrent glucoregulatory responses. Specific catecholamine phenotypes may mediate the individual components of the overall response. Glucoreceptive control of these neurons resides within the hindbrain.

Cellular and molecular mechanisms of Parkinson's disease: neurotoxins, causative genes, and inflammatory cytokines.

1. Parkinson's disease (PD) is considered to be an aging-related neurodegeneration of catecholamine (CA) systems [typically A9 dopamine (DA) neurons in the substantia nigra and A6 noradrenaline (NA) neurons in the locus coeruleus]. The main symptom is movement disorder caused by a DA deficiency at the nerve terminals of fibers that project from the substantia nigra to the striatum. Most PD is sporadic (sPD) without any hereditary history. sPD is speculated to be caused by some exogenous or endogenous substances that are neurotoxic toward CA neurons, which toxicity leads to mitochondrial dysfunction and subsequent oxidative stress resulting in the programmed cell death (apoptosis or autophagy) of DA neurons. 2. Recent studies on the causative genes of rare familial PD (fPD) cases, such as alpha-synuclein and parkin, suggest that dysfunction of the ubiquitin-proteasome system (UPS) and the resultant accumulation of misfolded proteins and endoplasmic reticulum stress may cause the death of DA neurons. 3. Activated microglia, which accompany an inflammatory process, are present in the nigro-striatum of the PD brain; and they produce protective or toxic substances, such as cytokines, neurotrophins, and reactive oxygen or nitrogen species. These activated microglia may be neuroprotective at first in the initial stage, and later may become neurotoxic owing to toxic change to promote the progression toward the death of CA neurons.4. All of these accumulating evidences on sPD and fPD points to a hypothesis that multiple primary causes of PD may be ultimately linked to a final common signal-transduction pathway leading to programmed cell death, i.e., apoptosis or autophagy, of the CA neurons.

The neuronal noradrenaline transporter, anxiety and cardiovascular disease

Panic disorder can serve as a clinical model for testing whether mental stress can cause heart disease. Potential neural mechanisms of cardiac risk are the sympathetic activation during panic attacks, continuing release of adrenaline as a co-transmitter in the cardiac sympathetic nerves, and impairment of noradrenaline neuronal reuptake, augmenting sympathetic neural respnses. The phenotype of impaired neuronal reuptake of noradrenaline: an epigenetic mechanism? We suspect that this phenotype, in sensitizing people to heart symptom development, is a cause of panic disorder, and by magnifying the sympathetic neural signal in the heart, underlies increased cardiac risk. No loss of function mutations of the coding region of the norepinephrine transporter (NET) are evident, but we do detect hypermethylation of CpG islands in the NET gene promoter region. Chromatin immunoprecipitation methodology demonstrates binding of the inhibitory transcription factor, MeCP2, to promoter region DNA in panic disorder patients. Cardiovascular illnesses co-morbid with panic disorder. Panic disorder commonly coexists with essential hypertension and the postural tachycardia syndrome. In both of these cardiovascular disorders the impaired neuronal noradrenaline reuptake phenotype is also present and, as with panic disorder, is associated with NET gene promoter region DNA hypermethylation. An epigenetic 'co-morbidity' perhaps underlies the clinical concordance. Brain neurotransmitters. Using internal jugular venous sampling, in the absence of a panic attack we find normal norepinephrine turnover, but based on measurements of the overflow of the serotonin metabolite, 5HIAA, a marked increase (six to sevenfold) in brain serotonin turnover in patients with panic disorder. This appears to represent the underlying neurotransmitter substrate for the disorder. Whether this brain serotonergic activation is a prime mover, or consequential on other primary causes of panic disorder, including cardiac sensitization by faulty neuronal noradrenaline reuptake leading to cardiac symptoms and the enhanced vigilance which accompanies them, is unclear at present.

Endogenous Monoamine Receptor Activation Is Essential for Enabling Persistent Sodium Currents and Repetitive Firing in Rat Spinal Motoneurons

The spinal cord and spinal motoneurons are densely innervated by terminals of serotonin (5-HT) and norepinephrine (NE) neurons arising mostly from the brain stem, but also from intrinsic spinal neurons. Even after long-term spinal transection (chronic spinal), significant amounts (10%) of 5-HT and NE (monoamines) remain caudal to the injury. To determine the role of such endogenous monoamines, we blocked their action with monoamine receptor antagonists and measured changes in the sodium currents and firing in motoneurons. We focused on persistent sodium currents (Na PIC) and sodium spike properties because they are critical for enabling repetitive firing in motoneurons and are facilitated by monoamines. Intracellular recordings were made from motoneurons in the sacrocaudal spinal cord of normal and chronic spinal rats (2 mo postsacral transection) with the whole sacrocaudal cord acutely removed and maintained in vitro (cords from normal rats termed acute spinal). Acute and chronic spinal rats had TTX-sensitive Na PICs that were respectively 0.62 +/- 0.76 and 1.60 +/- 1.04 nA, with mean onset voltages of -63.0 +/- 5.6 and -64.1 +/- 5.4 mV, measured with slow voltage ramps. Application of 5-HT2A, 5-HT2C, and alpha1-NE receptor antagonists (ketanserin, RS 102221, and WB 4101, respectively) significantly reduced the Na PICs, and a combined application of these three monoamine antagonists completely eliminated the Na PIC, in both acute and chronic spinal rats. Likewise, reduction of presynaptic transmitter release (including 5-HT and NE) with long-term application of cadmium also eliminated the Na PIC. Associated with the elimination of the Na PIC in monoamine antagonists, the motoneurons lost their ability to fire during slow current ramps. At this point, the spike evoked by antidromic stimulation was not affected, suggesting that activation of the transient sodium current was not impaired. However, the spike evoked after a slow ramp depolarization was slightly reduced in height and rate-of-rise, suggesting decreased sodium channel availability as a result of increased channel inactivation. These results suggest that endogenous monoamine receptor activation is critical for enabling the Na PIC and decreasing sodium channel inactivation, ultimately enabling steady repetitive firing in both normal and chronic spinal rats.

Sympathetic neurotransmission in the rat testicular capsule: Functional characterization and identification of mRNA encoding α 1-adrenoceptor subtypes

The rat testicular capsule is a thin tissue surrounding the testis, whose precise function is still unknown. We have studied the contractile effects of electrical field stimulation, noradrenaline, and the blockade by antagonists of adrenergic receptors, in order to characterize sympathetic neurotransmission, and adrenoceptor subtypes. In addition, reverse transcription polymerase chain reaction (RT-PCR) assays were made to check for the expression of the three known subtypes of α 1-adrenoceptors. The effects of electrical field stimulation (2 to 20 Hz, 1 ms, 60 V) were almost totally abolished by depletion of neuronal noradrenaline storage with reserpine (10 mg/Kg), but not by the purinergic receptor antagonist suramin (10 − 5 M), indicating that noradrenaline, but not ATP, was involved in contractions. The selective α 1-adrenoceptor antagonist prazosin (10 − 7 M) was more effective than the selective α 2-adrenoceptor antagonist idazoxan (10 − 7 M) to inhibit contractions induced by electrical field stimulation, pointing out a major involvement of α 1-adrenoceptor. When noradrenaline was used instead of electrical field stimulation, it showed a high potency (pD 2 = 7.9). Noradrenaline-induced contractions were competitively blocked by the selective α 1A-adrenoceptor antagonists WB 4101 (pA 2 = 8.88), phentolamine (pA 2 = 8.39) and by the α 1B-adrenoceptor antagonist spiperone (pA 2 = 8.57), indicating the presence of functional α 1A- and α 1B-adrenoceptors. In addition, contractions were not blocked by the selective α 1D-adrenoceptor antagonist BMY 7378 (up to 10 − 6 M), while selective α 2-adrenoceptor antagonists showed low pA 2 values (yohimbine, 7.25 and idazoxan, 7.49), suggesting a minor role, if any, for α 1D- and α 2-adrenoceptors. To check the proportionate role of α 1A- and α 1B-adrenoceptors, we blocked α 1B-adrenoceptors with chloroethylclonidine (CEC, 30 μM, 45 min), that reduced the maximal effect of noradrenaline by about 60%. The remnant CEC-insensitive noradrenaline contraction was assumed to be unrelated to α 1B-adrenoceptor, and was inhibited by 5-methyl-urapidil (pA 2 = 8.94) and by the Ca 2+ channel blocker nifedipine (3 μM), confirming the involvement of α 1A-adrenoceptors. The presence of mRNA encoding α 1A- and α 1B-adrenoceptor was also shown on RT-PCR assays. Unexpectedly, α 1D-transcripts were also detected in these assays. Taken together, our results show that ATP co-transmission could not be detected, and that neurotransmission involves the interaction of noradrenaline with both α 1A- and α 1B-, but not with α 1D- or α 2-adrenoceptor. The fact that the functional α 1D-adrenoceptor could not be detected in spite of the presence of the corresponding mRNA, remains to be investigated.

Prospects for neuroprotection in Parkinson’s disease

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder, affecting more than an estimated one million persons in the United States. With the aging of the population, it is anticipated that this number will rise substantially during the next 25 to 50 years, perhaps by as much as fourfold. Remarkable discoveries a half century ago led to the discovery that PD is associated with a nigrostriatal dopamine deficiency and the introduction of levodopa therapy, a therapeutic “miracle” that provided benefit to millions of patients. However, it is now clear that degeneration in PD can affect more than dopaminergic neurons in the substantia nigra pars compacta and that patients can suffer disability from features that do not respond to levodopa. Degeneration can involve norepinephrine neurons in the locus coeruleus, cholinergic neurons in the nucleus basalis of Meynert, and serotonin …

Influences of Norepinephrine Transporter Function on the Distribution of Sympathetic Activity in Humans

Previous studies suggest that neuronal norepinephrine transporter function may regulate the distribution of sympathetic activity among blood vessels, heart, and kidney; we tested the functional relevance in humans. Sixteen healthy men (26+/-1 years) ingested 8 mg of the selective norepinephrine reuptake transporter inhibitor reboxetine or a matching placebo on 2 separate days in a double-blind, randomized, crossover fashion. We monitored heart rate, thoracic bioimpedance, blood pressure, glomerular filtration rate, and renal blood flow. Ninety minutes after ingestion of the test medication, subjects were tilted to a 45 degrees head-up position, where they remained for an additional 30 minutes. Reboxetine increased supine systolic blood pressure through an increase in cardiac output whereas systemic vascular resistance decreased. Furthermore, reboxetine increased heart rate, particularly with a head-up tilt. Supine plasma renin activity was 0.71+/-0.15 ng angiotensin (Ang)/L per mL/h with placebo and 0.36+/-0.07 ngAng/L per mL/h with reboxetine (P<0.01). Supine plasma Ang II concentrations were also decreased with reboxetine. Both plasma renin activity and Ang II concentrations remained suppressed during head-up tilt. On placebo, renal vascular resistance increased with head-up tilt. The response was abolished with norepinephrine reuptake inhibition. We conclude that norepinephrine reuptake function profoundly influences the distribution of sympathetic activity between the heart, vasculature, and kidney in humans. All of these changes are physiologically relevant because they lead to corresponding changes in organ function.

Does MPTP induced Parkinson's disease produce a loss of norepinephrine neurons in the locus coeruleus: A retrospective study of non-human primates?

Does MPTP induced Parkinson's disease produce a loss of norepinephrine neurons in the locus coeruleus: A retrospective study of non-human primates?

Blockade of the α‐MMT‐induced depletion of rat cortical norepinephrine levels: a method for determining the potency and duration of action of compounds with norepinephrine reuptake inhibition

Neurotransmitter transporter inhibitors can prevent the depletion of brain monoamines when the depleting agent requires active uptake into neurons via a transporter. α-Methyl-m-tyrosine (α-MMT), a monoaminergic depleting agent, is β-hydroxylated to metaraminol in vivo and actively transported into noradrenergic neurons, leading to decreased levels of norepinephrine (NE). This depletion of NE by α-MMT is prevented by inhibitors of the neuronal NE transporter, but is dependent upon the dose of α-MMT administered. A 6.25 mg/kg, sc dose of α-MMT produced a 40% to 60% depletion of rat cortical NE 2 to 4 hours after administration that persisted up to 16 hours. Pretreatment with desipramine (DMI) at 10 mg/kg, sc significantly blocked NE depletion produced by a-MMT up to 8 hours regardless of whether measured 2 or 16 hours after a-MMT administration. The α-MMT-induced decrease in brain NE at 2 hours was dose-dependently blocked by a 1 hour pretreatment with DMI and reboxetine (REB) with ED50 doses of <1 and 2.0 mg/kg, sc, respectively. When administered at various times prior to α-MMT, DMI and REB pretreatment significantly blocked the α-MMT-induced depletion of rat cortical NE levels up to 8 hours with no significant effect at 24 hours. This experimental protocol allows for a rapid comparison of the potency and duration of NE reuptake inhibition in rat cortex, which has implications for development of agents effective in the treatment of central nervous system disorders.

Spironolactone Preserves Cardiac Norepinephrine Reuptake in Salt-Sensitive Dahl Rats

An impairment of cardiac norepinephrine (NE) reuptake via the neuronal NE transporter (NET) enhances the effects of increased cardiac NE release in heart failure patients. Increasing evidence suggests that aldosterone and endothelins promote sympathetic overstimulation of failing hearts. Salt-sensitive Dahl rats (DS) fed a high-salt diet developed arterial hypertension and diastolic heart failure as well as elevated plasma levels of endothelin-1 and NE. Cardiac NE reuptake and NET-binding sites, as assessed by clearance of bolus-injected [(3)H]NE in isolated perfused rat hearts and [(3)H]mazindol binding, were reduced. Treatment of DS with the mineralocorticoid receptor antagonist spironolactone preserved the plasma levels of endothelin-1 and NE, cardiac NE reuptake, and myocardial NET density. Moreover, the ventricular function and survival of spironolactone-treated DS were significantly improved compared with untreated DS. The alpha(1)-inhibitor prazosin decreased blood pressure in DS similar to spironolactone treatment, but did not normalize the plasma levels of endothelin-1 and NE, NE reuptake, or ventricular function. In a heart failure-independent model, Wistar rats that were infused with aldosterone and fed a high-salt diet developed impaired cardiac NE reuptake. Treatment of these rats with the endothelin A receptor antagonist darusentan attenuated the impairment of NE reuptake. In conclusion, spironolactone preserves NET-dependent cardiac NE reuptake in salt-dependent heart failure. Evidence is provided that aldosterone inhibits NET function through an interaction with the endothelin system. Selective antagonism of the mineralocorticoid and/or the endothelin A receptor might represent therapeutic principles to prevent cardiac sympathetic overactivity in salt-dependent heart failure.

Chlorpheniramine, selective serotonin-reuptake inhibitors (SSRIs) and over-the-counter (OTC) treatment

Some old antihistamines were selective serotonin-reuptake inhibitors (SSRIs) and the SSRI effect was discovered by Nobel Laureate Professor Arvid Carlsson as early as 1969. Chlorpheniramine was the most active of the tested drugs, and it compares favourably with amitriptyline and imipramine with respect to actions on both serotonergic and noradrenergic neurons. Chlorpheniramine can be called a SSRI, since the blocking of 5HT is stronger than the effect on noradrenaline neurons; however it might also be called a selective serotonin and noradrenaline reuptake inhibitor (SSNRI) and be compared with new drugs, such as venlafaxine. Carlsson suggested the potential value of clinical studies of the antidepressant properties of this and related antihistamine drugs. But, in the event, no such trials were ever performed at the time. However, later clinical observations of the benefits of dex-chlorpheniramine treatment in panic disorder have been published. Clinical experience suggests that patients using chlorpheniramine, and having also a concomitant depression or panic disorder, may experience a return of symptoms when their old drug is changed to a new antihistamine lacking SSRI effects. Yet this phenomenon is not known to many doctors, and even less known to the large number of patients buying chlorpheniramine under various trade names over-the-counter (OTC) at a low price for self-treatment of hay fewer or as a cold remedy. Chlorpheniramine was introduced in USA under the name Chlor-Trimeton as long ago as July 1950, and is still on the market. Therefore, this SSRI is now over 50 years old. If chlorpheniramine had been tested in depression in the nineteen seventies, it is probable that a safe, inexpensive SSRI drug could have been used some 15 years earlier than fluoxetine - which became available in 1987. Chlorpheniramine might have been the first safe, non-cardiotoxic and well-tolerated antidepressant. Billions of dollars in the development and marketing costs would have been saved, and the suffering of millions of patients alleviated.