Serotonergic Transmission Research Articles

Toxic influence of subchronic paraquat administration on dopaminergic neurons in rats

Paraquat is a toxin suggested to contribute to pathogenesis of Parkinson’s disease. The aim of the present study was to examine toxic influence of subchronic treatment with this pesticide (5 days, one injection per day, 2–3 days of withdrawal) on dopaminergic, serotonergic, noradrenergic and GABAergic neurons. Paraquat decreased the number of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra by 22% (measured 3 days after withdrawal). Two days after withdrawal the levels of the dopamine metabolites and dopamine turnover in the caudate–putamen, substantia nigra and prefrontal cortex were reduced by ca. 20–60%, and the binding of [3H]GBR 12,935 to dopamine transporter dropped by 25–40% in the caudate–putamen. Three days after paraquat withdrawal, the level of dopamine in the caudate–putamen was significantly increased, and earlier decreases in DOPAC and HVA in the substantia nigra, as well as [3H]GBR 12,935 binding in the caudate–putamen were reversed. Moreover, an increase in serotonin turnover in the caudate–putamen and prefrontal cortex, and noradrenaline level in the former structure was observed 2–3 days after paraquat withdrawal. Three days after the last paraquat injection 24–35% decreases in the proenkephalin mRNA levels and 5–7% reduction in glutamic acid decarboxylase (GAD)67 mRNA were found in the caudate–putamen. The present study suggests that subchronic paraquat administration triggers processes characteristic of early stages of dopaminergic neuron degeneration, and activates compensatory mechanisms involving dopaminergic, noradrenergic, serotonergic and GABAergic transmissions.

Morphometry of Dorsal Raphe Nucleus Serotonergic Neurons in Alcoholism

Reduced serotonergic function is hypothesized in alcohol abuse and dependence. Serotonergic innervation of the cortex arises predominantly from the dorsal raphe nucleus (DRN). We sought to determine the number and morphometric characteristics of DRN serotonergic neurons postmortem in alcoholic individuals (n=9; age: 16-66 years; 8M:1F) compared with psychiatrically normal, nonalcoholic controls (n=6; age: 17-74 years; 4M:2F). Brainstems were collected at autopsy, fixed and cryoprotected. Alcohol dependence or abuse was determined by psychological autopsy (DSM-IV), the presence of liver fatty changes or cirrhosis and/or high blood alcohol level. Tissue was sectioned at 50 microm (-25 degrees C). A series of 1:10 sections was immunoreacted with antiserum to tryptophan hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of serotonin. The total number of TPH-immunoreactive (IR) DRN neurons was determined by stereology. Neuron morphometry indices were determined using a video-based imaging system attached to a microscope. We identified TPH-IR neurons every 1,000 microm in each brainstem and measured neuron area, total cross sectional neuron area, and the total area and density of immunolabeled processes. Dorsal raphe nucleus neuron number (controls: 80,386+/-10,238; alcoholic individuals: 85,884+/-12,478) was not different between groups but TPH-IR was greater in alcoholic individuals throughout the rostrocaudal extent of the DRN. The volume of the DRN was 66+/-9 mm3 in controls and 55+/-5 mm3 in alcoholic individuals (p>0.05). The average size of DRN neurons did not differ between groups (353+/-12 microm2 for controls vs 360+/-15 microm2 for alcoholic subjects). However, the area occupied by neuron processes (area of processes/DRN area) was 2.2-fold greater in alcoholic individuals compared with controls (p<0.05). The increased area occupied by neuron processes in alcoholic individuals may represent sprouting and, together with greater TPH-IR, be a compensatory response to impaired serotonergic transmission or cumulative effects of alcohol on the serotonin system.

Serotonin syndrome caused by interaction between citalopram and fentanyl

To report a case of serotonin syndrome associated with interaction between fentanyl and citalopram, as evidenced by medication history, clinical features and reversal following discontinuation of fentanyl. A 65-year-old patient chronically treated with the selective serotonin reuptake inhibitor (SSRI) citalopram developed confusion, agitation, tachycardia, tremors, myoclonic jerks and unsteady gait, consistent with serotonin syndrome, following initiation of fentanyl, and all symptoms and signs resolved following discontinuation of fentanyl. Based on the Naranjo probability scale, serotonin syndrome was a probable adverse reaction associated with co-administration of citalopram and fentanyl. Serotonin syndrome is a potentially lethal pharmacodynamic interaction between medications that increase serotonergic transmission at the synaptic junction. The development of new pharmacological agents with varied properties and actions has increased the risk of serotonin syndrome as a clinical diagnosis. SSRIs and fentanyl are commonly co-administered, especially in the setting of chronic or malignant pain, as underlying depression may contribute to the pathogenesis of pain. Healthcare professionals should be aware of the possible development of serotonin syndrome as a complication of initiation of fentanyl and other phenylpiperidine opioids in patients treated with SSRIs.

Clozapine and Haloperidol Differently Suppress the MK-801-Increased Glutamatergic and Serotonergic Transmission in the Medial Prefrontal Cortex of the Rat

The administration of noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine and ketamine has been shown to increase the extracellular concentration of glutamate and serotonin (5-HT) in the medial prefrontal cortex (mPFC). In the present work, we used in vivo microdialysis to examine the effects of the more potent noncompetitive NMDA receptor antagonist, MK-801, on the efflux of glutamate and 5-HT in the mPFC, and whether the MK-801-induced changes in the cortical efflux of both transmitters could be blocked by clozapine and haloperidol given systemically or intra-mPFC. The systemic, but not the local administration of MK-801, induced an increased efflux of 5-HT and glutamate, which suggests that the NMDA receptors responsible for these effects are located outside the mPFC, possibly in GABAergic neurons that tonically inhibit glutamatergic inputs to the mPFC. The MK-801-induced increases of extracellular glutamate and 5-HT were dependent on nerve impulse and the activation of mPFC AMPA/kainate receptors as they were blocked by tetrodotoxin and NBQX, respectively. Clozapine and haloperidol blocked the MK-801-induced increase in glutamate, whereas only clozapine was able to block the increased efflux of 5-HT. The local effects of clozapine and haloperidol paralleled those observed after systemic administration, which emphasizes the relevance of the mPFC as a site of action of these antipsychotic drugs in offsetting the neurochemical effects of MK-801. The ability of clozapine to block excessive cortical 5-HT efflux elicited by MK-801 might be related to the superior efficacy of this drug in treating negative/cognitive symptoms of schizophrenia.

The indirect serotonergic agonist d-fenfluramine and prepulse inhibition in healthy men

The specific serotonin (5-HT) releaser, d-fenfluramine (DFEN) was used as a probe of serotonergic effects on prepulse inhibition (PPI). We wished to explore the notion that increased central serotonergic transmission was in part responsible for the psychotomimetic effects of hallucinogens using a relevant and objective physiological measure. Disruption of PPI is considered a valid pharmacological model of some aspects of the behavioural abnormalities in schizophrenia. The aim of this study was to test the hypothesis that increasing central 5-HT neurotransmission with DFEN would produce disruption of PPI. Eighteen healthy male subjects received 45 mg of DFEN or placebo in a random order, within-subject, double-blind, and cross-over design. Prepulse to pulse intervals were 30 ms and 120 ms. The Brief Psychiatric Rating Scale (BPRS) was administered. Although mean PPI at the two prepulse intervals was not significantly different, DFEN prevented the increase in PPI usually seen at the 120 ms interval and significantly increased startle magnitude, but did not alter habituation. There were no significant associations between PPI effects and behaviour.

Neurological complications of psychiatric drugs: clinical features and management

This paper reviews the main neurological complications of psychiatric drugs, in particular antipsychotics and antidepressants. Extrapyramidal syndromes include acute dystonia, parkinsonism, akathisia, tardive dyskinesia and tardive dystonia. Extrapyramidal symptoms (EPS) are less frequent with atypical than with conventional antipsychotics but remain common in clinical practice partly due to lack of screening by health professionals. Neuroleptic malignant syndrome (NMS) consists of severe muscle rigidity, pyrexia, change in conscious level and autonomic disturbance but partial forms also occur. NMS is particularly associated with the initiation and rapid increase in dose of high-potency antipsychotics but it has been reported with all the atypical antipsychotics and rarely with other drugs including antidepressants. Serotonin toxicity comprises altered mental state (agitation, excitement, confusion), neuromuscular hyperactivity (tremor, clonus, myoclonus, hyper-reflexia) and autonomic hyperactivity and occurs on a spectrum. Severe cases, termed serotonin syndrome, usually follow the co-prescription of drugs that increase serotonergic transmission by different pathways, for example a monoamine oxidase inhibitor (MAOI) and a selective serotonin reuptake inhibitor (SSRI). Most antipsychotics and antidepressants lower the seizure threshold and can cause seizures; the risk is greater with clozapine than with other atypical antipsychotics and greater with tricyclic antidepressants (TCAs) than with SSRIs. In randomised controlled trials in elderly patients with dementia atypical antipsychotics are associated with a higher risk of stroke and death than placebo. Cohort studies suggest that conventional drugs carry at least the same risk. Cessation of treatment with antipsychotics and antidepressants can lead to a wide range of discontinuation symptoms which include movement disorders and other neurological symptoms. Clinicians need to be familiar with strategies to reduce the risk of these adverse events and to manage them when they arise. Their occurrence needs to be balanced against the benefits of psychiatric drugs in terms of efficacy and improved quality of life in a range of disorders.

Systematic Screening of the Serotonin Receptor 1A (5-HT1A) Gene in Chronic Tinnitus

ObjectiveChronic tinnitus is a highly prevalent condition and has been hypothesized to result from an innate disturbance in central nervous serotonergic transmission. Given the frequent comorbidity with major depression and anxiety, we argue that candidate genes for these disorders are likely to overlap. The present study addresses the gene encoding for the 5-HT1A receptor as a putative risk factor for tinnitus. MethodsIn 88 subjects with a diagnosis of chronic subjective tinnitus who underwent a detailed neurootological examination, the entire 5-HT1A gene was amplified using overlapping PCR products. Amplicons were custom sequenced bidirectionally and were screened for variants in multiple alignments against the human genome reference. ResultsWe identified a synonymous C>T exchange at residue 184 (Pro) in 7/88 subjects, but detected no missense variants in the population under study. Specifically, the following residues were fully conserved: 16 (Pro), 22(Gly), 28(Ile), 98 (Val), 220(Arg), 267 (Val), 273 (Gly), and 418 (Asn). DiscussionThe present data count against the causation of chronic tinnitus by a change in the 5-HT1A receptor’s amino acid sequence. However, the allele frequency for the 184Pro minor allele (0.04) reached twice the frequency reported in control cohorts from the same ethnicity. Additional investigations are invited to clarify the role of the 5-HT1A polymorphism in larger samples, and to control for comorbid affective disorders.

The Effect of Combined Administration of Ethanol and Gabapentin on Rabbit Electroencephalographic Activity

The central effect of ethanol is mainly connected with the effect on GABAergic, glutamatergic, serotonergic and opioid transmission. The mechanism of gabapentin effect suggests that it may alleviate the rewarding effect of ethanol, which may be used in the treatment of addiction. We decided to examine the interaction of ethanol with gabapentin by a pharmaco-electroencephalographic (EEG) method. The influence of gabapentin on the effect of ethanol on EEG of rabbits (midbrain reticular formation, hippocampus, frontal cortex) was tested. Gabapentin was administered at a single dose (25 and 100 mg/kg orally) or repeatedly twice a day at a total dose of 25 mg/kg for 14 days. Ethanol was injected at a dose of 0.8 g/kg 60 min. after gabapentin treatment. Ethanol caused an increase in the slow frequencies (0.5-4 Hz) in the recording, as well as a marked decrease of the fastest frequencies (13-30 and 30-45 Hz). Gabapentin lead to changes in rabbit EEG recording suggesting an depressant effect on the CNS (increase of slow and decrease of fast frequencies). The effects were less pronounced after repeated doses, which may indicate adaptative changes in the receptors. Gabapentin administered both in a single dose and for 7 days markedly enhanced the effect of ethanol on EEG recordings in rabbits. Repeated doses of gabapentin decrease the sensitivity of the hippocampus to the effect of ethanol.

Relationship of presympathetic‐premotor neurons to the serotonergic transmitter system in the rat brainstem

Numerous physiological conditions and emotionally motivated behaviors require concomitant activation of somatomotor and sympathetic efferents. Using a virally mediated retrograde transsynaptic tract-tracing approach, we have previously determined locations of presympathetic-premotor neurons (PSPMNs) in the rat brainstem. These putative dual-function neurons send projections to somatomotor and sympathetic targets and likely participate in sympatho-somatomotor integration. A significant portion of these neurons is found within brainstem areas known to contain serotonergic neurons. Thus, we hypothesized that some of the PSPMNs utilize serotonin as their neurotransmitter. To test this hypothesis we first produced an antibody against TPH2, a brain-specific isoform of tryptophan hydroxylase (serotonin synthetic enzyme). We identified PSPMNs by using recombinant strains of the pseudorabies virus (PRV) for transsynaptic tract-tracing. PRV-152, a strain that expresses enhanced green fluorescent protein, was injected into sympathectomized gastrocnemius muscle, while PRV-BaBlu, which expresses beta-galactosidase, was injected into the adrenal gland in the same animals. Using immunofluorescent methods we determined whether coinfected neurons expressed TPH2. Our findings demonstrate that TPH2-positive PSPMNs are present at different rostrocaudal levels of the brainstem. Just over half of them are found at the pontomedullary junction within raphe obscurus, raphe magnus, and gigantocellular nucleus pars alpha. These cells may play a role in mediating responses to acute pain stimuli and/or participate in the central control of exercise. Overactivity of these serotonergic sympatho-somatomotor circuits may also play a role in the pathophysiology of serotonin syndrome.

The role of noradrenergic tone in the dorsal raphe nucleus of the mouse in the acute behavioral effects of antidepressant drugs

Serotonin neurons of the dorsal raphe nucleus (DRN) receive dense noradrenergic innervation and are under tonic activation by noradrenergic input. Thus, afferent noradrenergic input to the DRN could modify the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) by regulating serotonergic transmission. This study investigated whether noradrenergic innervation of the DRN contributes to the acute behavioral effects of different types of antidepressant drugs in the mouse tail suspension test (TST). Noradrenergic terminals in the DRN were destroyed selectively by the local application of 6-hydroxydopamine (6-OHDA). Immunohistochemical analysis confirmed the presence of noradrenergic fibers in the mouse DRN, that 6-OHDA-induced destruction of noradrenergic terminals was confined to the DRN, and serotonergic cell bodies were not affected by 6-OHDA treatment. The antidepressants tested included the SSRIs, fluoxetine and citalopram, and the norepinephrine reuptake inhibitor (NRI) desipramine. The behavioral effects of fluoxetine (20 mg/kg, IP) were blocked by the destruction of noradrenergic terminals. In contrast, pretreatment with 6-OHDA did not alter the ability of citalopram (20 mg/kg, IP) or desipramine (10 mg/kg, IP) to reduce immobility in the TST. Destruction of noradrenergic projections from the locus ceruleus (LC) by DSP-4 treatment did not alter the behavioral effects of any of the antidepressants tested, or the presence of noradrenergic terminals in the DRN, thus indicating that noradrenergic pathways originating from the LC do not mediate the acute behavioral effects of antidepressants in this test. Thus, afferent noradrenergic activity at the level of the DRN can modulate serotonergic transmission in forebrain structures and the behavioral effects of SSRIs, such as fluoxetine, which use noradrenergic input to the DRN to increase forebrain serotonin.

Acute restraint increases NADPH-diaphorase staining in distinct subregions of the rat dorsal raphe nucleus: Implications for raphe serotonergic and nitrergic transmission

The brainstem dorsal raphe nucleus (DRN) maintains a rough topographic cell ordering with respect to biological function. This study examined the influence of acute restraint on nitric oxide (NO) synthase (NOS) neurons in distinct DRN subregions. NADPH diaphorase staining (NOS index) intensity was higher in the DRN dorsomedial, ventromedial and lateral wings subregions of restrained vs. control rats. The mean number of cells was not significantly different between both groups of animals. The restrained-induced NADPH-diaphorase activity was significantly higher in the rostral ventromedial and caudal lateral wings than the corresponding caudal and rostral subregions but no significant difference was observed between rostral and caudal dorsomedial subregions. These observations suggest that restraint stress differentially activates NO-producing neurons in distinct DRN subregions.

Spatial and temporal patterns of serotonin release in the rat’s lumbar spinal cord following electrical stimulation of the nucleus raphe magnus

The monoamine neurotransmitter serotonin is released from spinal terminals of nucleus raphe magnus (NRM) neurons and important in sensory and motor control, but its pattern of release has remained unclear. Serotonin was measured by the high-resolution method of fast cyclic voltammetry (2 Hz) with carbon-fiber microelectrodes in lumbar segments (L3–L6) of halothane-anesthetized rats during electrical stimulation of the NRM. Because sites of serotonin release are often histologically remote from membrane transporters and receptors, rapid emergence into aggregate extracellular space was expected. Increased monoamine oxidation currents were found in 94% of trials of 50-Hz, 20-s NRM stimulation across all laminae. The estimated peak serotonin concentration averaged 37.8 nM (maximum 287 nM), and was greater in dorsal and ventral laminae (I–III and VIII–IX) than in intermediate laminae (IV–VI). When measured near NRM-evoked changes, basal monoamine levels (relative to dorsal white matter) were highest in intermediate laminae, while changes in norepinephrine level produced by locus ceruleus (LC) stimulation were lowest in laminae II/III and VII. The NRM-evoked monoamine peak was linearly proportional to stimulus frequency (10–100 Hz). The peak often occurred before the stimulus ended (mean 15.6 s at 50 Hz, range 4–35 s) regardless of frequency, suggesting that release per impulse was constant during the rise but fell later. The latency from stimulus onset to electrochemical signal detection (mean 4.2 s, range 1–23 s) was inversely correlated with peak amplitude and directly correlated with time-to-peak. Quantitative modeling suggested that shorter latencies mostly reflected the time below detection threshold (5–10 nM), so that extrasynaptic serotonin was significantly elevated well within 1 s. Longer latencies (>5 s), which were confined to intermediate laminae, appeared mainly to be due to diffusion from distant sources. In conclusion, except possibly in intermediate laminae, serotonergic volume transmission is a significant mode of spinal control by the NRM.

Neurophysiologic changes during estrogen augmentation in perimenopausal depression

BackgroundEstrogen augmentation of antidepressant medication has been an effective treatment in a subgroup of women experiencing affective symptoms during perimenopause. It has been suggested that estrogen facilitates serotonergic transmission in brain regions involved in mood disorders. We investigated differences in physiologic brain changes with estrogen augmentation in women with perimenopausal depression who reached remission compared to those who did not reach remission. We also assessed whether such changes were correlated with serum hormone levels. MethodsQuantitative electroencephalography (QEEG) was used to examine neurophysiologic brain changes in remission and non-remission of depressive symptoms. Women with major depressive disorder (MDD) in partial remission who were taking antidepressant medication for a minimum of 8 weeks and were experiencing two or more perimenopausal symptoms (hot flashes, night sweats, irregular periods, memory impairment, vaginal dryness) were recruited from the community. Absolute power, relative power, and QEEG cordance, a measure that has moderately strong associations with cerebral perfusion, were obtained before and after 6 weeks of treatment with 0.625mg of conjugated estrogen per day. ResultsWomen who experienced remission of depressive symptoms (Ham-D≤7) had a significant decrease in right frontal QEEG cordance (p=0.008, t(8)=−3.54) which was not present in non-remitters. No significant correlations were found between hormone levels and QEEG cordance. ConclusionIn women with perimenopausal depression, physiologic brain changes in the right frontal region during estrogen augmentation were associated with remission of depression.

Intensity Dependence of Auditory-Evoked Cortical Potentials in Fibromyalgia Patients: A Test of the Generalized Hypervigilance Hypothesis

On the basis of recent evidence concerning the amplification of incoming stimulation in fibromyalgia (FM) patients, it has been proposed that a generalized hypervigilance of painful and nonpainful sensations may be at the root of this disorder. So far, research into this issue has been inconclusive, possibly owing to the lack of agreement as to the operational definition of “generalized hypervigilance” and to the lack of robust objective measures characterizing the sensory style of FM patients. In this study, we recorded auditory-evoked potentials (AEPs) elicited by tones of increasing intensity (60, 70, 80, 90, and 105 dB) in 27 female FM patients and 25 healthy controls. Fibromyalgia patients presented shorter N1 and P2 latencies and a stronger intensity dependence of their AEPs. Both results suggest that FM patients may be hypervigilant to sensory stimuli, especially when very loud tones are used. The most noteworthy difference between patients and control subjects is at the highest stimulus intensity, for which far more patients maintained increased N1-P2 amplitudes in relation to the 90-dB tones. The larger AEP amplitudes to the 105-dB tones suggest that defects in an inhibitory system protecting against overstimulation may be a crucial factor in the pathophysiology of FM. Because a stronger loudness dependence of AEPs has been related to weak serotonergic transmission, it is hypothesized that for many FM patients deficient inhibition of the response to noxious and intense auditory stimuli may be due to a serotonergic deficit. Perspective The study of auditory-evoked potentials in response to tones of increasing intensity in FM patients may help to clarify the pathophysiology of this disorder, especially regarding the role of inhibition deficits involving serotonergic dysfunction, and may be a useful tool to guide the pharmacologic treatment of FM patients.

Selective Serotonin Reuptake Inhibitors, Fluoxetine and Paroxetine, Attenuate the Expression of the Established Behavioral Sensitization Induced by Methamphetamine

To obtain an insight into the development of a new pharmacotherapy that prevents the treatment-resistant relapse of psychostimulant-induced psychosis and schizophrenia, we have investigated in the mouse the effects of selective serotonin reuptake inhibitors (SSRI), fluoxetine (FLX) and paroxetine (PRX), on the established sensitization induced by methamphetamine (MAP), a model of the relapse of these psychoses, because the modifications of the brain serotonergic transmission have been reported to antagonize the sensitization phenomenon. In agreement with previous reports, repeated MAP treatment (1.0 mg/kg a day, subcutaneously (s.c.)) for 10 days induced a long-lasting enhancement of the increasing effects of a challenge dose of MAP (0.24 mg/kg, s.c.) on motor activity on day 12 or 29 of withdrawal. The daily injection of FLX (10 mg/kg, s.c.) or PRX (8 mg/kg, s.c.) from 12 to 16 days of withdrawal of repeated MAP administration markedly attenuated the ability of the MAP pretreatment to augment the motor responses to the challenge dose of the stimulant 13 days after the SSRI injection. The repeated treatment with FLX or PRX alone failed to affect the motor stimulation following the challenge of saline and MAP 13 days later. These results suggest that the intermittent and repetitive elevation of serotonergic tone may inhibit the expression of the motor sensitization induced by pretreatment with MAP. It is proposed that clinically available serotonin reuptake inhibitors could be useful for preventing the recurrence of hallucinatory-paranoid state in drug-induced psychosis and schizophrenia.

Effect of Vagus Nerve Stimulation on Serotonergic and Noradrenergic Transmission

Vagus nerve stimulation (VNS) is an antiepileptic treatment, which has recently shown promise as an antidepressant. Yet, its antidepressant mechanisms of action are unknown. Serotonergic [5-hydroxytryptamine (5-HT, serotonin)] and noradrenergic [norepinephrine (NE)] systems are involved in the pathophysiology of depression and in the mechanisms of action of antidepressants. The present study analyzes 5-HT and NE neuronal firing rates in their brainstem nuclei: the dorsal raphe nucleus (DRN) and locus coeruleus (LC), respectively. The basal firing rates in the DRN and LC were significantly increased after long-term treatments with VNS. After short-term VNS treatments, firing rates were significantly higher for LC (at 1 h and 3 days). As changes in their firing rate may have been due to altered autoreceptor sensitivities, the responses of autoreceptors to the acute administration of their respective agonists were assessed. However, no significant difference was seen in the DRN. No significant differences in dose response curves for 5-HT(1A) somatodendritic and alpha 2-adrenergic autoreceptors were noticed between long-term VNS and controls. VNS appears to have a novel mechanism of antidepressant action, enabling its effectiveness in treatment-resistant depression. LC firing rates significantly increase earlier than the DRN basal firing. As the LC has an excitatory influence on DRN, it is possible that the increased DRN firing rate is secondary to an initial increased LC firing rate from VNS.

Suicidology Meeting Genetics

In 2000, the so-called book of life (the human genome) was revealed. Six years later a range of genetic tests has been developed. The genetic code seems to influence almost everything from health through potential to develop disorders to disorders themselves – and the effects of drugs in these disorders. Inherited predisposition is an important component in a number of common diseases that contribute significantly to the health burden of our societies, e.g., atherosclerosis, hypertension, diabetes mellitus, cancer, mental disorders, and many others. Indeed, recent developments in molecular genomics and accompanying technologies have changed our understanding of both health and disease. Consequently, changes in our approaches to treatment and prevention have followed. For example, because it appears that genetic approaches are likely to become an important part of health care, it is necessary for health workers to improve their overall knowledge of health genetics. As a response, the World Health Organization (WHO) has launched the Human Genetics Programme as a separate program in the WHO dealing with genetic approaches to prevention and control of diseases. Their main priorities are not only genetic diseases and congenital disorders, but also common diseases with genetic predisposition (such as coronary heart disease or depression), the analysis of the relevant ethical, legal, and social issues, and education and training aimed at patients, families, and health professionals alike. Suicidal ideation and behavior are not considered disorders like depression. However, they do represent one of the biggest public health concerns in the contemporary world. Like many other complex traits, suicidal behavior too seems to cluster in families. Moreover, first-degree relatives of individuals who have committed suicide (including dizygotic twins) are more than twice as likely to die by suicide compared with the general population. In the case of identical twins, the concordance of suicide is even greater than is the case with fraternal twins (Roy, Segal, Centerwall, & Robinette, 1991). Genetic model fitting on one of the largest studies of twins showed more that 40% of the variability of suicidal behavior can be explained by genetics (McGuffin, Marusi2, & Farmer, 2001). The mode of inheritance of suicidal behavior is almost certain to be complex, involving many genes, and there have already been several studies and meta-analyses of allelic association with polymorphisms in candidate genes such as those involved in serotonergic transmission. Most recently, attention has also been paid to the possible interplay of these genes with environmental factors. In an interesting example of such simultaneously performed research, Caspi et al. (2003) tested why stressful experiences lead to depression in some people but not in others, using a prospective-longitudinal study of a representative birth cohort. The functional polymorphism in the promoter region of the serotonin transporter (5-HTT) gene was found to moderate the influence of stressful life events on depression, one of the main risk factors for suicidal behavior. It is therefore very likely that evidence in the future will show, replicate, and confirm some genetic risk factors for suicidal behavior of small effect, at least in some parts in the world. Being able to identify people who may be at a higher risk for suicidal ideation and/or behavior will have several implications. In particular, the possibility that we may be able to identify people potentially vulnerable to suicidal behavior will raise a number of ethical public policy issues (Meltzer, 2000): 1. First, as with any other investigation in mental health and in genetics, we must make sure that potential subjects in genetic research studies are able to provide informed consent. They have to be informed that their participation is voluntary, and that they may withdraw at any time. The risks and the benefits of the study must be clearly stated, and alternatives to the study should be made available to the participants. It may be necessary to explain genetic technology to participants before obtaining informed consent. 2. Second, it is very important to protect the confidentiality of data on individuals (both suicidal cases and their controls), from whom material for molecular genetic research studies of suicidal behavior is taken. 3. Third, in the case of possible collaborative research with the pharmaceutical industry, anyone involved in the genetic investigation of suicidal behavior should be aware of the separate and careful delineation of researcher and clinical roles.

Midbrain binding of [ 123I]nor-β-CIT in atypical depression

Background Altered serotonin (SERT) and dopamine transporter (DAT) densities have been recorded in major depression. Atypical depression (ATD) has been suggested to be connected to decreased serotonergic transmission, but no studies have been published on the association between brain serotonin transporter density and ATD. Methods PATIENTS with depression ( n = 29) were divided into three groups according to DSM-IV criteria: atypically depressed, melancholic patients, and “undifferentiated” patients. Depressive symptoms were evaluated with the 29-item Hamilton Depression Rating Scale (HAM-D-29). Single photon emission computed tomography (SPECT) with [ 123I]nor-β-CIT was used to evaluate serotonin transporter density (SERT) in the midbrain and dopamine transporter density (DAT) in the striatum of patients and healthy controls ( n = 18). Results All subgroups except those with undifferentiated depression had lower SERT densities compared to controls. No significant differences were found in the densities between the subgroups. Atypical scores of HAM-D-29 were associated with SERT densities in the midbrain ( β = − 0.40, t = − 2.3, p = 0.03), even after adjustment for age, gender and HAM-D-21 scores ( β = − 0.39, t = − 2.32, p = 0.03). Conclusions The association between atypical scores of HAM-D-29 and midbrain SERT densities suggests a relationship between serotonergic dysfunction and ATD.

Development of better antidepressant using Nelumbinis Semen in an animal model of depression

Depression is associated with a dysfunctional 5-HT system. Recently, several lines of evidence have suggested that a very important evoking factor in depression may be a 5-HT deficit in the hippocampus. The present study assessed the antidepression effects of Nelumbinis Semen (NS) through increasing 5-HT concentrations in the hippocampus under chronic mild stress (CMS). NS significantly increased 5-HT in normal conditions and reversed a stress-induced decrease of 5-HT release in the hippocampus under CMS for 8 weeks. These results suggest that NS increases the serotonin levels normally decreased in depression, resulting in an enhancement of central serotonergic transmission and possible therapeutic action for depression.

The genetics of alcohol dependence

Alcohol dependence is a common, complex disorder, which affects millions of people worldwide and causes considerable burden in terms of interpersonal and societal costs. Family, twin, and adoption studies have convincingly demonstrated that genes play an important role in the development of alcohol dependence, with heritability estimates in the range of 50% to 60% for both men and women. A number of studies are under way to identify specific genes involved in the predisposition toward alcohol dependence, and there is reason to be enthusiastic about recent progress. Several associated susceptibility genes are reviewed here, including genes involved in alcohol metabolism, as well as genes involved in GABAergic, endogenous opioid, dopaminergic, cholinergic, and serotonergic transmission. The next challenge will be to further characterize the risk associated with these susceptibility genes, examining how they may be related to comorbid disorders, developmental trajectories of risk, and potential moderation by environmental factors.