Serotonin: Modulator of a drive to withdraw
Introduction
The serotonergic system is phylogenetically ancient, and yet has become exceedingly complex in the vertebrate brain. For example, there are over a dozen subtypes of serotonin receptors, many of which have separate functions. Not surprisingly, it has been difficult to specify general behavioral and psychological functions of serotonin systems, and this has led to reluctance to formulate a general theory (Deakin, 1996, Spoont, 1992). However, if it were possible to formulate a general theory, this could be critical to understanding the strong evidence that serotonin plays a key role in certain psychiatric disorders. Serotonin has been implicated in many psychiatric disorders, but the most consistent evidence for an impairment of serotonin function has been found for depression (where selective serotonin reuptake inhibitors or SSRIs have been clinically effective) and impulsive aggressive personality disorders (where abnormally low serotonin levels have been observed; Deakin, 2003). We will review support for a novel hypothesis, that a phylogenetically old function of serotonin – as a neuromodulator of a drive to withdraw – provides a common framework for interpreting the apparently diverse functions of serotonergic systems in modern humans. By this notion of a drive to withdraw we mean a primitive motive to reduce the present or anticipated environmental stimulation mentally or behaviorally, such as by moving into an environment of lower stimulation levels.
There are multiple groups of serotonin containing cells within the brainstem raphe nucleus, and these project to different forebrain areas. Cells of the dorsal raphe nucleus project to dopaminergic structures of the forebrain, whereas cells in the median raphe nucleus project to the hippocampus, in parallel with noradrenergic nerve terminals (Imai et al., 1986, Vertes, 1991, Vertes et al., 1999). Deakin (2003) proposed that projections of the dorsal group of raphe serotonin cells oppose the action of dopamine and mediate avoidance of threats. In humans, impaired function of this serotonergic projection sensitizes the dopamine system, thereby resulting in symptoms such as impulsivity and drug addiction. Posterior serotonin cells innervate the hippocampus and cingulate gyrus and suppress memory and awareness of current and past adversity (see Deakin, 2003, for details and references). Deakin proposed that impaired function of this serotonergic projection results in low mood, low self-esteem, hopelessness, pessimism and reduces stress resilience. With this theory Deakin (2003) explained why the symptoms of one so-called low serotonin syndrome (depression) are very different from those of another syndrome (antisocial personality disorder).
Although Deakin’s (2003) model provides a useful conceptual approach in differentiating functions of the major serotonin projections, we propose it may be possible to simplify and improve this theory by identifying a common denominator of the functions of the two serotonergic projection groups originating from the raphe. Suppression of awareness and memory of current and past adversity facilitates withdrawal, and hence is compatible with the present primitive withdrawal drive hypothesis of serotonin function. In contrast, reduction of aversive memory does not seem to fit the threat avoidance framework; threat avoidance would be better served by improved aversive memory. However, we will argue that a subtly different interpretation of the function of the anterior serotonergic cells, in favor of increased withdrawal drive in response to threats instead of avoidance of threats, will suggest a common functional framework for both serotonergic projection groups. At the same time this interpretation is a better fit to the physiological properties of the serotonergic system. Finally, the withdrawal hypothesis may be compatible with other evidence on serotonergic function, such as in fatigue.
Section snippets
The serotonergic drive to withdraw
Testing a general theory of opposing effects of serotonin vs. noradrenalin on arousal and behavioral activation (Brodie & Shore, 1957), Ellison (1979) applied serotonin and noradrenalin neurotoxins to rats and compared the effects on behavior in a familiar environment with effects on behavior in a novel environment. He concluded that the low-serotonin animal can be thought of as being in a state of central functioning appropriate for any animal out in the environment, foraging for food: it is
Serotonin and anxiety
The hypothesis that serotonin possesses a positive relation to anxiety-related traits derives primarily from animal studies using punishment paradigms which, for a number of reasons (including their motoric and positive motivational components), may not represent an appropriate model for assessing anxiety (Soubrie, 1986; see Harro, 2002, for a similar argument). In fact, the burial of the serotonin theory of anxiety was announced more than 20 years ago (Panksepp & Cox, 1986). The majority of
Serotonin, impulsivity and aggression
The concept that impulsivity is a failure in serotonergically mediated behavioral inhibition has proved remarkably fertile. In most cases, serotonin appears to exert an inhibitory influence on behavior, whereby reductions of serotonin result in exaggerated behavioral responding (see Lucki, 1998, Zald and Depue, 2001). Previous reviews of serotonergic function concluded that serotonin seems to decrease responsiveness to current motivational stimuli, increasing constraint by allowing for
Serotonin and depression
Deakin (1996) proposes that forebrain serotonin has a special general role in minimizing the impact of aversive events on behavior, and when severe psychosocial and other stressors disturb it then depression and anxiety are the result. Also other authors suggested that the primary effect of serotonin may be to inhibit negative emotion and induce sanguinity, i.e. a quiet, low-arousal or satiated waking state (e.g. Healey and McMonagle, 1997, Jones, 2003, Miller and O’Callaghan, 2006, Tse and
Serotonin and fatigue
It appears that important relations exist between brain serotonin and central fatigue (Davis et al., 2000, Davis and Bailey, 1996, Newsholme et al., 1987). In a challenge test of the serotonergic system, serotonergic reactivity related strongly to the fatigability and asthenia subscale of the Harm Avoidance scale of the Cloninger Tridimensional Personality Questionnaire, but to no other scales (Hennig, Toll, Schonlau, Rohrmann, & Netter, 2000). Increases in brain serotonin concentrations and
Serotonin and social behavior
Although the serotonergic drive to withdraw may originally have evolved to withdraw from dangerous, aversive, or high stimulation environments, during evolution animals developed new behavioral repertoire. Some of these behaviors were best performed in safe and relatively low arousal conditions. Hence serotonergic function may have become involved in these behaviors by providing a drive to seek out suitable environments and arousal states. One important class of behaviors in humans to which
Conclusion
Some understanding of what serotonin normally does seems crucial for a deep understanding of its suspected role in many mental disorders. Because of the complexity of serotonergic function, researchers have been reluctant to formulate a general theory. However, serotonin systems have been suggested to be involved in the avoidance of threat. We propose that there is substantial evidence for an alternative hypothesis, that a phylogenetically old function of serotonin is to mediate a drive to
Acknowledgments
Part of this research was supported by a grant of the Niels Stensen Foundation and a Veni grant of the Netherlands Organization for Scientific Research (NWO) (451-07-013).
References (123)
Depressive disorders-is it time to endorse different pathophysiologies?
Psychoneuroendocrinology
(2006)- et al.
A single serotonergic modulatory cell can mediate reinforcement in the withdrawal network of the terrestrial snail
Neurobiology of Learning and Memory
(2001) - et al.
Mental fatigue, motivation and action monitoring
Biological Psychology
(2006) - et al.
Migraine, physical health and psychiatric disorder: A prospective epidemiologic study in young adults
Journal of Psychiatric Research
(1993) - et al.
Modulators in concert for cognition: Modulator interactions in the prefrontal cortex
Progress in Neurobiology
(2007) - et al.
Relations of serotonin function to personality: Current views and a key methodological issue
Psychiatry Research
(2006) - et al.
Amphetamine and alpha-methyl-p-tyrosine affect the exercise-induced balance between the availability of tryptophan and synthesis of serotonin in the brain of the rat
Neuropharmacology
(1987) - et al.
Serotonergic regulation of emotional and behavioral control processes
Trends in Cognitive Neuroscience
(2008) - et al.
Serotonin and central nervous system fatigue: Nutritional considerations
American Journal of Clinical Nutrition
(2000) - et al.
Opponent interactions between serotonin and dopamine
Neural Networks
(2002)
Some predictors of psychiatric consultation in nursing home residents
American Journal of Geriatric Psychiatry
Cholinergic–serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer’s disease
Neuropsychologia
Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: A hypothesis for the etiology of schizophrenia
Neuroscience
Depression as a spreading adjustment disorder of monoaminergic neurons: A case for primary implication of the locus coeruleus
Brain Research Reviews
Stability of interindividual differences in serotonin function and its relationship to severe aggression and competent social behavior in rhesus macaque females
Neuropsychopharmacology
Central nervous system monoamine correlates of social dominance in cynomolgus monkeys (Macaca fascicularis)
Neuropsychopharmacology
Augmentation of serotonin enhances pleasant and suppresses unpleasant cortical electrophysiological responses to visual emotional stimuli in humans
Neuroimage
Hypothalamic serotonin in control of eating behavior, meal size, and body weight
Biological Psychiatry
Nucleus accumbens oxytocin and dopamine interact to regulate pair bond formation in female prairie voles
Neuroscience
Caffeine and effects on cognition, with special attention to adenosine–dopamine interactions
Brain and Cognition
The spectrum of behaviors influenced by serotonin
Biological Psychiatry
The need for power, brain norepinephrine turnover and learning
Biological Psychology
Biochemical markers for post-operative fatigue after major surgery
Brain Research Bulletin
The pharmacology of wakefulness
Metabolism Clinical and Experimental
The effect of tryptophan on social interaction in everyday life: A placebo-controlled study
Neuropsychopharmacology
The polyvagal theory: Phylogenetic substrates of a social nervous system
International Journal of Psychophysiology
Female influence of male dominance acquisition in captive vervet monkeys (Cercopithecus aethiops sabeus)
Animal Behavior
Serotonergic mechanisms promote dominance acquisition in male vervet monkeys
Brain Research
Arousal systems and attentional processes
Biological Psychology
Plasma oxytocin levels in female fibromyalgia syndrome patients
Zeitschrift für Rheumatolofie
5HT2C receptor activation by m-chlorophenylpiperazine detected in humans with fMRI
Neuro Report
Atypical depressive syndromes in varying definitions
European Archives of Psychiatry and Clinical Neuroscience
Locus coeruleus, stress and post-traumatic stress disorder: Neurobiological and clinical parallels
Ascending visceral regulation of cortical affective information processing
European Journal of Neurosciences
Pleasure, pain, desire, and dread: Hidden core processes of emotion
The debate over dopamine’s role in reward: The case for incentive salience
Psychopharmacology
Dissociable neural responses to facial expression of sadness and anger
Brain
A concept for the role of serotonin and norepinephrine as chemical mediators in the brain
Annals of the New York Academy of Sciences
Human motivation and emotion
Anger is an approach-related affect: Evidence and implications
Psychological Bulletin
Origins and functions of positive and negative affect: A control-process view
Psychological Review
The concepts of stress and stress system disorders: Overview of physical and behavioral homeostasis
Journal of the American Medical Association
Acute tryptophan depletion in healthy volunteers enhances punishment prediction but does not affect reward prediction
Neuropsychopharmacology
Negative life events, social support and gender difference in depression: A multinational community survey with data from the ODIN study
Social Psychiatry and Psychiatric Epidemiology
Possible mechanisms of central nervous system fatigue during exercise
Medicine and Science in Sports and Exercise
Long-term reward prediction in TD models of the dopamine system
Neural Computation
5-HT, antidepressant drugs and the psychosocial origins of depression
Journal of Psychopharmacology
The role of serotonin in depression and anxiety
European Psychiatry
Depression and antisocial personality disorder: Two contrasting disorders of 5HT function
Journal of Neural Transmission Supplementum
The effect of citalopram pretreatment on neuronal responses to neuropsychological tasks in normal volunteers: An FMRI study
Neuropsychopharmacology
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