Depletion Of Norepinephrine Research Articles

Noradrenaline and Parkinson's Disease

Parkinson's disease (PD) is characterized by the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta, and motor symptoms including bradykinesia, rigidity, and tremor at rest. These symptoms are exhibited when striatal dopamine concentration has decreased by around 70%. In addition to motor deficits, PD is also characterized by the non-motor symptoms. However, depletion of DA alone in animal models has failed to simultaneously elicit both the motor and non-motor deficits of PD, possibly because the disease is a multi-system disorder that features a profound loss in other neurotransmitter systems. There is growing evidence that additional loss of noradrenaline (NA) neurons of the locus coeruleus, the principal source of NA in the brain, could be involved in the clinical expression of motor as well as in non-motor deficits. In the present review, we analyze the latest evidence for the implication of NA in the pathophysiology of PD obtained from animal models of parkinsonism and from parkinsonian patients. Recent studies have shown that NA depletion alone, or combined with DA depletion, results in motor as well as in non-motor dysfunctions. In addition, by using selective agonists and antagonists of noradrenaline alpha receptors we, and others, have shown that α2 receptors are implicated in the control of motor activity and that α2 receptor antagonists can improve PD motor symptoms as well as l-Dopa-induced dyskinesia. In this review we argue that the loss of NA neurons in PD has an impact on all PD symptoms and that the addition of NAergic agents to dopaminergic medication could be beneficial in the treatment of the disease.

Distinct adrenergic system changes and neuroinflammation in response to induced locus ceruleus degeneration in APP/PS1 transgenic mice

Degeneration of locus ceruleus (LC) neurons and subsequent reduction of norepinephrine (NE) in LC projection areas represent an early pathological indicator of Alzheimer's disease (AD). In order to study the effects of NE depletion on cortical and hippocampal adrenergic system changes, LC degeneration was induced in 3-month-old APP/PS1 mice by the neurotoxin N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4). Dsp4 induced a widespread loss of norepinephrine transporter binding in multiple brain structures already at 4.5 months. This was accompanied by changes of α-1-, α-2-, and β-1-adreneroceptor binding sites as well as altered adrenoceptor mRNA expression. In parallel, we observed increased micro- and astrogliosis in cortical and hippocampal structures in dsp4-treated groups. In addition, the expression of the pro-inflammatory cytokines CCL2 and IL-1β were induced in both, dsp4-treated and APP/PS1-transgenic mice, whereas IL-1α was only up-regulated in dsp4-treated APP/PS1 mice. Concerning amyloid β (Aβ) deposition, we observed an elevation of Aβ1-42 levels in aged dsp4-treated APP/PS1 mice. These data support the hypothesis that LC degeneration leads to dysregulation of adrenergic receptors and exacerbation of Aβ-induced neuroinflammation, both of which are exploitable for early disease marker development.

P.1.c.048 Modulating effect of new L-valine derivatives on brain serotonin uptake in aggressive socially isolated mice

We have previously demonstrated that chronic l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) infusion to the substantia nigra (SN) and the locus coeruleus (LC) both produce a long-lasting neurotoxicity on dopamine (DA) and norepinephrine (NE) neurons in these two areas, respectively. In the present study, we further examined the toxicity of MPTP in these two areas by using the immunohistochemical method. We have also assessed the role of glia cells in the SN and LC in mediating the toxicity of MPTP. Immunohistochemical results have confirmed the direct toxicity of MPTP in the SN, as revealed by significant decreases of tyrosine hydroxylase (TH)-positive cells in the SN and TH-positive fibers in the striatum. The specific gliotoxin a-aminoadipic acid (α-AA), when administered to the SN at 48 h interval, partially antagonized DA depletions and behavioral deficits produced by chronic MPTP treatment. When α-AA was administered to the SN every 24 h, it completely abolished the toxicity of MPTP. On the other hand, chronic MPTP infusions to the LC significantly decreased DA-β-hydroxylase-positive cells in this area. When α-AA was injected into the LC at 48 h intervals, it did not prevent depletions of NE in the LC and the hippocampus caused by chronic MPTP infusions. It did not protect against the behavioral deficits produced by MPTP, either. When α-AA was injected into the LC every 24 h, it only partially prevented the toxicity of MPTP on NE in the LC. It also partially prevented the motor-impairing effect of MPTP; however, it barely protected against MPTP's toxicity on NE in the hippocampus and it did not antagonize the stereotypy deficit produced by chronic MPTP, either. Phasic tremor and rigidity were observed following MPTP infusions to the SN and the LC every day, but these symptoms were less frequently observed during the later experimental stage. Serotonin measures were not significantly altered by these treatments throughout these experiments. Immunoblotting results of glial fibrillary acidic protein (GFAP), a marker protein of astrocytes, have confirmed proper lesions of astrocytes by α-AA. These results together suggest that chronic MPTP treatment exerts a direct and long-lasting toxicity on DA neurons along the nigrostriatal pathway and NE neurons along the coeruleus-hippocampal pathway. The neurotoxicity of MPTP is probably mediated through astrocytes in the SN, and may be partly mediated through astrocytes in the LC also. These results imply a role for dendritic uptake of DA and NE in these cell body regions. However, these findings also suggest the possibility of differential mechanisms of MPTP's toxicity in these two areas.

Contribution of limbic norepinephrine to cannabinoid-induced aversion

The cannabinoid system has risen to the forefront in the development of novel treatments for a number of pathophysiological processes. However, significant side effects have been observed in clinical trials raising concerns regarding the potential clinical utility of cannabinoid-based agents. Understanding the neural circuits and neurochemical substrates impacted by cannabinoids will provide a better means of gaging their actions within the central nervous system that may contribute to the expression of unwanted side effects. In the present study, we investigated whether norepinephrine (NE) in the limbic forebrain is a critical determinant of cannabinoid receptor agonist-induced aversion and anxiety in rats. An immunotoxin lesion approach was combined with behavioral analysis using a place conditioning paradigm and the elevated zero maze. Our results show that the non-selective CB1/CB2 receptor agonist, WIN 55,212-2, produced a significant place aversion in rats. Further, NE in the nucleus accumbens was critical for WIN 55,212-2-induced aversion but did not affect anxiety-like behaviors. Depletion of NE from the bed nucleus of the stria terminalis was ineffective in altering WIN 55,212-2-induced aversion and anxiety. These results indicate that limbic, specifically accumbal, NE is required for cannabinoid-induced aversion but is not essential to cannabinoid-induced anxiety.

Noradrenergic Control of Cortico-Striato-Thalamic and Mesolimbic Cross-Structural Synchrony

Although normal dopaminergic tone has been shown to be essential for the induction of cortico-striatal and mesolimbic theta oscillatory activity, the influence of norepinephrine on these brain networks remains relatively unknown. To address this question, we simultaneously recorded local field potentials and single-neuron activity across 10 interconnected brain areas (ventral striatum, frontal association cortex, hippocampus, primary motor cortex, orbital frontal cortex, prelimbic cortex, dorsal lateral striatum, medial dorsal nucleus of thalamus, substantia nigra pars reticularis, and ventral tegmental area) in a combined genetically and pharmacologically induced mouse model of hyponoradrenergia. Our results show that norepinephrine (NE) depletion induces a novel state in male mice characterized by a profound disruption of coherence across multiple cortico-striatal circuits and an increase in mesolimbic cross-structural coherence. Moreover, this brain state is accompanied by a complex behavioral phenotype consisting of transient hyperactivity, stereotypic behaviors, and an acute 12-fold increase in grooming. Notably, treatment with a norepinephrine precursors (l-3,4-dihydroxyphenylalanine at 100 mg/kg or l-threo-dihydroxyphenylserine at 5 mg/kg) or a selective serotonin reuptake inhibitor (fluoxetine at 20 mg/kg) attenuates the abnormal behaviors and selectively reverses the circuit changes observed in NE-depleted mice. Together, our results demonstrate that norepinephrine modulates the dynamic tuning of coherence across cortico-striato-thalamic circuits, and they suggest that changes in coherence across these circuits mediate the abnormal generation of hyperactivity and repetitive behaviors.

Early and late effects of iron deficiency on heart and baroreflex function

Iron deficiency (ID) induces cardiac and neural alterations, such as cardiac hypertrophy and apoptosis, electron transport dysfunction, and brain mitochondrial disruption. Cardiac norepinephrine (NE) depletion suggests chronically high sympathetic nervous system (SNS) traffic to the heart. Thus, ID would be expected to affect heart function and blood pressure, and our previous experiments have shown baroreflex alterations after 4 weeks of ID.HYPOTHESES(1) Chronic high SNS output initially leads to a hyperfunctional heart with higher left ventricular pressure (LVP) and heart rates (HR) at each mean arterial pressure (MAP), and (2) eventual depletion of NE, along with heart apoptosis and debility, is coincident with reduced LVP and HR at all MAP.METHODSRats were fed control (CN) or ID diets for 2 or 4 weeks. Baroreflex experiments were conducted using ramp (before and after atropine) and steady state protocols. Hearts were excised for Langendorff experiments to obtain LVP at set flow rates.RESULTSHematocrit verified ID (p ≤ 0.05); heart mass verified hypertrophy. Baroreflex preliminary data suggests higher HR at all MAP at 2 weeks, but lower HR after 4 weeks; experiments continue at time of writing. Langendorff data indicates higher LVP with ID at 2 weeks, but lower LVP after 4 weeks.CONCLUSIONChanges with ID are adaptive at 2 weeks but pathological after 4 weeks. Supported by WY INBRE (LC4090).

Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine

Locus ceruleus (LC)-supplied norepinephrine (NE) suppresses neuroinflammation in the brain. To elucidate the effect of LC degeneration and subsequent NE deficiency on Alzheimer's disease pathology, we evaluated NE effects on microglial key functions. NE stimulation of mouse microglia suppressed Abeta-induced cytokine and chemokine production and increased microglial migration and phagocytosis of Abeta. Induced degeneration of the locus ceruleus increased expression of inflammatory mediators in APP-transgenic mice and resulted in elevated Abeta deposition. In vivo laser microscopy confirmed a reduced recruitment of microglia to Abeta plaque sites and impaired microglial Abeta phagocytosis in NE-depleted APP-transgenic mice. Supplying the mice the norepinephrine precursor L-threo-DOPS restored microglial functions in NE-depleted mice. This indicates that decrease of NE in locus ceruleus projection areas facilitates the inflammatory reaction of microglial cells in AD and impairs microglial migration and phagocytosis, thereby contributing to reduced Abeta clearance. Consequently, therapies targeting microglial phagocytosis should be tested under NE depletion.

Vulnerability of peripheral catecholaminergic neurons to MPTP is not regulated by α-synuclein

Although generally considered a prototypical movement disorder, Parkinson's disease is commonly associated with a broad-spectrum of non-motor symptoms, including autonomic dysfunctions caused by significant alterations in catecholaminergic neurons of the peripheral sympathetic nervous system. Here we present evidence that α-synuclein is highly expressed by sympathetic ganglion neurons throughout embryonic and postnatal life and that it is found in tyrosine hydroxylase-positive sympathetic fibers innervating the heart of adult mice. However, mice deficient in α-synuclein do not exhibit any apparent alterations in sympathetic development. Sympathetic neurons isolated from mouse embryos and early postnatal mice are sensitive to the parkinsonian drug MPTP/MPP + and intoxication requires entry of the neurotoxin through the noradrenaline transporter. Furthermore, recovery of noradrenaline from cardiac sympathetic fibers is reduced in adult mice treated with MPTP systemically. However, MPP +-induced sympathetic neuron loss in vitro or MPTP-induced cardiac noradrenaline depletion in vivo is not modified in mice lacking α-synuclein. This is in clear contrast with the observation that dopaminergic neurons of the central nervous system are significantly less vulnerable to MPTP/MPP + in the absence of α-synuclein, suggesting different actions of this molecule in central and peripheral catecholaminergic neurons.

Antidepressant- and anxiolytic-like properties of dopamine receptor agonist cabergoline

Non-motor symptoms of Parkinson's disease are under-studied and therefore not well treated. Here, we investigated the role of combined depletions of dopamine, norepinephrine and/or serotonin in the manifestation of motor and non-motor deficits in the rat. Then, we studied the impact of these depletions on the efficacy of deep brain stimulation of the subthalamic nucleus (STN–DBS). We performed selective depletions of dopamine, norepinephrine and serotonin, and the behavioral effects of different combined depletions were investigated using the open field, the elevated plus maze and the forced swim test. Bilateral dopamine depletion alone induced locomotor deficits associated with anxiety and mild “depressive-like” behaviors. Although additional depletions of norepinephrine and/or serotonin did not potentiate locomotor and anxiety disorders, combined depletions of the three monoamines dramatically exacerbated “depressive-like” behavior. STN–DBS markedly reversed locomotor deficits and anxiety behavior in animals with bilateral dopamine depletion alone. However, these improvements were reduced or lost by the additional depletion of norepinephrine and/or serotonin, indicating that the depletion of these monoamines may interfere with the antiparkinsonian efficacy of STN–DBS. Furthermore, our results showed that acute STN–DBS improved “depressive-like” disorder in animals with bilateral depletion of dopamine and also in animals with combined depletions of the three monoamines, which induced severe immobility in the forced swim test. Our data highlight the key role of monoamine depletions in the pathophysiology of anxiety and depressive-like disorders and provide the first evidence of their negative consequences on the efficacy of STN–DBS upon the motor and anxiety disorders in the context of Parkinson's disease.

Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms

A dopaminergic deficiency in patients with Parkinson's disease (PD) causes abnormalities of movement, behaviour, learning, and emotions. The main motor features (ie, tremor, rigidity, and akinesia) are associated with a deficiency of dopamine in the posterior putamen and the motor circuit. Hypokinesia and bradykinesia might have a dual anatomo-functional basis: hypokinesia mediated by brainstem mechanisms and bradykinesia by cortical mechanisms. The classic pathophysiological model for PD (ie, hyperactivity in the globus pallidus pars interna and substantia nigra pars reticulata) does not explain rigidity and tremor, which might be caused by changes in primary motor cortex activity. Executive functions (ie, planning and problem solving) are also impaired in early PD, but are usually not clinically noticed. These impairments are associated with dopamine deficiency in the caudate nucleus and with dysfunction of the associative and other non-motor circuits. Apathy, anxiety, and depression are the main psychiatric manifestations in untreated PD, which might be caused by ventral striatum dopaminergic deficit and depletion of serotonin and norepinephrine. In this Review we discuss the motor, cognitive, and psychiatric manifestations associated with the dopaminergic deficiency in the early phase of the parkinsonian state and the different circuits implicated, and we propose distinct mechanisms to explain the wide clinical range of PD symptoms at the time of diagnosis.

Brain Norepinephrine System as a Target for Antidepressant and Mood Stabilizing Medications

There are numerous lines of evidence pointing to norepinephrine being of crucial importance in pathophysiology of anxiety and mood disorders. First, norepinephrine projections innervate the limbic system, suggesting the involvement of norepinephrine in the regulation of emotions and cognition. Second, norepinephrine closely interacts with serotonin and dopamine systems, which also play very important roles in the regulation of mood. Third, it has been shown that various agents which increase norepinephrine availability, such as norepinephrine reuptake inhibitors, are also effective antidepressant drugs. And fourth, the depletion of norepinephrine causes a resurgence of depressive symptoms after successful treatment with antidepressant drugs. These observations suggest that the intensification of norepinephrine transmission can be beneficial in the treatment of affective disorders. However, various psychotropic medications have indirect effect on norepinephrine transmission. This review examines the effects of psychiatric medications on the norepinephrine system and proposes how they might be used to improve treatment outcome.

Incentive Motivation, Conditioning, Stress, and Neuropsychiatric Disorders: A Tribute to Jane Stewart

This issue of Biological Psychiatry is dedicated to the lifetime contributions of Jane Stewart (who retired in 2008) to the fields of psychology, psychiatry, psychopharmacology, and neuroscience. Jane Stewart has been a leader whose contributions over the past half-century have profoundly influenced these fields. In an era of increasing specialization and exponential growth in the number of publications, her research interests have remained exceptionally broad, reflecting her genuine interest in understanding how the brain controls behavior. Jane is well known for her seminal contributions to the study of conditioned drug effects ( 1 Eikelboom R. Stewart J. Conditioning of drug-induced physiological responses. Psychol Rev. 1982; 89: 507-528 Crossref PubMed Scopus (350) Google Scholar , 2 Stewart J. Neurobiology of conditioning to drug abuse. Ann N Y Acad Sci. 1992; 654: 335-346 Crossref PubMed Scopus (93) Google Scholar ), incentive motivational effects of drugs and drug cues ( 3 Stewart J. de Wit H. Eikelboom R. Role of unconditioned and conditioned drug effects in the self-administration of opiates and stimulants. Psychol Rev. 1984; 91: 251-268 Crossref PubMed Scopus (988) Google Scholar ), psychomotor sensitization and cross-sensitization with stress ( 4 Flores C. Stewart J. Basic fibroblast growth factor as a mediator of the effects of glutamate in the development of long-lasting sensitization to stimulant drugs: Studies in the rat. Psychopharmacology. 2000; 151: 152-165 Crossref PubMed Scopus (58) Google Scholar , 5 Kalivas P.W. Stewart J. Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Rev. 1991; 16: 223-244 Crossref PubMed Scopus (1808) Google Scholar ), and the behavioral and neuronal mechanisms of relapse to drug-seeking ( 6 Shaham Y. Shalev U. Lu L. de Wit H. Stewart J. The reinstatement model of drug relapse: History, methodology and major findings. Psychopharmacology. 2003; 168: 3-20 Crossref PubMed Scopus (1246) Google Scholar , 7 de Wit H. Stewart J. Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology. 1981; 75: 134-143 Crossref PubMed Scopus (752) Google Scholar ). In addition, Jane has made significant contributions to other areas of research, including circadian rhythms ( 8 Amir S. Stewart J. Resetting of the circadian clock by a conditioned stimulus. Nature. 1996; 379: 542-545 Crossref PubMed Scopus (82) Google Scholar ), stress ( 9 Funk D. Stewart J. Role of catecholamines in the frontal cortex in the modulation of basal and stress-induced autonomic output in rats. Brain Res. 1996; 741: 220-229 Crossref PubMed Scopus (39) Google Scholar ), recovery of function after brain lesions ( 10 Kolb B. Stewart J. Sutherland R.J. Recovery of function is associated with increased spine density in cortical pyramidal cells after frontal lesions and/or noradrenaline depletion in neonatal rats. Behav Brain Res. 1997; 89: 61-70 Crossref PubMed Scopus (42) Google Scholar ), sex differences in drug effects ( 11 Forgie M.L. Stewart J. Sex differences in amphetamine-induced locomotor activity in adult rats: Role of testosterone exposure in the neonatal period. Pharmacol Biochem Behav. 1993; 46: 637-645 Crossref PubMed Scopus (47) Google Scholar ), mechanisms of antidepressant and antipsychotic drugs ( 12 Stewart J. Rajabi H. Initial increases in extracellular dopamine in the ventral tegmental area provide a mechanism for the development of desipramine-induced sensitization within the midbrain dopamine system. Synapse. 1996; 23: 258-264 Crossref PubMed Scopus (16) Google Scholar , 13 Samaha A.N. Seeman P. Stewart J. Rajabi H. Kapur S. “Breakthrough” dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neurosci. 2007; 27: 2979-2986 Crossref PubMed Scopus (200) Google Scholar ), pain ( 14 Altier N. Stewart J. The role of dopamine in the nucleus accumbens in analgesia. Life Sci. 1999; 65: 2269-2287 Crossref PubMed Scopus (228) Google Scholar ), and sexual behavior ( 15 Mitchell J.B. Stewart J. Facilitation of sexual behaviors in the male rat associated with intra-VTA injections of opiates. Pharmacol Biochem Behav. 1990; 35: 643-650 Crossref PubMed Scopus (77) Google Scholar , 16 Stewart J. How does incentive motivational theory apply to sexual behavior?. in: Bancroft J. The Pharmacology of Sexual Function and Dysfunction. Excerpta Medica (Elsevier Science B.V.), Amsterdam1995: 3-11 Google Scholar ). In each of these diverse research areas, Jane's work is highly regarded. Jane has also been integrally involved in academic issues relating to science education and policy in Canada. Her former pre-doctoral and post-doctoral trainees hold academic positions at McGill University, University of Toronto, University of Chicago, University of Wisconsin, National Institutes of Health, University of Rome, and many other academic institutions.

Norepinephrine mediates the transcriptional effects of heterotypic chronic stress on colonic motor function.

Chronic stress precipitates or exacerbates the symptoms of functional bowel disorders, including motility dysfunction. The cellular mechanisms of these effects are not understood. We tested the hypothesis that heterotypic chronic stress (HeCS) elevates the release of norepinephrine from the adrenal medulla, which enhances transcription of the gene-regulating expression of Ca(v)1.2 (L-type) channels in colonic circular smooth muscle cells, resulting in enhanced colonic motor function. The experiments were performed in rats using a 9-day heterotypic chronic stress (HeCS) protocol. We found that HeCS, but not acute stress, time dependently enhances the contractile response to ACh in colonic circular smooth muscle strips and in single dissociated smooth muscle cells, the plasma levels of norepinephrine and the mRNA and protein expressions of the alpha(1C) subunit of Ca(v)1.2 channels. These effects result in faster colonic transit and increase in defecation rate. The effects of HeCS are blocked by adrenalectomy but not by depletion of norepinephrine in sympathetic neurons. The inhibition of receptors for glucocortocoids, corticotropin-releasing hormone or nicotine also does not block the effects of heterotypic chronic stress. Norepinephrine acts on alpha- and beta(3)-adrenergic receptors to induce the transcription of alpha(1C) subunit. We conclude that HeCS alters colonic motor function by elevating the plasma levels of norepinephrine. Colonic motor dysfunction is associated with enhanced gene transcription of Ca(v)1.2 channels in circular smooth muscle cells. These findings suggest the potential cellular mechanisms by which heterotypic chronic stress may exacerbate motility dysfunction in patients with irritable bowel syndrome.

Noradrenergic Control of Associative Synaptic Plasticity by Selective Modulation of Instructive Signals

Synapses throughout the brain are modified through associative mechanisms in which one input provides an instructive signal for changes in the strength of a second coactivated input. In cerebellar Purkinje cells, climbing fiber synapses provide an instructive signal for plasticity at parallel fiber synapses. Here, we show that noradrenaline activates alpha2-adrenergic receptors to control short-term and long-term associative plasticity of parallel fiber synapses. This regulation of plasticity does not reflect a conventional direct modulation of the postsynaptic Purkinje cell or presynaptic parallel fibers. Instead, noradrenaline reduces associative plasticity by selectively decreasing the probability of release at the climbing fiber synapse, which in turn decreases climbing fiber-evoked dendritic calcium signals. These findings raise the possibility that targeted presynaptic modulation of instructive synapses could provide a general mechanism for dynamic context-dependent modulation of associative plasticity.

Methamphetamine Preconditioning: Differential Protective Effects on Monoaminergic Systems in the Rat Brain

Pretreatment with methamphetamine (METH) can attenuate toxicity due to acute METH challenges. The majority of previous reports have focused mainly on the effects of the drug on the striatal dopaminergic system. In the present study, we used a regimen that involves gradual increases in METH administration to rats in order to mimic progressively larger doses of the drug used by some human METH addicts. We found that this METH preconditioning was associated with complete protection against dopamine depletion caused by a METH challenge (5 mg/kg x 6 injections given 1 h apart) in the striatum and cortex. In contrast, there was no preconditioning-mediated protection against METH-induced serotonin depletion in the striatum and hippocampus, with some protection being observed in the cortex. There was also no protection against METH-induced norepinephrine (NE) depletion in the hippocampus. These results indicate that, in contrast to the present dogmas, there might be differences in the mechanisms involved in METH toxicity on monoaminergic systems in the rodent brain. Thus, chronic injections of METH might activate programs that protect against dopamine toxicity without influencing drug-induced pathological changes in serotoninergic systems. Further studies will need to evaluate the cellular and molecular bases for these differential responses.

Monoaminergic regulation of Sonic hedgehog signaling cascade expression in the adult rat hippocampus

Monoamines are implicated in the modulation of adult hippocampal neurogenesis in depression models and following chronic antidepressant treatment. Given the key role of Sonic hedgehog (Shh) in adult neurogenesis, we examined whether monoaminergic perturbations regulate the expression of Shh or its co-receptors Smoothened (Smo) and Patched (Ptc). Combined depletion of both serotonin and norepinephrine with para-chlorophenylalanine (PCPA) resulted in a significant decrease in Smo and Ptc mRNA within the dentate gyrus subfield of the hippocampus. However, selective depletion of serotonin, using the serotonergic neurotoxin 5,7-dihyrdroxytryptamine (5,7-DHT), or norepinephrine, using the noradrenergic neurotoxin DSP-4, did not alter expression of Shh and its co-receptors, Smo and Ptc. Acute treatment with the monoamine releasing agent, para-chloroamphetamine (PCA) significantly upregulated Smo mRNA within the dentate gyrus. However, acute or chronic treatment with pharmacological antidepressants that modulate monoaminergic neurotransmission did not regulate Shh cascade expression. These results indicate that robust changes in monoamine levels can regulate the expression of the Shh signaling cascade in the adult rodent brain.

Monoaminergic Changes in Locus Coeruleus and Dorsal Raphe Nucleus Following Noradrenaline Depletion

The goal of our study was to assess the monoaminergic changes in locus coeruleus (LC) and dorsal raphe nucleus (DRN) following noradrenaline (NA) depletion. Seven days after a single N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) intraperitoneal administration in mice, we observed a decrease of NA in both the LC and DRN, as well as in prefrontal cortex (PFC) and hippocampus (HIPP). Moreover, an increase of serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) was detected at LC level, while no change was found in DRN. DSP-4 also caused a significant decrease of dopamine (DA) tissue content in HIPP and DRN, without affecting the LC and the PFC. A decrease of DA metabolite, homovanillic acid (HVA), was found in the DRN of NA-depleted mice. These results highlight that the neurotoxic action of DSP-4 is not restricted to LC terminal projections but also involves NA depletion at the cell body level, where it is paralleled by adaptive changes in both serotonergic and dopaminergic systems.

Nonenzymatic role of acetylcholinesterase in neuritic sprouting: Regional changes in acetylcholinesterase and choline acetyltransferase after neonatal 6-hydroxydopamine lesions

Acetylcholinesterase (AChE) is postulated to play a nonenzymatic role in the development of neuritic projections. We gave the specific neurotoxin, 6-OHDA to rats on postnatal day (PN) 1, a treatment that destroys noradrenergic nerve terminals in the forebrain while producing reactive sprouting in the brainstem. AChE showed profound decreases in the forebrain that persisted in males over the entire phase of major synaptogenesis, from PN4 through PN21; in the brainstem, AChE was increased. Parallel examinations of choline acetyltransferase, an enzymatic marker for cholinergic nerve terminals, showed a different pattern of 6-OHDA-induced alterations, with initial decreases in both forebrain and brainstem in males and regression toward normal by PN21; females were far less affected. The sex differences are in accord with the greater plasticity of the female brain and its more rapid recovery from neurotoxic injury; our findings indicate that these differences are present well before puberty. These results support the view that AChE is involved in neurite formation, unrelated to its enzymatic role in cholinergic neurotransmission. Further, the results for choline acetyltransferase indicate that early depletion of norepinephrine compromises development of acetylcholine systems, consistent with a trophic role for this neurotransmitter.

A Computational Model of Stress Coping in Rats

This work presents a computational neural-network model explaining the brain processes underlying stress coping in rats exposed to long lasting inescapable stress conditions, focussing on the three neuromodulators dopamine (DA), noradrenaline (NE) and serotonin (5-HT). The importance of the model relies on the fact that stress coping experiments are considered a good animal model of the mechanisms underlying human depression. Pascucci et al. (2007) used microdialysis to investigate the correlation existing between the presence of NE and DA in medial prefrontal cortex (mPFC) and the quantity of mesoaccumbens DA during a restraint test lasting 240 min. The comparison of the microdialysis results related to sham rats and rats with either NE or DA depletion in mPFC showed the role played by such neuromodulators on DA release in nucleus accumbens (NAcc) and the active/passive modality of stress coping.

Effects of noradrenaline depletion in intact and 6 – hydroxydopamine – lesioned rats: behavioural and electrophysiological studies

Effects of noradrenaline depletion in intact and 6 – hydroxydopamine – lesioned rats: behavioural and electrophysiological studies