Mood, emotion, cognition, and motor functions as well as circadian and neuroendocrine rhythms, including food intake, sleep, and reproductive activity, are modulated by the midbrain raphe serotonin (5-HT) system. By directing the magnitude and duration of postsynaptic responses, carrier-facilitated 5-HT transport into and release from the presynaptic neuron are essential for the fine tuning of serotonergic neurotransmission. Interest in the mechanism of environmental factor-, disease-, and therapy-induced modification of 5-HT transporter (5-HTT) function and its impact on early brain development, event-related synaptic plasticity, and neurodegeneration is widespread and intensifying. We have recently characterized the human and murine 5-HTT genes and performed functional analyses of their 5'-flanking regulatory regions. A tandemly repeated sequence associated with the transcriptional apparatus of the human 5-HTT gene displays a complex secondary structure, represses promoter activity in nonserotonergic neuronal cells, and contains positive regulatory components. We now report a novel polymorphism of this repetitive element and provide evidence for allele-dependent differential 5-HTT promoter activity. Allelic variation in 5-HTT-related functions may play a role in the expression and modulation of complex traits and behavior.

Allelic Variation of Human Serotonin Transporter Gene Expression

SELECTIVE antagonism of serotonin (5-hydroxytryptamine, 5HT) and noradrenaline transport by antidepressants is a key element in the 'amine' hypothesis of affective disorders1. Uptake2,3 and/or transport sites4,5 of 5HT have been reported to be reduced in platelets of patients suffering from depression and in post-mortem brain samples of depressed patients6 and suicide victims7. To date there has been little molecular information available on the structure and regulation of 5HT transporters. Using the polymerase chain reaction8with degenerate oligonucleotides9 derived from two highly conserved regions of the transporters for noradrenaline10 and γ-aminobutyric acid11(GABA), we have identified a large family of related gene products expressed in rodent brain. One of these products hybridizes to a single 3.7-kilobase RNA restricted to rat midbrain and brainstem, where it is highly enriched within the serotonergic raphe complex. Transfection with a single 2.3-kilobase brainstem complementary DNA clone is sufficient to confer expression of a Na+-dependent 5HT transporter upon non-neural cells, with transport selectively and potently antagonized by 5HT uptake-specific antidepressants, including paroxetine, citalopram and fluoxetine.

Cloning and expression of a functional serotonin transporter from rat brain.

The significant role of emotions in evolution and adaptation suggests that there must be more than 1 mechanism for generating them. Nevertheless, much of current emotion theory focuses on cognitive processes (appraisal, attribution, and construal) as the sole, or primary, means of eliciting emotions. As an alternative to this position, the present model describes 4 types of emotion-activating systems, 3 of which involve noncognitive information processing. From an evolutionary-developmental perspective, the systems maybe viewed as a loosely organized hierarchical arrangement, with neural systems, the simplest and most rapid, at the base and cognitive systems, the most complex and versatile, at the top. The emotion-activating systems operate under a number of constraints, including genetically influenced individual differences. The hierarchical organization of the systems for generating emotions provides an adaptive advantage.

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Four Systems for Emotion Activation: Cognitive and Noncognitive Processes

The gene encoding the human serotonin transporter (5-HTT) has been isolated and characterized. The human 5-HTT gene is composed of 14 exons spanning approximately 31 kb. The sequence of all exons including adjacent intronic sequences and a tandem repeat DNA polymorphism (VNTR) has been determined and deposited in the EMBL/GenBank data base with the accession numbers X76753 to X76762. The characterization of 5-HTT gene will aid to advance molecular pharmacologic studies of 5-HT uptake regulation and facilitate investigations of its role in psychiatric disorders.

Organization of the human serotonin transporter gene.

Role of the serotonergic system in the pathogenesis of major depression and suicidal behavior.

• Platelet serotonin (5-HT) uptake was determined in 72 newly admitted, unmedicated psychiatric patients. Decreased maximum velocity (V max ) of 5-HT uptake was present in unipolar and bipolar depressed patients as well as schizoaffective depressed patients. The apparent Michaelis constant (k m ) of 5-HT uptake was normal in these groups, as was V max and K m in manicdepressive and chronic schizophrenic patients. Treatment of depressed patients with notriptyline hydrochloride or imipramine hydrochloride increased K m significantly. There was a trend for the increase in K m in the nortriptyline-treated patients to correlate with clinical improvement. Decreased 5-HT uptake in platelets provides additional evidence for the role of 5-HT in the pathophysiologic process of some forms of depression.

Riaz Baber

Papers

Serotonin Uptake in Blood Platelets of Psychiatric Patients

Serotonin uptake in blood platelets of psychiatric patients

Clonal hematopoiesis of indeterminate potential in peripheral artery disease