Noradrenergic innervation of serotonergic neurons in the dorsal raphe: Demonstration by electron microscopic autoradiography

doi:10.1016/0006-8993(81)90646-6

Brain Research

Volume 204, Issue 1, 5 January 1981, Pages 1-11

https://doi.org/10.1016/0006-8993(81)90646-6 Get rights and content

Summary

In this study, noradrenergic (NE) terminals in the dorsal raphe were identified by [³H]NE electron microscopic (EM) autoradiography. Lesioning of NE terminals by treatment with the selective catecholamine neurotoxin, 6-hydroxydopamine produced a marked decrease in NE-labelled terminals. [³H]5-HT EM autoradiography of the dorsal raphe produced labelling of cell bodies, dendrites and axons but labelled terminals with synaptic junctions were not observed. Serotonergic (5-HT) neurons were identified at an early state of degeneration following treatment with the selective 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). When both [³H]NE autoradiography and 5,7-DHT lesioning were combined, a majority of NE-labelled terminals, which formed synaptic specializations, innervated degenerating dendrites. These findings suggest that NE terminals directly innervate 5-HT cells in the dorsal raphe.

References (43)

AghajanianG.K. et al.
Serotonergic and non-serotonergic neurons of the dorsal raphe: reciprocal changes in firing induced by peripheral nerve stimulation
Brain Research
(1978)
BarabanJ.M. et al.
Reserpine suppression of dorsal raphe neuronal firing: mediation by adrenergic system
Europ. J. Pharmacol.
(1978)
BarabanJ.M. et al.
Suppression of firing activity of 5-HT neurons in the dorsal raphe by alpha-adrenoceptor antagonists
Neuropharmacology
(1980)
BreeseG.R. et al.
Behavioral and biochemical interactions of 5,7-dihydroxytryptamine with various drugs when administered intracisternally to adult and developing rats
Brain Research
(1975)
GersonS. et al.
Selective destruction of serotonin terminals in rat forebrain by high doses of 5,7-dihydroxytryptamine
Brain Research
(1975)
GrzannaR. et al.
The locus coeruleus in the rat: an immunohistochemical delineation
Neuroscience
(1980)
JonesG. et al.
Locus coeruleus neurons in freely moving rats exhibit pronounced alterations of discharge rate during sensory stimulations and stages of the sleep-wake cycle
McGeerE.G. et al.
Confirmatory data on habenular projections
Brain Research
(1979)
McGintyD.J. et al.
Dorsal raphe neurons: depression of firing during sleep in cats
Brain Research
(1976)
NowaczykT. et al.
Differential radioautographic visualization of central catecholaminergic neurons following introcisternal or intraventricular injection of tritiated norephrine
Brain Research
(1978)

RichardsJ.G. et al.

Indolealkylamine nerve terminals in cerebral ventricles: identification by electron microscopy and fluorescence histochemistry

Brain Research

(1973)

SaavedraJ.M. et al.

Catecholamines in the raphe nuclei of the rat

Brain Research

(1976)

SvenssonT.H. et al.

Inhibition of both noradrenergic and serotonergic neurons in brain by the alpha-adrenergic agonist, clonidine

Brain Research

(1975)

TrulsonM.E. et al.

Raphe unit activity in freely moving cats: correlation with level of behavioral arousal

Brain Research

(1979)

VersteegD.H.G. et al.

Regional concentrations of noradrenaline and dopamine in rat brain

Brain Research

(1976)

WangR.Y. et al.

Antidromically identified serotonergic neurons in the rat midbrain raphe: evidence for collateral inhibition

Brain Research

(1977)

WangR.Y. et al.

Collateral inhibition of serotonergic neurones in the rat dorsal raphe nucleus: pharmacological evidence

Neuropharmacology

(1978)

AghajanianG.K. et al.

Electron microscopic autoradiography of rat hypothalamus after intraventricular³H-norepinephrine

Science

(1966)

AghajanianG.K. et al.

Electron microscopic localization of tritiated norepinephrine in rat brain: effects of drugs

J. Pharmacol. exp. Ther.

(1967)

AghajanianG.K. et al.

Localization of tritiated serotonin in rat brain by electron-microscopic autoradiography

J. Pharmacol. exp. Ther.

(1967)

Baraban, J. M. and Aghajanian, G. K., Suppression of serotonergic neuronal firing by alpha-adrenoceptor antagonists:...

Cited by (232)

Role of central serotonin and noradrenaline interactions in the antidepressants’ action: Electrophysiological and neurochemical evidence
2021, Progress in Brain Research
The development of antidepressant drugs, in the last 6 decades, has been associated with theories based on a deficiency of serotonin (5-HT) and/or noradrenaline (NA) systems. Although the pathophysiology of major depression (MD) is not fully understood, numerous investigations have suggested that treatments with various classes of antidepressant drugs may lead to an enhanced 5-HT and/or adapted NA neurotransmissions. In this review, particular morpho-physiological aspects of these systems are first considered. Second, principal features of central 5-HT/NA interactions are examined. In this regard, the effects of the acute and sustained antidepressant administrations on these systems are discussed. Finally, future directions including novel therapeutic strategies are proposed.
Two models of inescapable stress increase tph2 mRNA expression in the anxiety-related dorsomedial part of the dorsal raphe nucleus
2018, Neurobiology of Stress
Citation Excerpt :
Most studies associate an increase in swimming behavior with a stimulated serotonergic system, while increased climbing behavior is attributed to altered dopaminergic or noradrenergic systems (Detke et al., 1995; Cryan et al., 2005; Perona et al., 2008). One hypothesis is that activation of the locus coeruleus selectively activates DRD serotonergic neurons, which are potently activated by α1 adrenergic receptors (Baraban and Aghajanian, 1980; 1981; Day et al., 2004). In another rat model of passive coping during both social defeat and forced swim, peripheral IL-1β expression is elevated (Finnell et al., 2017), while intra-DR expression of IL-1 receptor type 2, a “decoy” receptor and endogenous inhibitor of IL-1, was found to be decreased (Wood et al., 2015), potentially exaggerating a proinflammatory state and depressive-like behavioral responses during forced swimming.
Expression of TPH2, the rate-limiting enzyme for brain serotonin synthesis, is elevated in the dorsal raphe nucleus (DR) of depressed suicide victims. One hypothesis is that this increase in TPH2 expression is stress-induced. Here, we used an established animal model to address whether exposure to an acute stressor, inescapable tail shock (IS), increases tph2 mRNA and Tph2 protein expression, and if IS sensitizes the DR to a subsequent, heterotypic stressor. In Experiment 1, we measured tph2 mRNA expression 4 h after IS or home cage (HC) control conditions in male rats, using in situ hybridization histochemistry. In Experiment 2, we measured Tph2 protein expression 12 h or 24 h after IS using western blot. In Experiment 3, we measured tph2 mRNA expression following IS on Day 1, and cold swim stress (10 min, 15 °C) on Day 2. Inescapable tail shock was sufficient to increase tph2 mRNA expression 4 h and 28 h later, selectively in the dorsomedial DR (caudal aspect of the dorsal DR, cDRD; an area just rostral to the caudal DR, DRC) and increased Tph2 protein expression in the DRD (rostral and caudal aspects of the dorsal DR combined) 24 h later. Cold swim increased tph2 mRNA expression in the dorsomedial DR (cDRD) 4 h later. These effects were associated with increased immobility during cold swim, elevated plasma corticosterone, and a proinflammatory plasma cytokine milieu (increased interleukin (IL)-6, decreased IL-10). Our data demonstrate that two models of inescapable stress, IS and cold swim, increase tph2 mRNA expression selectively in the anxiety-related dorsomedial DR (cDRD).
Wiring Diagram of the RAS
2015, Waking and the Reticular Activating System in Health and Disease
The wiring diagram of the main nuclei of the reticular activating system (RAS) is well known, as are the intrinsic membrane properties of cells in these nuclei. The major transmitter inputs to these cells have also been described, as have the main cell types and their transmitter outputs. In addition, the presence of electrical coupling in some cells in these nuclei has been determined. These properties allow us to gain a measure of the types of firing patterns that these neurons are capable of maintaining. The firing patterns and transmitter inputs of these cells across the wake–sleep cycle have also been determined. Current research is directed at how the cell clusters within the RAS nuclei function to modulate thalamic and cortical EEG rhythms in the presence of sporadic and continuous sensory inputs. This information is critical for determining how the states of waking and REM sleep are modulated by the RAS.
Computational modeling of spike generation in serotonergic neurons of the dorsal raphe nucleus
2014, Progress in Neurobiology
Serotonergic neurons of the dorsal raphe nucleus, with their extensive innervation of limbic and higher brain regions and interactions with the endocrine system have important modulatory or regulatory effects on many cognitive, emotional and physiological processes. They have been strongly implicated in responses to stress and in the occurrence of major depressive disorder and other psychiatric disorders. In order to quantify some of these effects, detailed mathematical models of the activity of such cells are required which describe their complex neurochemistry and neurophysiology. We consider here a single-compartment model of these neurons which is capable of describing many of the known features of spike generation, particularly the slow rhythmic pacemaking activity often observed in these cells in a variety of species. Included in the model are 11 kinds of ion channels: a fast sodium current I_Na, a delayed rectifier potassium current I_KDR, a transient potassium current I_A, a slow non-inactivating potassium current I_M, a low-threshold calcium current I_T, two high threshold calcium currents I_L and I_N, small and large conductance potassium currents I_SK and I_BK, a hyperpolarization-activated cation current I_H and a leak current I_Leak. In Sections 3–8, each current type is considered in detail and parameters estimated from voltage clamp data where possible. Three kinds of model are considered for the BK current and two for the leak current. Intracellular calcium ion concentration Ca_i is an additional component and calcium dynamics along with buffering and pumping is discussed in Section 9. The remainder of the article contains descriptions of computed solutions which reveal both spontaneous and driven spiking with several parameter sets. Attention is focused on the properties usually associated with these neurons, particularly long duration of action potential, steep upslope on the leading edge of spikes, pacemaker-like spiking, long-lasting afterhyperpolarization and the ramp-like return to threshold after a spike. In some cases the membrane potential trajectories display doublets or have humps or notches as have been reported in some experimental studies. The computed time courses of I_A and I_T during the interspike interval support the generally held view of a competition between them in influencing the frequency of spiking. Spontaneous activity was facilitated by the presence of I_H which has been found in these neurons by some investigators. For reasonable sets of parameters spike frequencies between about 0.6 Hz and 1.2 Hz are obtained, but frequencies as high as 6 Hz could be obtained with special parameter choices. Topics investigated and compared with experiment include shoulders, notches, anodal break phenomena, the effects of noradrenergic input, frequency versus current curves, depolarization block, effects of cell size and the effects of I_M. The inhibitory effects of activating 5-HT1A autoreceptors are also investigated. There is a considerable discussion of in vitro versus in vivo firing behavior, with focus on the roles of noradrenergic input, corticotropin-releasing factor and orexinergic inputs. Location of cells within the nucleus is probably a major factor, along with the state of the animal.
Consciousness and Subcortical Arousal Systems
2014, Neuronal Networks in Brain Function, CNS Disorders, and Therapeutics
The “consciousness system” encompasses brain areas that are crucial for maintaining the diverse behavioral components of consciousness. Both subcortical and cortical networks contribute to the content and level of consciousness. Although small in number, the subcortical neuromodulatory systems exert a powerful effect on our behavior and electroencephalogram while we are both awake and asleep. This chapter aims to provide the reader with an introduction to the seven principal subcortical arousal systems organized by neurotransmitters (acetylcholine, norepinephrine, histamine, serotonin, orexin, glutamate, and dopamine). These parallel systems exhibit a diverse range of firing patterns across the sleep–wake cycle and govern both overlapping and unique behaviors. Their stimulation or inhibition affects behavior, as well as the encephalogram, by complex and multifactorial means. It is our hope that this chapter will provide an adequate foundation on which to understand central nervous system disorders that disrupt consciousness via subcortical structures.
The effects of the co-administration of the α<inf>1</inf>-adrenoreceptor antagonist prazosin on the anxiolytic effect of citalopram in conditioned fear stress in the rat
2012, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Several studies have shown that the α₁-adrenoreceptor is involved in controlling extracellular serotonin levels. The administration of the α₁-adrenoreceptor antagonist prazosin was shown to decrease extracellular serotonin levels in the hippocampus, the prefrontal cortex and the raphe nucleus, while the administration of the α₁-adrenoreceptor agonist cirazoline was shown to increase serotonin levels. Furthermore, the elevation of serotonin levels induced by the selective serotonin reuptake inhibitor (SSRI) citalopram was attenuated by prazosin. Thus, α₁-adrenoreceptor antagonists may affect SSRI-induced increases in extracellular serotonin levels and their antidepressive and anxiolytic effects. However, little is known about the influence of α₁-adrenoreceptor antagonists on the behavioral pharmacological effects of SSRIs. The conditioned fear stress-induced freezing behavior is an animal model of anxiety and can detect the anxiolytic effect of SSRIs. To clarify whether an α₁-adrenoreceptor antagonist affects the anxiolytic action of SSRIs, we examined the effects of the co-administration of the α₁-adrenoreceptor antagonist prazosin and the SSRI citalopram using the contextual conditioned fear stress model. Low-dose prazosin (0.03 mg/kg) significantly attenuated the citalopram (3 mg/kg)-induced decrease in conditioned freezing. Moreover, high-dose (0.5 mg/kg), but not low-dose (0.03 mg/kg), prazosin significantly attenuated citalopram (10 mg/kg)-induced decreases in conditioned freezing. These drugs did not affect the spontaneous motor activity of the rats. Therefore, these results suggest that blocking the α₁-adrenoreceptor decreases the anxiolytic effect of citalopram.

View all citing articles on Scopus

View full text

Noradrenergic innervation of serotonergic neurons in the dorsal raphe: Demonstration by electron microscopic autoradiography

Summary

Brain Research

Europ. J. Pharmacol.

Neuropharmacology

Brain Research

Brain Research

Neuroscience

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

Neuropharmacology

Electron microscopic autoradiography of rat hypothalamus after intraventricular3H-norepinephrine

Science

Electron microscopic localization of tritiated norepinephrine in rat brain: effects of drugs

J. Pharmacol. exp. Ther.

Localization of tritiated serotonin in rat brain by electron-microscopic autoradiography

J. Pharmacol. exp. Ther.

Electron microscopic autoradiography of rat hypothalamus after intraventricular³H-norepinephrine