Evidence for dual serotonergic projections to neocortex: Axons from the dorsal and median raphe nuclei are differentially vulnerable to the neurotoxin p-chloroamphetamine (PCA)

doi:10.1016/0014-4886(88)90075-1

Experimental Neurology

Volume 102, Issue 1, October 1988, Pages 23-36

https://doi.org/10.1016/0014-4886(88)90075-1 Get rights and content

Abstract

Previous studies have shown that there are morphologically dissimilar serotonergic (5-HT) axon types in rat cerebral cortex which are differentially sensitive to the neurotoxic effects of certain psychotropic drugs: methylenedioxyamphetamines (MDA and MDMA) and p-chloroamphetamine (PCA) cause degeneration of fine 5-HT axon terminals in cortex, while sparing beaded axons. Moreover, a recent anterograde transport study suggests that fine and beaded 5-HT axons arise from the dorsal raphe (DR) and median raphe (MR) nuclei, respectively. These data led us to propose that the DR projection to neocortex is selectively vulnerable to the neurotoxic effects of PCA, while the MR projection is resistant; this hypothesis was tested in the present study by comparing retrograde axonal transport of the fluorescent tracer Fluoro-Gold in PCA-treated and control rats. Using this method, only axons that survive PCA treatment can take up and transport the injected label back to the cell bodies of origin, thus allowing us to determine which raphe—cortical projections remain intact after PCA. The results show that PCA administration produces a loss of fine 5-HT axon terminals in neocortex and a concomitant reduction in the number of retrogradely labeled neurons in the DR (77% decrease), when compared to controls. In contrast, beaded 5-HT axon terminals are spared and the number of labeled neurons in the MR remains unchanged after PCA. These results demonstrate that DR and MR projections to cortex are differentially vulnerable to PCA: fine axon terminals arise from neurons in the Dr and are highly sensitive to the neurotoxic effects, whereas beaded axons from the MR are resistant. We therefore propose that there are two anatomically and functionally separate 5-HT projections to cortex having different (1) nuclei of origin, (2) axon morphology, (3) regional distributions, and (4) pharmacological properties. Since the mood-altering substances MDA, MDMA, and PCA act specifically upon 5-HT axon terminals from the dorsal raphe nucleus, DR neurons may be preferentially involved in the control of affective state.

References (71)

M.E. Blue et al.
Correspondence between 5-HT₂ receptors and serotonergic axons in rat neocortex
Brain Res.
(1988)
P. Bobillier et al.
Differential projections of the nucleus raphe dorsalis and nucleus raphe centralis as revealed by autoradiography
Brain Res.
(1975)
R.W. Fuller et al.
Lowering of brain serotonin level by chloroamphetamines
Biochem. Pharmacol.
(1965)
R.W. Fuller et al.
Reversible and irreversible phases of serotonin depletion by 4-chloroamphetamine
Eur. J. Pharmacol.
(1975)
D. Galindo-Mireles et al.
Cortical projections of the nucleus centralis superior and the adjacent reticular tegmentum in the mouse
Brain Res.
(1985)
M.A. Geyer et al.
Histologic and enzymatic studies of the mesolimbic and neostriatal serotonergic pathways
Brain Res.
(1976)
M.A. Geyer et al.
Behavioral studies following lesions of the mesolimbic and mesostriatal serotonergic pathways
Brain Res.
(1976)
R.A. Glennon et al.
Evidence for 5-HT₂ involvement in the mechanism of action of hallucinogenic agents
Life Sci.
(1984)
J. Heym et al.
Some behavioral effects of hallucinogens are mediated by a postsynaptic serotonergic action: Evidence from single unit studies in freely moving cats
Eur. J. Pharmacol.
(1984)
B.L. Jacobs et al.
Differential projections of neurons within the dorsal raphe nucleus of the rat: A horseradish peroxidase (HRP) study
Brain Res.
(1978)

B.L. Jacobs et al.

Differential behavioral and neurochemical effects following lesions of the dorsal or median raphe nuclei in rats

Brain Res.

(1974)

K.J. Kellar et al.

Origins of serotonin innervation of forebrain structures

Exp. Neurol.

(1977)

C. Köhler et al.

Identification of serotonin and non-serotonin-containing neurons of the midbrain raphe projecting to the entorhinal area and the hippocampal formation. A combined immunohistochemical and fluorescent retrograde tracing study in the rat brain

Neuroscience

(1982)

H.G.W. Lidov et al.

The serotonin innervation of the cerebral cortex in the rat—An immunohistochemical analysis

Neuroscience

(1980)

H.G.W. Lidov et al.

Immunohistochemical study of the development of serotonergic neurons in the rat CNS

Brain Res. Bull.

(1982)

S.A. Lorens et al.

Regional 5-hydroxy-tryptamine following selective midbrain raphe lesions in the rat

Brain Res.

(1974)

F.P. Miller et al.

Comparative effects of p-chlorophenylalanine, p-chloroamphetamine and p-chloro-N-methylamphetamine on rat brain norepinephrine, serotonin and 5-hydroxyindole-3-acetic acid

Biochem. Pharmacol.

(1970)

E. O'Hearn et al.

Organization of raphecortical projections in rat: A quantitative retrograde study

Brain Res. Bull.

(1984)

A. Parent et al.

Organization of ascending serotonin neurons in the adult rat brain. A radioautographic study after intraventricular administration of [³H]5-hydroxytryptamine

Neuroscience

(1981)

O. Pucilowski et al.

Effects of stimulation of the raphe nuclei on muricide behavior in rats

Pharmacol. Biochem. Behav.

(1981)

E. Sanders-Bush et al.

Longterm effects of p-chloroamphetamine on tryptophan hydroxylase activity and on levels of 5-hydroxytryptamine and 5-hydroxyindole acetic acid in brain

Eur. J. Pharmacol.

(1972)

C.J. Schmidt et al.

Methylenedioxymethamphetamine: A potentially neurotoxic amphetamine analogue

Eur. J. Pharmacol.

(1986)

B. Srebro et al.

Behavioral effects of selective midbrain raphe lesions in the rat

Brain Res.

(1975)

M. Stanley et al.

Increased serotonin-2 binding sites in frontal cortex of suicide victims

Lancet

(1983)

D.M. Stone et al.

The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain

Eur. J. Pharmacol.

(1986)

L.D. Van de Kar et al.

Evidence that serotonergic neurons in the dorsal raphe nucleus exert a stimulatory effect on the secretion of renin but not of corticosterone

Brain Res.

(1982)

R.J. Waldbillig

The role of the dorsal and median raphe in the inhibition of muricide

Brain Res.

(1979)

N.E. Anden et al.

Ascending monoamine neurons to the telencephalon and diencephalon

Acta Physiol. Scand.

(1966)

E.C. Azmitia

The serotonin-producing neurons of the midbrain median and dorsal raphe nuclei

E.C. Azmitia et al.

An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat

J. Comp. Neurol.

(1978)

G. Battaglia et al.

3,4-Methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) preferentially destroy serotonin terminals in rat brain: Quantification of neurodegeneration by measurement of ³H-paroxetine-labeled serotonin uptake sites

J. Pharmacol. Exp. Ther.

(1987)

M. Bentivoglio et al.

Brain stem neurons projecting to neocortex: A HRP study in the cat

Exp. Brain Res.

(1978)

U. Berger et al.

Psychotropic amphetamines have different sites of action at serotonergic (5-HT) synapses: A comparison of p-chloroamphetamine (PCA) and 3,4-methylenedioxyamphetamine (MDA) with 2,5-dimethoxy-4-methylamphetamine (DOM)

Soc. Neurosci. Abstr.

(1987)

A.L. Berman

V. Chan-Palay

Fine structure of labeled axons in the cerebellar cortex and nuclei of rodents and primates after intraventricular infusions with tritiated serotonin

Anat. Embryol.

(1975)

Cited by (183)

Anatomical and neurochemical organization of the serotonergic system in the mammalian brain and in particular the involvement of the dorsal raphe nucleus in relation to neurological diseases
2021, Progress in Brain Research
Citation Excerpt :
The morphology and origin of the axons from these nuclei have been linked to differential drug-sensitivity. Thus, the neurotoxic amphetamine derivatives methylenedioxyamphetamine (MDA) and p-chloroamphetamine (PCA) induce denervation of the fine axons, whereas the thick ones are unaffected by the drugs (Mamounas and Molliver, 1988; Mamounas et al., 1991; O'Hearn and Molliver, 1984). The expression the serotonin transporter (SERT) is a reason for this difference.
The brainstem is a neglected brain area in neurodegenerative diseases, including Alzheimer's and Parkinson's disease, frontotemporal lobar degeneration and autonomic dysfunction. In Depression, several observations have been made in relation to changes in one particular the Dorsal Raphe Nucleus (DRN) which also points toward as key area in various age-related and neurodevelopmental diseases. The DRN is further thought to be related to stress regulated processes and cognitive events. It is involved in neurodegeneration, e.g., amyloid plaques, neurofibrillary tangles, and impaired synaptic transmission in Alzheimer's disease as shown in our autopsy findings. The DRN is a phylogenetically old brain area, with projections that reach out to a large number of regions and nuclei of the central nervous system, particularly in the forebrain. These ascending projections contain multiple neurotransmitters. One of the main reasons for the past and current interest in the DRN is its involvement in depression, and its main transmitter serotonin. The DRN also points toward the increased importance and focus of the brainstem as key area in various age-related and neurodevelopmental diseases.
This review describes the morphology, ascending projections and the complex neurotransmitter nature of the DRN, stressing its role as a key research target into the neural bases of depression.
Serotonergic mechanisms in spinal cord injury
2019, Experimental Neurology
Spinal cord injury (SCI) is a tragic event causing irreversible losses of sensory, motor, and autonomic functions, that may also be associated with chronic neuropathic pain. Serotonin (5-HT) neurotransmission in the spinal cord is critical for modulating sensory, motor, and autonomic functions. Following SCI, 5-HT axons caudal to the lesion site degenerate, and the degree of axonal degeneration positively correlates with lesion severity. Rostral to the lesion, 5-HT axons sprout, irrespective of the severity of the injury. Unlike callosal fibers and cholinergic projections, 5-HT axons are more resistant to an inhibitory milieu and undergo active sprouting and regeneration after central nervous system (CNS) traumatism. Numerous studies suggest that a chronic increase in serotonergic neurotransmission promotes 5-HT axon sprouting in the intact CNS. Moreover, recent studies in invertebrates suggest that 5-HT has a pro-regenerative role in injured axons. Here we present a brief description of 5-HT discovery, 5-HT innervation of the CNS, and physiological functions of 5-HT in the spinal cord, including its role in controlling bladder function. We then present a comprehensive overview of changes in serotonergic axons after CNS damage, and discuss their plasticity upon altered 5-HT neurotransmitter levels. Subsequently, we provide an in-depth review of therapeutic approaches targeting 5-HT neurotransmission, as well as other pre-clinical strategies to promote an increase in re-growth of 5-HT axons, and their functional consequences in SCI animal models. Finally, we highlight recent findings signifying the direct role of 5-HT in axon regeneration and suggest strategies to further promote robust long-distance re-growth of 5-HT axons across the lesion site and eventually achieve functional recovery following SCI.
Identification and distribution of projections from monoaminergic and cholinergic nuclei to functionally differentiated subregions of prefrontal cortex
2013, Brain Research
The prefrontal cortex (PFC) is implicated in a variety of cognitive and executive functions and is composed of several distinct networks, including anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). These regions serve dissociable cognitive functions, and are heavily innervated by acetylcholine, dopamine, serotonin and norepinephrine systems. In this study, fluorescently labeled retrograde tracers were injected into the ACC, mPFC, and OFC, and labeled cells were identified in the nucleus basalis (NB), ventral tegmental area (VTA), dorsal raphe nucleus (DRN) and locus coeruleus (LC). DRN and LC showed similar distributions of retrogradely labeled neurons such that most were single labeled and the largest population projected to mPFC. VTA showed a slightly greater proportion of double and triple labeled neurons, with the largest population projecting to OFC. NB, on the other hand, showed mostly double and triple labeled neurons projecting to multiple subregions. Therefore, subsets of VTA, DRN and LC neurons may be capable of modulating individual prefrontal subregions independently, whereas NB cells may exert a more unified influence on the three areas simultaneously. These findings emphasize the unique aspects of the cholinergic and monoaminergic projections to functionally and anatomically distinct subregions of PFC.
Raphe Nuclei
2012, The Human Nervous System, Third Edition
The serotonergic system in fish
2011, Journal of Chemical Neuroanatomy
Citation Excerpt :
Based on topography these two main populations can be further subdivided into 9 diffusely organized nuclei (B1-4 covering the IR, and B5-9 covering the SR). The anatomical separation into different nuclei is, at least partly, correlated with functional specializations of the raphe serotonergic neurons based on innervation of target area, input, electrophysiological properties, receptor and neuropeptide expression and vulnerability to neurotoxins (Brown and Molliver, 2000; Fuxe et al., 2007; Hajos et al., 2007; Jacobs and Azmitia, 1992; Lacoste et al., 2006; Mamounas and Molliver, 1988; Mamounas et al., 1991; Törk, 1990). Based on location and morphology, more than 20 different clusters of 5-HT neurons have been identified in certain fishes (Pierre et al., 1992).
Neurons using serotonin (5-HT) as neurotransmitter and/or modulator have been identified in the central nervous system in representatives from all vertebrate clades, including jawless, cartilaginous and ray-finned fishes. The aim of this review is to summarize our current knowledge about the anatomical organization of the central serotonergic system in fishes. Furthermore, selected key functions of 5-HT will be described. The main focus will be the adult brain of teleosts, in particular zebrafish, which is increasingly used as a model organism. It is used to answer not only genetic and developmental biology questions, but also issues concerning physiology, behavior and the underlying neuronal networks. The many evolutionary conserved features of zebrafish combined with the ever increasing number of genetic tools and its practical advantages promise great possibilities to increase our understanding of the serotonergic system. Further, comparative studies including several vertebrate species will provide us with interesting insights into the evolution of this important neurotransmitter system.
Role of serotonin transporter inhibition in the regulation of tryptophan hydroxylase in brainstem raphe nuclei: Time course and regional specificity
2010, Neuroscience
Drugs that selectively inhibit the serotonin transporter (SERT) are widely prescribed for treatment of depression and a range of anxiety disorders. We studied the time course of changes in tryptophan hydroxylase (TPH) in four raphe nuclei after initiation of two different SERT inhibitors, citalopram and fluoxetine. In the first experiment, groups of Sprague–Dawley rats received daily meals of rice pudding either alone (n=9) or mixed with citalopram 5 mg/kg/day (n=27). Rats were sacrificed after 24 h, 7 days or 28 days of treatment. Sections of dorsal raphe nucleus (DRN), median raphe nucleus (MRN), raphe magnus nucleus (RMN) and caudal linear nucleus (CLN) were processed for TPH immunohistochemistry. Citalopram induced a significant reduction in DRN TPH-positive cell counts at 24 h (41%), 7 days (38%) and 28 days (52%). Similar reductions in TPH-positive cell counts were also observed at each timepoint in the MRN and in the RMN. In the MRN, citalopram resulted in significant reductions at 24 h (26%), 7 days (16%) and 28 days (23%). In the RMN, citalopram induced significant reductions of TPH-positive cell counts at 24 h (45%), 7 days (34%) and 28 days (43%). By contrast, no significant differences between control and treatment groups were observed in the CLN at any of the time points that we studied. To investigate whether these changes would occur with other SERT inhibitors, we conducted a second experiment, this time with a 28-day course of fluoxetine. As was observed with citalopram, fluoxetine induced significant reductions of TPH cell counts in the DRN (39%), MRN (38%) and RMN (41%), with no significant differences in the CLN. These results indicate that SERT inhibition can alter the regulation of TPH, the rate limiting enzyme for serotonin biosynthesis. This persistent and regionally specific downregulation of serotonin biosynthesis may account for some of the clinical withdrawal symptoms associated with drugs that inhibit SERT.

View all citing articles on Scopus

View full text

Evidence for dual serotonergic projections to neocortex: Axons from the dorsal and median raphe nuclei are differentially vulnerable to the neurotoxin p-chloroamphetamine (PCA)

Abstract

Brain Res.

Brain Res.

Biochem. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Brain Res.

Brain Res.

Life Sci.

Eur. J. Pharmacol.

Brain Res.

Brain Res.

Exp. Neurol.

Neuroscience

Neuroscience

Brain Res. Bull.

Brain Res.

Biochem. Pharmacol.

Brain Res. Bull.

Neuroscience

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Lancet

Eur. J. Pharmacol.

Brain Res.

Brain Res.

Ascending monoamine neurons to the telencephalon and diencephalon

Acta Physiol. Scand.

The serotonin-producing neurons of the midbrain median and dorsal raphe nuclei

An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat

J. Comp. Neurol.

3,4-Methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) preferentially destroy serotonin terminals in rat brain: Quantification of neurodegeneration by measurement of 3H-paroxetine-labeled serotonin uptake sites

J. Pharmacol. Exp. Ther.

Brain stem neurons projecting to neocortex: A HRP study in the cat

Exp. Brain Res.

Psychotropic amphetamines have different sites of action at serotonergic (5-HT) synapses: A comparison of p-chloroamphetamine (PCA) and 3,4-methylenedioxyamphetamine (MDA) with 2,5-dimethoxy-4-methylamphetamine (DOM)

Soc. Neurosci. Abstr.

Fine structure of labeled axons in the cerebellar cortex and nuclei of rodents and primates after intraventricular infusions with tritiated serotonin

Anat. Embryol.

3,4-Methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) preferentially destroy serotonin terminals in rat brain: Quantification of neurodegeneration by measurement of ³H-paroxetine-labeled serotonin uptake sites