- Email: [email protected]
Serotonin revisited
Accepted Manuscript Title: Preface Author: Christian P. M¨uller Judith R. Homberg PII: DOI: Reference:
S0166-4328(14)00656-1 http://dx.doi.org/doi:10.1016/j.bbr.2014.10.008 BBR 9197
To appear in:
Behavioural Brain Research
Please cite this article as: M¨uller CP, Homberg JR, Preface, Behavioural Brain Research (2014), http://dx.doi.org/10.1016/j.bbr.2014.10.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Special issue - Serotonin Behavioural Brain Research
ip t
Preface
cr
Serotonin revisited
The serotonergic system is one of the longest known transmitter systems in the brain.
us
Decades of research have elucidated a widespread functional involvement in sensation, memory, and behaviour, though no normal or aberrant behaviour has its
an
origin in a sole serotonergic process [1]. Serotonin (5-HT) is a sphinx as the words coined by B.L. Jacobs: ‘It is involved in everything, but responsible for nothing’ still hold true. It is now widely accepted that also the modulatory transmitter 5-HT acts in
M
interplay with various - if not all - other transmitter and signalling systems. In that role it appears as one of the most diverse transmitters in the brain. Not only that
ed
serotonergic innervations from the raphe nuclei reach also the remotest corners of the central nervous system, 5-HT appeared to modulate many - if not all - processes the brain is capable of. As such it remains no surprize that natural variation in the
ce pt
serotonergic system, e.g. by gene polymorphisms, or variants in serotonin levels that are induced by environmental factors or pathological processes, are closely interlinked with the occurrence of psychiatric and neurological disorders. This involvement, however, has also driven the hope to find in the many proteins involved
Ac
in serotonergic signalling a potential target for pharmacotherapies. Despite of a rather thorough understanding of many features of the serotonergic system, ongoing research still provides new and surprising insights that regularly open a fresh view on the serotonergic system’s complex function and offer approaches for mental disorder treatment. As bundled in this special issue of Behavioural Brain Research, serotonin is implicated in neurodevelopmental processes influencing behaviour as discussed by Kesper and Homberg [2], Mosienko et al. [3], and Miyagawa et al. [4]. The role of 5HT in the regulation of body weight and metabolism is reviewed by Mosienko et al. [3]. Alenina and Klempin [5] outline how the important role of 5-HT in neuroplastic 1 Page 1 of 7
events in early life is maintained into adulthood, given 5-HT’s role in hippocampal neurogenesis. 5-HT is well known to control satiety in feeding. An update and discussion of the role of serotonergic receptors is provided by Voigt and Fink [6]. How the gut-brain-microbiome axis is involved in the control of the serotonergic system and behaviour is discussed by O’Mahony and colleges [7]. Serotonin is implicated in stress-coping as reviewed by Andolina and Puglisi-Allegra [8]. The essential
ip t
involvement of serotonin in fear conditioning and extinction processes, as shown by influences of (prenatal) stress, pharmacological agents and genetic variance in
cr
humans and rodents is updated by Bauer [9]. The neurobiological pathway underlying these serotonin-mediated processes involves, at least in part, the
us
interaction between the lateral habenula and dorsal raphe nucleus. In the lateral habenula, input from the basal ganglia and limbic forebrain is integrated, and the
an
lateral habenula on its turn projects to the raphe nuclei and ventral tegmental area regulate 5-HT and dopamine release. The role of lateral habenula-dorsal raphe nucleus circuits in higher brain functions and psychiatric illness is reviewed by Zhao
M
and colleges [10]. It is, therefore, not surprising that the serotonergic and dopaminergic systems are tightly linked and influence each other [11], with 5-HT
ed
being increasingly suggested to play a role in mental disorders that had been considered to be predominantly dopaminergic dysfunctions. Parkinson’s disease, for example, is also characterized by a loss of serotonergic neurons in the raphe nuclei,
ce pt
leading to depression, fatigue, visual hallucinations, weight loss, and appetite dysfunction as suggested by the review of Politis and Nicollini [12]. Hallucinogenic drugs, as well as some drugs of abuse, exert their effects through 5HT2A receptors. An update on recent findings on hallucinogenic action is presented
Ac
by Adam L. Halberstadt [13]. Interestingly, whereas hallucinations can be experienced as side effects of drugs of abuse, hallucinogens may possess therapeutic efficacy in the treatment of drug addiction. Hallucinogens and antipsychotics act, at least in part, through sensory systems where 5-HT plays a major role in sensory information processing as suggested by Juckel [14]. Besides hallucinogens, also antipsychotic drugs act through the serotonergic system. Specifically the 5-HT1A and 5-HT2A/2C receptors appear to play an important role as outlined in the article by Davide Amato [15], and thereby functionally overlap with drugs of abuse and hallucinogens. The finding that genetic down-regulation of the neuronal tetraspan protein M6B (Gpm6b) decreasing cell-surface expression of 5-HT 2 Page 2 of 7
transporter (SERT) impaired sensorimotor gating [16] also fits with a role of 5-HT in sensory information processing. Müller and Homberg [17] review the role of the serotonergic system in psychoactive drug use and addiction. Thereby, an important distinction is suggested. Accumulating evidence suggests that a drug-induced serotonergic activation is essentially required to establish highly organized drug seeking and consummatory behaviour in non-
ip t
addicted animals and humans. With repeated drug exposition over long periods of time, the serotonergic system undergoes complex changes, which may facilitate the
cr
transition to compulsive drug seeking and finally addiction. A new functional model for adaptations of serotonergic synapses during addiction development is suggested
us
here [17]. Serotonin, through the 5-HT1A, 5-HT2A and 5-HT3 receptors, may control appetitive conditioning [18].
an
Too high serotonin levels are detrimental, given that the application of a combination of 5-HT increasing antidepressant agents can lead to the serotonin syndrome, characterized by motor symptoms (e.g. myoclonus, tremor), autonomic responses
M
(e.g. hyperthermia, tachycardia), and altered mental state (e.g. agitation, confusion) [19].
ed
Of interest, 5-HT does not only affect a multitude of behavioural, cognitive and physiological processes, the bodily responses to environmental challenges also influence the serotoninergic system. It was demonstrated that water pollution leads to
ce pt
a decrease in SERT expression in mice and vulnerability to depression-like behaviour [20]. Yet, neither negative nor positive life events altered the functionality of the serotonergic system in humans characterized by inherited SERT down-regulation as shown by Wielpuetz et al. [21]. This finding implies that a certain threshold is needed
Ac
for environmental stimuli to affect the serotonergic system. In sum, as addressed in this special issue of Behavioural Brain Research, 5-HT is implicated in a wide variety of behavioural, cognitive, and physiological processes, and the functions as listed here are certainly not complete. Although the serotonergic system is very complicated due to the multiple receptors mediating 5-HT’s effects, controlled manipulation of the serotonergic system together with control over environmental stimuli with which 5-HT interacts holds heuristic value for increasing the understanding of the pathophysiology underlying psychiatric, neurological, and metabolic disorders, as well as their treatment.
3 Page 3 of 7
References
[1] Müller CP, Jacobs BL, editors. Handbook of the Behavioral Neurobiology of Serotonin, London: Academic Press; 2010.
cr
behavioural perspective. Behavioural Brain Research 2014;
ip t
[2] Kepser LJ, Homberg JR. The neurodevelopmental effects of serotonin: a
[3] Mosienko V, Beis D, Pasqualetti M, Waider J, Matthes S, Qadri F, Bader M,
us
Alenina N. Life without brain serotonin: reevaluation of serotonin function with
an
mice deficient in brain serotonin synthesis. Behavioural Brain Research 2014;
[4] Miyagawa K, Tsuji M, Ishii D, Takeda K, Takeda H. Prenatal stress induces vulnerability to stress together with the disruption of central serotonin neurons in
M
mice. Behavioural Brain Research 2014;
ed
[5] Alenina N, Klempin F. The role of serotonin in adult hippocampal neurogenesis. Behavioural Brain Research 2014;
ce pt
[6] Voigt JP, Fink H. Serotonin controlling feeding and satiety. Behavioural Brain Research 2014;
[7] O’Mahony SM, Clarke G, Borre YE, Dinan TG, Cryan JF. Seotonin, tryptophan
Ac
metabolism and the brain-gut-microbiome axis. Behavioural Brain Research 2014;
[8] Puglisi-Allegra S, Andolina D. Serotonin and stress coping. Behavioural Brain Research 2014;
[9] Bauer EP. Serotonin in fear conditioning processes. Behavioural Brain Research 2014;
4 Page 4 of 7
[10] Zhaoa H, Zhanga BL, Yanga SJ, Rusakb B. The role of lateral habenula-dorsal raphe nucleus circuits in higher brain functions and psychiatric illness. Behavioural Brain Research 2014;
[11] Hui YP, Wang T, Han LN, Li LB, Sun YN, Liu J, Qiao HF, Zhang QJ. Anxiolytic effects of prelimbic 5-HT1A receptor activation in the hemiparkinsonian rat.
ip t
Behavioural Brain Research 2014;
cr
[12] Politis M, Niccolini F. Serotonin in Parkinson's disease. Behavioural Brain
us
Research 2014;
[13] Halberstadt AL. Recent advances in the neuropsychopharmacology of
an
serotonergic hallucinogens. Behavioural Brain Research 2014;
[14] Juckel G. Serotonin: from sensory processing to schizophrenia using an
M
electrophysiological method. Behavioural Brain Research 2014;
ed
[15] Amato D. Serotonin in antipsychotic drugs action. Behavioural Brain Research 2014;
ce pt
[16] Dere E, Winkler D, Ritter C, Ronnenberg A, Poggi G, Patzig J, Gernert M, Müller C, Nave KA, Ehrenreich H, Werner HB. Gpm6b deficiency impairs sensorimotor gating and modulates the behavioral response to a 5-HT2A/C receptor agonist.
Ac
Behavioural Brain Research 2014;
[17] Müller CP, Homberg JR, The role of serotonin in drug use and addiction. Behavioural Brain Research 2014;
[18] Frick L, Bernardez-Vidal M, Hocht C, Zanutto S, Rapanelli M. Dual role of serotonin in the acquisition and extinction of reward-driven learning: involvement of 5-HT1A, 5-HT2A and 5-HT3 receptors. Behavioural Brain Research 2014;
5 Page 5 of 7
[19] Haberzettl R, Fink H, Bert B. The murine serotonin syndrome - Evaluation of responses to 5-HT-enhancing drugs in NMRI mice. Behavioural Brain Research 2014;
[20] Strekalovaa T, Evans M, Chernopiatko A, Couch Y, Costa-Nunes J, Cespuglio R, Chesson L, Vignisse J, Steinbusch HW, Anthony DC, Pomytkin I, Lesch KP.
ip t
Deuterium content of water increases depression susceptibility: the potential role
cr
of a serotonin-related mechanism. Behavioural Brain Research 2014;
[21] Wielpuetz C, Kuepper Y, Grant P, Munk AJL, Hennig J. Variations in central
Ac
ce pt
ed
M
an
interaction. Behavioural Brain Research 2014;
us
serotonergic activity - relevance of the 5-HTTLPR, life events and their
6 Page 6 of 7
Christian P. Müller* Section of Addiction Medicine Department of Psychiatry and Psychotherapy University Clinic
ip t
Friedrich-Alexander-University Erlangen-Nuremberg Schwabachanlage 6
cr
91054 Erlangen
us
Germany
an
Judith R. Homberg Donders Institute for Brain, Cognition, and Behaviour Radboud University Medical Centre
M
Geert Grooteplein 21 Nijmegen 6525 EZ
ce pt
ed
Netherlands
Ac
*Corresponding author:
Christian P. Müller Email: [email protected]
7 Page 7 of 7
S0166-4328(14)00656-1 http://dx.doi.org/doi:10.1016/j.bbr.2014.10.008 BBR 9197
To appear in:
Behavioural Brain Research
Please cite this article as: M¨uller CP, Homberg JR, Preface, Behavioural Brain Research (2014), http://dx.doi.org/10.1016/j.bbr.2014.10.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Special issue - Serotonin Behavioural Brain Research
ip t
Preface
cr
Serotonin revisited
The serotonergic system is one of the longest known transmitter systems in the brain.
us
Decades of research have elucidated a widespread functional involvement in sensation, memory, and behaviour, though no normal or aberrant behaviour has its
an
origin in a sole serotonergic process [1]. Serotonin (5-HT) is a sphinx as the words coined by B.L. Jacobs: ‘It is involved in everything, but responsible for nothing’ still hold true. It is now widely accepted that also the modulatory transmitter 5-HT acts in
M
interplay with various - if not all - other transmitter and signalling systems. In that role it appears as one of the most diverse transmitters in the brain. Not only that
ed
serotonergic innervations from the raphe nuclei reach also the remotest corners of the central nervous system, 5-HT appeared to modulate many - if not all - processes the brain is capable of. As such it remains no surprize that natural variation in the
ce pt
serotonergic system, e.g. by gene polymorphisms, or variants in serotonin levels that are induced by environmental factors or pathological processes, are closely interlinked with the occurrence of psychiatric and neurological disorders. This involvement, however, has also driven the hope to find in the many proteins involved
Ac
in serotonergic signalling a potential target for pharmacotherapies. Despite of a rather thorough understanding of many features of the serotonergic system, ongoing research still provides new and surprising insights that regularly open a fresh view on the serotonergic system’s complex function and offer approaches for mental disorder treatment. As bundled in this special issue of Behavioural Brain Research, serotonin is implicated in neurodevelopmental processes influencing behaviour as discussed by Kesper and Homberg [2], Mosienko et al. [3], and Miyagawa et al. [4]. The role of 5HT in the regulation of body weight and metabolism is reviewed by Mosienko et al. [3]. Alenina and Klempin [5] outline how the important role of 5-HT in neuroplastic 1 Page 1 of 7
events in early life is maintained into adulthood, given 5-HT’s role in hippocampal neurogenesis. 5-HT is well known to control satiety in feeding. An update and discussion of the role of serotonergic receptors is provided by Voigt and Fink [6]. How the gut-brain-microbiome axis is involved in the control of the serotonergic system and behaviour is discussed by O’Mahony and colleges [7]. Serotonin is implicated in stress-coping as reviewed by Andolina and Puglisi-Allegra [8]. The essential
ip t
involvement of serotonin in fear conditioning and extinction processes, as shown by influences of (prenatal) stress, pharmacological agents and genetic variance in
cr
humans and rodents is updated by Bauer [9]. The neurobiological pathway underlying these serotonin-mediated processes involves, at least in part, the
us
interaction between the lateral habenula and dorsal raphe nucleus. In the lateral habenula, input from the basal ganglia and limbic forebrain is integrated, and the
an
lateral habenula on its turn projects to the raphe nuclei and ventral tegmental area regulate 5-HT and dopamine release. The role of lateral habenula-dorsal raphe nucleus circuits in higher brain functions and psychiatric illness is reviewed by Zhao
M
and colleges [10]. It is, therefore, not surprising that the serotonergic and dopaminergic systems are tightly linked and influence each other [11], with 5-HT
ed
being increasingly suggested to play a role in mental disorders that had been considered to be predominantly dopaminergic dysfunctions. Parkinson’s disease, for example, is also characterized by a loss of serotonergic neurons in the raphe nuclei,
ce pt
leading to depression, fatigue, visual hallucinations, weight loss, and appetite dysfunction as suggested by the review of Politis and Nicollini [12]. Hallucinogenic drugs, as well as some drugs of abuse, exert their effects through 5HT2A receptors. An update on recent findings on hallucinogenic action is presented
Ac
by Adam L. Halberstadt [13]. Interestingly, whereas hallucinations can be experienced as side effects of drugs of abuse, hallucinogens may possess therapeutic efficacy in the treatment of drug addiction. Hallucinogens and antipsychotics act, at least in part, through sensory systems where 5-HT plays a major role in sensory information processing as suggested by Juckel [14]. Besides hallucinogens, also antipsychotic drugs act through the serotonergic system. Specifically the 5-HT1A and 5-HT2A/2C receptors appear to play an important role as outlined in the article by Davide Amato [15], and thereby functionally overlap with drugs of abuse and hallucinogens. The finding that genetic down-regulation of the neuronal tetraspan protein M6B (Gpm6b) decreasing cell-surface expression of 5-HT 2 Page 2 of 7
transporter (SERT) impaired sensorimotor gating [16] also fits with a role of 5-HT in sensory information processing. Müller and Homberg [17] review the role of the serotonergic system in psychoactive drug use and addiction. Thereby, an important distinction is suggested. Accumulating evidence suggests that a drug-induced serotonergic activation is essentially required to establish highly organized drug seeking and consummatory behaviour in non-
ip t
addicted animals and humans. With repeated drug exposition over long periods of time, the serotonergic system undergoes complex changes, which may facilitate the
cr
transition to compulsive drug seeking and finally addiction. A new functional model for adaptations of serotonergic synapses during addiction development is suggested
us
here [17]. Serotonin, through the 5-HT1A, 5-HT2A and 5-HT3 receptors, may control appetitive conditioning [18].
an
Too high serotonin levels are detrimental, given that the application of a combination of 5-HT increasing antidepressant agents can lead to the serotonin syndrome, characterized by motor symptoms (e.g. myoclonus, tremor), autonomic responses
M
(e.g. hyperthermia, tachycardia), and altered mental state (e.g. agitation, confusion) [19].
ed
Of interest, 5-HT does not only affect a multitude of behavioural, cognitive and physiological processes, the bodily responses to environmental challenges also influence the serotoninergic system. It was demonstrated that water pollution leads to
ce pt
a decrease in SERT expression in mice and vulnerability to depression-like behaviour [20]. Yet, neither negative nor positive life events altered the functionality of the serotonergic system in humans characterized by inherited SERT down-regulation as shown by Wielpuetz et al. [21]. This finding implies that a certain threshold is needed
Ac
for environmental stimuli to affect the serotonergic system. In sum, as addressed in this special issue of Behavioural Brain Research, 5-HT is implicated in a wide variety of behavioural, cognitive, and physiological processes, and the functions as listed here are certainly not complete. Although the serotonergic system is very complicated due to the multiple receptors mediating 5-HT’s effects, controlled manipulation of the serotonergic system together with control over environmental stimuli with which 5-HT interacts holds heuristic value for increasing the understanding of the pathophysiology underlying psychiatric, neurological, and metabolic disorders, as well as their treatment.
3 Page 3 of 7
References
[1] Müller CP, Jacobs BL, editors. Handbook of the Behavioral Neurobiology of Serotonin, London: Academic Press; 2010.
cr
behavioural perspective. Behavioural Brain Research 2014;
ip t
[2] Kepser LJ, Homberg JR. The neurodevelopmental effects of serotonin: a
[3] Mosienko V, Beis D, Pasqualetti M, Waider J, Matthes S, Qadri F, Bader M,
us
Alenina N. Life without brain serotonin: reevaluation of serotonin function with
an
mice deficient in brain serotonin synthesis. Behavioural Brain Research 2014;
[4] Miyagawa K, Tsuji M, Ishii D, Takeda K, Takeda H. Prenatal stress induces vulnerability to stress together with the disruption of central serotonin neurons in
M
mice. Behavioural Brain Research 2014;
ed
[5] Alenina N, Klempin F. The role of serotonin in adult hippocampal neurogenesis. Behavioural Brain Research 2014;
ce pt
[6] Voigt JP, Fink H. Serotonin controlling feeding and satiety. Behavioural Brain Research 2014;
[7] O’Mahony SM, Clarke G, Borre YE, Dinan TG, Cryan JF. Seotonin, tryptophan
Ac
metabolism and the brain-gut-microbiome axis. Behavioural Brain Research 2014;
[8] Puglisi-Allegra S, Andolina D. Serotonin and stress coping. Behavioural Brain Research 2014;
[9] Bauer EP. Serotonin in fear conditioning processes. Behavioural Brain Research 2014;
4 Page 4 of 7
[10] Zhaoa H, Zhanga BL, Yanga SJ, Rusakb B. The role of lateral habenula-dorsal raphe nucleus circuits in higher brain functions and psychiatric illness. Behavioural Brain Research 2014;
[11] Hui YP, Wang T, Han LN, Li LB, Sun YN, Liu J, Qiao HF, Zhang QJ. Anxiolytic effects of prelimbic 5-HT1A receptor activation in the hemiparkinsonian rat.
ip t
Behavioural Brain Research 2014;
cr
[12] Politis M, Niccolini F. Serotonin in Parkinson's disease. Behavioural Brain
us
Research 2014;
[13] Halberstadt AL. Recent advances in the neuropsychopharmacology of
an
serotonergic hallucinogens. Behavioural Brain Research 2014;
[14] Juckel G. Serotonin: from sensory processing to schizophrenia using an
M
electrophysiological method. Behavioural Brain Research 2014;
ed
[15] Amato D. Serotonin in antipsychotic drugs action. Behavioural Brain Research 2014;
ce pt
[16] Dere E, Winkler D, Ritter C, Ronnenberg A, Poggi G, Patzig J, Gernert M, Müller C, Nave KA, Ehrenreich H, Werner HB. Gpm6b deficiency impairs sensorimotor gating and modulates the behavioral response to a 5-HT2A/C receptor agonist.
Ac
Behavioural Brain Research 2014;
[17] Müller CP, Homberg JR, The role of serotonin in drug use and addiction. Behavioural Brain Research 2014;
[18] Frick L, Bernardez-Vidal M, Hocht C, Zanutto S, Rapanelli M. Dual role of serotonin in the acquisition and extinction of reward-driven learning: involvement of 5-HT1A, 5-HT2A and 5-HT3 receptors. Behavioural Brain Research 2014;
5 Page 5 of 7
[19] Haberzettl R, Fink H, Bert B. The murine serotonin syndrome - Evaluation of responses to 5-HT-enhancing drugs in NMRI mice. Behavioural Brain Research 2014;
[20] Strekalovaa T, Evans M, Chernopiatko A, Couch Y, Costa-Nunes J, Cespuglio R, Chesson L, Vignisse J, Steinbusch HW, Anthony DC, Pomytkin I, Lesch KP.
ip t
Deuterium content of water increases depression susceptibility: the potential role
cr
of a serotonin-related mechanism. Behavioural Brain Research 2014;
[21] Wielpuetz C, Kuepper Y, Grant P, Munk AJL, Hennig J. Variations in central
Ac
ce pt
ed
M
an
interaction. Behavioural Brain Research 2014;
us
serotonergic activity - relevance of the 5-HTTLPR, life events and their
6 Page 6 of 7
Christian P. Müller* Section of Addiction Medicine Department of Psychiatry and Psychotherapy University Clinic
ip t
Friedrich-Alexander-University Erlangen-Nuremberg Schwabachanlage 6
cr
91054 Erlangen
us
Germany
an
Judith R. Homberg Donders Institute for Brain, Cognition, and Behaviour Radboud University Medical Centre
M
Geert Grooteplein 21 Nijmegen 6525 EZ
ce pt
ed
Netherlands
Ac
*Corresponding author:
Christian P. Müller Email: [email protected]
7 Page 7 of 7