1Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
2Addiction Research Center, National Cheng Kung University, Tainan, Taiwan.
Serotonin is one of the most important neurotransmitters influencing mental health.1) Most serotonin is distributed outside of the central nervous system (CNS), and influences a wide range of physiologic processes in many organs.2) However, the 2% of serotonin that is present in the CNS plays a pivotal role in the etiology of many mental disorders. Both receptors and transporters play important roles in synapses. 5-Hydroxytryptamine (5-HT) receptors are activated by the serotonin neurotransmitter, while the 5-HT transporter reuptakes the serotonin neuro-transmitter from the synaptic cleft. Altered receptor and/or serotonin transporter (SERT) function may be associated with mental disorders.
The development of selective serotonin reuptake inhibitors (SSRIs) illustrates the importance of the serotonergic system with regard to the treatment of mental disorders. Further, the discovery of the role that the serotonin-transporter-linked polymorphic region (5-HTTLPR) plays in the association between stress and mental health highlights the pervasive influence of the serotonin transporter gene. Meanwhile, noninvasive neuroimaging techniques, such as positron-emission tomography (PET) and single photon emission computed tomography (SPECT), can be used to study regional receptor and transporter concentrations in specific brain areas. These are important tools that can be used to acquire in vivo brain images and quantitative measurements with regard to the activities of the serotonergic system.3,4)
Although there are many families of 5-HT receptors, most studies rely on radioligands for 5-HT1A and 5-HT2A. Some of the important radioligands used to study the serotonergic system are shown in Table 1. For instance, [11C]WAY-100635 may be the most important radioligand for 5-HT1A; however, there are also other available radioligands. Several radioligands were also developed for 5-HT2A. For SERT, Beta-[123I]CIT is one of the most useful radioligands for the SPECT. However, this radiotracer binds both on SERT and dopamine transporter (DAT). Another important radiotracer for SEPCT is [123I]ADAM, which selectively binding on SERT only. [11C]DASB and [11C]MADAM are important radioligands for PET. Evidence from neuroimaging studies may enhance our understanding of the role of serotonin in many mental disorders, and the aim of this essay was thus to provide a concise and updated review of the literature on this topic.
MDD is one of the most important mental disorders associated with altered serotonergic activity, and several extensive reviews of the literature exist on this topic.5) Drevets et al.6) used PET in conjunction with [11C] WAY-100635, and found that the binding potential of 5-HT1A receptors in the raphe and mesiotemporal cortex of unmedicated subjects with MDD was lower than that in controls. Similar results were found among medicated and unmedicated MDD subjects in other studies,7,8) as well as among patients with recurrent MDD.9) However, not all studies agree on this issue. For example, in another PET study that used the same radioligand, MDD patients using antidepressants had greater 5-HT1A receptor binding potential in the raphe and mesiotemporal cortex than controls and antidepressant-na?ve patients with MDD; however, receptor binding potential was not significantly different between drug-na?ve MDD patients and controls.10) All of these earlier studies indicate that serotonin receptors are associated with MDD. The role of serotonin transporters, which influence the level of serotonergic activity, has also been examined in related neuroimaging studies. While it was demonstrated that a lower level of SERT availability in the midbrain is related to MDD,11,12,13) several studies presented findings that contradicted this.14,15,16) No differences were found in SERT availability between drug-free euthymic patients with MDD and controls.17) However, our previous study demonstrated that SERT availability in the midbrain was significantly lower in subjects with a first-degree family history of MDD than in healthy subjects.18) Meanwhile, [11C]McN 5652 studies indicated a lower SERT availability binding potential in the amygdala of drug-na?ve patients with MDD,19) and increased SERT availability in the left frontal cortex and right cingulate cortex among drug-free patients.20) Greater SERT availability was reportedly associated with more negative and dysfunctional attitudes among patients with MDD,21) and an increase in SERT availability in the thalamus and striatum of patients with MDD was also found in a [11C]DASB study.22) These findings are shown in Table 2. As serotonergic antidepressants are an important treatment for MDD, PET is also used to probe SSRI occupancy. SERT occupancy is approximately 80% under the effective doses in PET studies using [11C]DASB.23,24)
Altered serotonergic activity is associated with various other mood disorders. For example, increased SERT binding potential was found among unmedicated subjects with bipolar disorder in a PET study using [11C]DASB,25) and similar findings were also reported in another PET study focused on 5-HT1A.26) However, a decreased level of SERT availability, as assessed by SPECT with [123I] ADAM, was found in medicated subjects with euthymic bipolar I, but not bipolar II.27) We speculate that these findings indicate that SERT availability might not only be a biomarker for bipolar disorder but is also influenced by medication or disease severity. In addition, the biological characteristics of bipolar I and II are different.27) It is also worth noting that altered serotonin activity may be related to the severity of symptoms associated with bipolar disorder.25) We speculate that the mechanism between abnormal serotonegic activity and bipolar disorder may be complex.
Studies also indicate that serotonergic activity may be associated with anxiety disorders,28) although the evidence remains inconclusive, with some studies reporting that there is no association,29) or only an unclear one.30,31) Meanwhile, reduced SERT32) and 5-HT2A33) binding potential was found among drug-na?ve subjects with obsessive-compulsive disorder. Kent et al.34) reported that occupancy of SERT by paroxetine (a kind of SSRI) was higher in patients with social anxiety disorder. Additionally, other authors found significantly lower 5-HT1A binding potential in several limbic and paralimbic areas.30) Our preliminary small sample study of patients with generalized anxiety disorder showed no significant difference with regard to SERT level compared with a control group (Yang et al., personal communication).
Although it has been proposed that the serotonergic system may interact with the dopaminergic system in ways that may be associated with schizophrenia,35,36) there remains little neuroimaging evidence regarding this issue. There is reportedly no significant decrease in 5-HT receptors or SERT among schizophrenic subjects, based on PET studies using different radiotracers,37,38,39,40) and similar findings were also reported in a SPECT study using [123I] β-CIT.41) The role of the serotonergic system in the treatment of schizophrenia should be explored further.
Although it has been proposed that serotonergic dysfunction may be associated with addictive behaviors,42,43) there is little evidence from neuroimaging studies, and what exists remains inconclusive. Significantly reduced SERT availability in the brain-stems of alcoholics was found with SPECT using [123I]β-CIT.44) However, another study using the same radiotracer indicated that brainstem SERT availability among smokers was higher than among non-smokers.45) Alcoholic nonsmokers reportedly had higher levels of SERT availability in the brainstem and diencephalon than controls.46) The serotonergic system might also be also associated with other harmful forms of addiction, although the detailed mechanisms remain to be elucidated. For example, the association between serotonin and heroin use is unclear, although a SPECT study with [123I]β-CIT indicated that the level of SERT availability was similar between heroin users and healthy controls.47) One of our studies48) indicated that midbrain SERT availability among opioiddependent patients being treated with low doses of methadone could be lower than that among controls and among former opioid addicts practicing methadone-free abstinence (Fig. 1). On the other hand, another study from our lab indicated that a higher level of SERT availability was associated with a greater likelihood of relapse among former heroin users.49) We speculate, therefore, that serotonin may play a number of roles in heroin addiction. For example, both biological (e.g., homeostasis of neuro-activity) and psychological factors (e.g., depressive tendency, personality traits and risk preference) might have joint effects. Altered serotonergic activity may be associated with use of other substances, such as cocaine. An animal study indicated that acute cocaine self-administration may induce higher levels of SERT availability.50) Evidence in humans is scarce. A SPECT study found elevated SERT availability in acutely abstinent patients with cocaine dependency.51) The association between serotonin and addiction remains to be elucidated.
It was proposed that serotonin may play a role in ADHD via its interplay with the dopaminergic system.52) Additionally, there was reportedly no difference in SERT availability between treatment-na?ve ADHD adults and their controls, while there was a lower level of DAT among ADHD subjects.53) Similar findings were reported in a recent small sample PET study using [11C]MADAM, which indicated that the level of SERT availability was similar between adult patients with ADHD and controls.54)
While the mechanisms of autism remain unclear, a lower level of 5-HT2A receptor binding was found among adult men with Asperger's syndrome in a small sample SPECT study.55) In a SPECT study using [123I]norβ-CIT, a significantly lower level of SERT availability in the medial frontal cortex was found among children with autism.56) More importantly, a PET study reported lower SERT levels throughout the brain in autistic men; reduced SERT level in the anterior/posterior cingulate cortex was associated with poor social cognition.57) Although there are few findings on autism in the literature, published work does shed some light on the etiology of this condition.
Neuroticism is a trait that may be associated with mood disorders. A PET study reported that a higher SERT binding potential was associated with neuroticism among healthy males.58) A higher level of frontolimbic 5-HT2A receptor binding was reportedly associated with neuroticism among subjects with a family history of mood disorders.59) However, little is known about the association between serotonin and other personality traits, although a lower SERT level was found among subjects with borderline personality disorder.60) The studies mentioned above suggest that a lower level of serotonergic activity might be associated with poor social interaction.56,57) Similarly, our recent study indicated that lower SERT availability was associated with a lower level of perceived social support,61) which is linked with stress-induced mental illness. In support of this, another of our studies also indicated that perceived stress was associated with SERT availability.62) Furthermore, hypothalamic-pituitary-adrenal (HPA) axis function, as measured by dexamethasone suppression test, was found to be associated with SERT availability in healthy subjects.63)
Serotonin is one of the most important neurotransmitters and, thus, is a potential target for pharmacological treatment. A large body of evidence supports the association between the serotonergic system with MDD and other mood disorders. However, while pharmacological data support the view that serotonin could be related to anxiety disorders, imaging findings remain insufficient and inconclusive. Moreover, the association between serotonin and schizophrenia, which is the most severe psychiatric disorder, has also not been demonstrated by neuroimaging studies. The association between addiction and the serotonergic system could be complex, as the direction of its effects remains unclear. At present, little evidence supports a link between serotonin and ADHD. However, a few studies suggest that altered hyposerotonergic activity might be one of the etiologies of autism. Even in healthy participants, correlations between SERT and stressful life events and stress hormones still exist, and these findings could have implications for clinical practice.