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.

Serotonin (5-HT)-receptor-based mechanisms have been postulated to play a critical role in the action of the new generation of antipsychotic drugs (APDs) that are usually referred to as atypical APDs because of their ability to achieve an antipsychotic effect with lower rates of extrapyramidal side effects (EPS) compared to first-generation APDs such as haloperidol. Specifically, it has been proposed by Meltzer et al. [J. Pharmacol. Exp. Ther. 251 (1989) 238] that potent 5-HT2A receptor antagonism together with weak dopamine (DA) D2 receptor antagonism are the principal pharmacologic features that differentiate clozapine and other apparent atypical APDs from first-generation typical APD. This hypothesis is consistent with the atypical features of quetiapine, olanzapine, risperidone, and ziprasidone, which are the most common treatments for schizophrenia in the United States and many other countries, as well as a large number of compounds in various stages of development. Subsequent research showed that 5-HT1A agonism may be an important consequence of 5-HT2A antagonism and that substitution of 5-HT1A agonism for 5-HT2A antagonism may also produce an atypical APD drug when coupled with weak D2 antagonism. Aripiprazole, the most recently introduced atypical APD, and a D2 receptor partial agonist, may also owe some of its atypical properties to its net effect of weak D2 antagonism, 5-HT2A antagonism and 5-HT1A agonism [Eur. J. Pharmacol. 441 (2002) 137]. By contrast, the alternative "fast-off" hypothesis of Kapur and Seeman [Am. J. Psychiatry 158 (2001) 360] applies only to clozapine and quetiapine and is inconsistent with the "slow" off rate of most atypical APDs, including olanzapine, risperidone and ziprasidone. 5-HT2A and 5-HT1A receptors located on glutamatergic pyramidal neurons in the cortex and hippocampus, 5-HT2A receptors on the cell bodies of DA neurons in the ventral tegmentum and substantia nigra and GABAergic interneurons in the cortex and hippocampus, and 5-HT1A receptors in the raphe nuclei are likely to be important sites of action of the atypical APDs. At the same time, evidence has accumulated for the important modulatory role of 5-HT2C and 5-HT6 receptors for some of the effects of some of the current APDs. Thus, 5-HT has joined DA as a critical target for developing effective APDs and led to the search for novel drugs with complex pharmacology, ending the exclusive search for single-receptor targets, e.g., the D3 or D4 receptor, and drugs that are selective for them.

Serotonin receptors: their key role in drugs to treat schizophrenia.

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

Sexual problems are highly prevalent in both men and women and are affected by, among other factors, mood state, interpersonal functioning, and psychotropic medications. The incidence of antidepressant-induced sexual dysfunction is difficult to estimate because of the potentially confounding effects of the illness itself, social and interpersonal comorbidities, medication effects, and design and assessment problems in most studies. Estimates of sexual dysfunction vary from a small percentage to more than 80%. This article reviews current evidence regarding sexual side effects of selective serotonin reuptake inhibitors (SSRIs). Among the sexual side effects most commonly associated with SSRIs are delayed ejaculation and absent or delayed orgasm. Sexual desire (libido) and arousal difficulties are also frequently reported, although the specific association of these disorders to SSRI use has not been consistently shown. The effects of SSRIs on sexual functioning seem strongly dose-related and may vary among the group according to serotonin and dopamine reuptake mechanisms, induction of prolactin release, anticholinergic effects, inhibition of nitric oxide synthetase, and propensity for accumulation over time. A variety of strategies have been reported in the management of SSRI-induced sexual dysfunction, including waiting for tolerance to develop, dosage reduction, drug holidays, substitution of another antidepressant drug, and various augmentation strategies with 5-hydroxytryptamine-2 (5-HT2), 5-HT3, and alpha2 adrenergic receptor antagonists, 5-HT1A and dopamine receptor agonists, and phosphodiesterase (PDE5) enzyme inhibitors. Sexual side effects of SSRIs should not be viewed as entirely negative; some studies have shown improved control of premature ejaculation in men. The impacts of sexual side effects of SSRIs on treatment compliance and on patients' quality of life are important clinical considerations.

Effects of SSRIs on sexual function: a critical review.

• 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.

Serotonin Uptake in Blood Platelets of Psychiatric Patients

Effects of phencyclidine on [3H]catecholamine and [3H]serotonin uptake in synaptosomal preparations from rat brain

Fluoxetine (Lilly 110140) is a potent, specific serotonin (5-HT) uptake blocker which is being tested in man for antidepressant activity. One of 9 depressed patients receiving this drug developed a dystonic reaction, parkinsonian rigidity, and increased serum prolactin levels, all signs of decreased dopaminergic activity. Homovanillic acid levels also decreased in the cerebrospinal fluid of this subject. We postulate that fluoxetine, via the increase in 5-HT activity resulting from 5-HT uptake blockade, inhibited both the nigro-striatal and tubero-infundibular dopaminergic neurons. These results provide additional evidence for a linkage between serotonergic and dopaminergic neurons in man.

Ramesh C. Arora

Papers

Serotonin Uptake in Blood Platelets of Psychiatric Patients

Effects of phencyclidine on [3H]catecholamine and [3H]serotonin uptake in synaptosomal preparations from rat brain

Extrapyramidal side effects and increased serum prolactin following fluoxetine, a new antidepressant.

Seasonal variation of serotonin uptake in normal controls and depressed patients.

Serotonin uptake and imipramine binding in blood platelets and brain of Fawn-hooded and Sprague Dawley rats.