Postsynaptic Serotonin Receptors Research Articles

The role of thrombocyte serotonin system and some thrombocyte characteristics in treatment of depressive patients with cardiovascular diseases

IntroductionAmong the known neurotransmitters, serotonin, norepinephrine and dopamine play the important roles in the development of psychiatric disturbances. The research so far has shown that this is not the matter of concentrations themselves, but of disbalance of concentrations between the neurotransmitter systems in CNS (central nervous system). There is proof that there is a decrease of serotonin, epinephrine and dopamine functions in patients suffering from the recurring depressive episodes, while there is a hyperactivity of norepinephrine and dopamine system in patients suffering from the bipolar affective disorder [1]. There is still a dilemma if there were a hypo or hyperactivity of serotonin system in generalized anxiety disorder [2,3]. The agonists of 5HT1A receptors reduce the symptoms of panic disorders, while the activation of 5HT2C receptors induces a panic attack [4]. Hypersensitivity of postsynaptic serotonin receptors plays an important role in obsessive-compulsive disorders [5]. Destabilization of serotonin system has been noted also in posttraumatic stress disorders. This fact had been confirmed by the efficiency of SIPPS in its treatment [6]. Dysfunction of serotonin system is also present in some personality disorders, urge-control disturbances, feeding disorders and dementia. It seems that the negative symptoms in schizophrenia are due to a dysfunction of serotonin system. In suicidal tendencies, the role of serotonin system is of the greatest importance and numerous post-mortem investigations had revealed lower concentrations of serotonin and its main metabolite 5-hydroxyindolacetate acid (5-HIAA) in brainstem, nuclei raphe, putamen and hypothalamus [7]. Some research show that lower levels of thrombocyte serotonin are connected with suicidal behaviour of depressive patients [8]. Numerous investigations have shown that, among the patients who had suffered a myocardial infarction or other diseases of cardiovascular system we can find depressive symptoms in the frame of depressive reaction, but also a real depression in its fully-blown clinical form. Depression slows the recovery in those patients but, even more importantly, some indices had been found in patients suffering from depression that it could be directly connected with an increased risk for the development of cardiovascular diseases and complications during recovery. Thrombocyte serotonin is a strong vasoconstrictor and the research has shown that the treatment with selective inhibitors of serotonin uptake (SIPPS) causes lowering of its concentration, thus reducing its role in increasing the cardiovascular risk and causing the complications of recovery. Also, the treatment of depressive patients with SIPPS lowers the values of MPV (mean platelet volume, mean thrombocyte cell volume), which had been recognized as an independent risk factor for the development of myocardial infarction and stroke.Serotonin system in thrombocytesEnterochromafine cells are the only cells besides 5HT neurons, that synthetize serotonin. They release it into the blood stream, from where it, bound to its transporter, goes mostly into the thrombocytes. Serotonin system in thrombocytes is very similar to the one in neurons. It is a part of the mechanism of thrombocyte response, which is actually a process of shape change and aggregation of thrombocytes [9,10]. Thrombocytes contain about 99% of total serotonin in circulation, so in physiological conditions, plasma levels of serotonin reflect the concentration of serotonin in thrombocytes. Human throm- bocytes contain averagely 150 to 600 ng of serotonin/109 thrombocytes [11]. Serotonin system of thrombocytes is made of: serotonin transmembrane carrier ( transporter), serotonin receptor, enzyme monoaminooxidase and serotonin stored in delta granules. Serotonin enters the thrombocytes and aggregates through actions of two carriers [12]. Protein 5-HT carrier (5HTt) is located at the membrane of thrombocyte and enables the intake of serotonin and other endogenous amines, for example dopamine, from plasma to the cytoplasmic fluid of thrombocytes [13]. …

Ovariectomy Drives Asynchronous Changes in Serotonin Receptor 2A and Transporter Availability in Rats

Ovarian hormones have potent effects on key features of the serotonergic neurotransmission. This includes effects that may counterbalance each other, e.g. postsynaptic receptor changes and change in serotonin transporter (SERT) levels, which regulates synaptic serotonin. Such mechanisms may be implicated in the heightened risk for depressive episodes seen in perimenopause or postpartum. However, to what extent transition to hypogonadism in it-self drives such serotonin related risk mechanism remains elusive. Here we evaluate if ovarian hormone withdrawal affects postsynaptic serotonin receptor 2A (5-HT2A) and presynaptic SERT availability differently across the early withdrawal phase in ovariectomized (OVXed) relative to sham operated rats. Cortical (prefrontal cortex (PFC)) and subcortical (striatum) 5-HT2A receptor and SERT binding were quantified with autoradiography at 8 and 23 days after ovariectomy (OVX). We observed that 8 and 23 days after withdrawal the level of 5-HT2A receptor binding was decreased relative to sham, while SERT binding was unaltered, however, with a weak trend to decrease at day 23. The dataset available is small and the results should be viewed as preliminary. If replicated, these data highlight a potential phase-specific and predominantly early challenge of serotonergic neurotransmission when ovarian hormone levels decline abruptly, which may translate to the risk for psychopathology, e.g. depressive episodes postpartum or during menopausal transition in humans.

Repeated lysergic acid diethylamide in an animal model of depression: Normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling.

A re-balance of postsynaptic serotonin (5-HT) receptor signalling, with an increase in 5-HT1A and a decrease in 5-HT2A signalling, is a final common pathway multiple antidepressants share. Given that the 5-HT1A/2A agonist lysergic acid diethylamide (LSD), when repeatedly applied, selectively downregulates 5-HT2A, but not 5-HT1A receptors, one might expect LSD to similarly re-balance the postsynaptic 5-HT signalling. Challenging this idea, we use an animal model of depression specifically responding to repeated antidepressant treatment (olfactory bulbectomy), and test the antidepressant-like properties of repeated LSD treatment (0.13 mg/kg/d, 11 d). In line with former findings, we observe that bulbectomised rats show marked deficits in active avoidance learning. These deficits, similarly as we earlier noted with imipramine, are largely reversed by repeated LSD administration. Additionally, bulbectomised rats exhibit distinct anomalies of monoamine receptor signalling in hippocampus and/or frontal cortex; from these, only the hippocampal decrease in 5-HT2 related [(35)S]-GTP-gamma-S binding is normalised by LSD. Importantly, the sham-operated rats do not profit from LSD, and exhibit reduced hippocampal 5-HT2 signalling. As behavioural deficits after bulbectomy respond to agents classified as antidepressants only, we conclude that the effect of LSD in this model can be considered antidepressant-like, and discuss it in terms of a re-balance of hippocampal 5-HT2/5-HT1A signalling.

Differential expression of hypothalamic fear- and stress-related genes in broiler chickens showing short or long tonic immobility

The serotonin system and the hypothalamic-pituitary-adrenal axis play important roles in modulating fear and stress-coping characteristics. Tonic immobility (TI) is a fear-related phenotype, and previously we have shown that broiler chickens showing short TI (STI) duration experience better growth performance and higher adaptability to stress. Here, we sought to further elucidate the central mechanisms underlying the phenotypic differences between chickens showing STI and long TI duration, by comparing the hypothalamic expression of genes in the serotonergic system and the hypothalamic-pituitary-adrenal axis under basal and corticosterone-exposed situations. The STI broilers had significantly lower (P < 0.01) hypothalamic expression of serotonin reuptake transporter and serotonin receptor 1A. Moreover, 11β-hydroxysteroid dehydrogenase type 2 was expressed significantly lower in STI chickens at the level of both mRNA (P < 0.01) and protein (P < 0.05). Hypothalamic expression of glucocorticoid receptor (GR) mRNA tended to be higher (P < 0.059) in long TI chickens, but the protein content was approximately 2 times higher (P < 0.01) in STI chickens. The uncoupled expression of GR mRNA and protein was associated with significantly lower (P < 0.05) expression of gga-miR-181a, gga-miR-211, and gga-miR-22, which are predicted to target GR, in STI chickens. Corticosterone administration reduced the mRNA expression of postsynaptic serotonin receptors, 5-hydroxytryptamine receptor 1B (P = 0.059) and 5-hydroxytryptamine receptor 7 (P < 0.05), yet significantly increased the protein content of 11β-hydroxysteroid dehydrogenase type 2 (P < 0.05). These results suggest that broilers of different TI phenotypes have a distinct pattern of hypothalamic expression of fear- and stress-related genes.

A Case of Galactorrhea With Escitalopram

A Case of Galactorrhea With Escitalopram

In Vivo Imaging of Cerebral Serotonin Transporter and Serotonin2A Receptor Binding in 3,4-Methylenedioxymethamphetamine (MDMA or “Ecstasy”) and Hallucinogen Users

Both hallucinogens and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin. To assess the differential effects of MDMA and hallucinogen use on cerebral serotonin transporter (SERT) and serotonin(2A) receptor binding. A positron emission tomography study of 24 young adult drug users and 21 nonusing control participants performed with carbon 11 ((11)C)-labeled 3-amino-4-[2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile (DASB) and fluorine 18 ((18)F)-labeled altanserin, respectively. Scans were performed in the user group after a minimum drug abstinence period of 11 days, and the group was subdivided into hallucinogen-preferring users (n = 10) and MDMA-preferring users (n = 14). Twenty-four young adult users of MDMA and/or hallucinogenic drugs and 21 nonusing controls. In vivo cerebral SERT and serotonin(2A) receptor binding. Compared with nonusers, MDMA-preferring users showed significant decreases in SERT nondisplaceable binding potential (neocortex, -56%; pallidostriatum, -19%; and amygdala, -32%); no significant changes were seen in hallucinogen-preferring users. Both cortical and pallidostriatal SERT nondisplaceable binding potential was negatively correlated with the number of lifetime MDMA exposures, and the time of abstinence from MDMA was positively correlated with subcortical, but not cortical, SERT binding. A small decrease in neocortical serotonin(2A) receptor binding in the serotonin(2A) receptor agonist users (both user groups) was also detected. We found evidence that MDMA but not hallucinogen use is associated with changes in the cerebral presynaptic serotonergic transmitter system. Because hallucinogenic drugs primarily have serotonin(2A) receptor agonistic actions, we conclude that the negative association between MDMA use and cerebral SERT binding is mediated through a direct presynaptic MDMA effect rather than by the serotonin(2A) agonistic effects of MDMA. Our cross-sectional data suggest that subcortical, but not cortical, recovery of SERT binding might take place after several months of MDMA abstinence.

SEROTONERGIC SYNAPSES MODULATE GENERATION OF SPIKES FROM RETINAL GANGLION CELLS OF TELEOSTS

Serotonin [5-hydroxytryptamine (5-HT)] is a common neurotransmitter/neuromodulator found widely in the nervous system. Cellular morphology and retinal distribution of serotonergic amacrine cells in the channel catfish (Ictalurus punctatus) retina are identified using monoclonal anti-5HT antibody. These cells receive ribbon synapses from OFF-center (hyperpolarizing) bipolar cells as well as conventional synapses with other non-serotonergic amacrine cells. Output synapses from the serotonergic cells are mainly channel onto retinal ganglion cells. Output synapses from the serotonergic cells occur as "the branched synapses" onto the ganglion cell dendrites at the dyads of the ribbon synaptic sites, and are made onto the ganglion cells, apart from the ribbon synapses. Application of serotonin receptor agonist: 5HT(1A) serotonin receptor agonist, (+)-8-hydroxy-dipropylaminotetralin [8-OH-DPAT; 1-10 muM] is also known to activate 5HT(7) serotonin receptor, coupled with activation of adenylate cyclase, generated continuous repetitive spikes from large retinal ganglion cells of the adult goldfish (Carassius auratus) in flat-mounted preparations, using amphotericin-B-perforated patch-clamp. Under control conditions of bleached retina with continuous light illumination, goldfish large retinal ganglion cells had generated only few spikes. This is the first observation of positive neuromodulation promoting retinal ganglion cell excitation in the retina. The results confirm previous reports of a serotonergic system in the mammalian retina. These results support the presence of developed postsynaptic serotonin receptors in cyprinid fish retina together with other physiological and anatomical studies, and suggest that the action of serotonin in the retina may be more important than previously believed.

Serotonergic‐postsynaptic receptors modulate gripping‐induced immobility episodes in male taiep rats

The Taiep rat is a myelin mutant with a motor syndrome characterized by tremor, ataxia, immobility, epilepsy, and paralysis. The rat shows a hypomyelination followed by a progressive demyelination. During immobilities taiep rats show a REM-like sleep pattern and a disorganized sleep-wake pattern suggesting taiep rats as a model of narcolepsy-cataplexy. Our study analyzed the role of postsynaptic serotonin receptors in the expression of gripping-induced immobility episodes (IEs) in 8-month-old male taiep rats. The specific postsynaptic serotonin agonist +/-1-(2,5-dimethoxy-4-iodoamphetamine hydrochloride (+/-DOI) decreased the frequency of gripping-induced IEs, but that was not the case with alpha-methyl-serotonin maleate (alpha-methyl-5HT), a nonspecific postsynaptic agonist. Although the serotonin antagonists, ketanserine and metergoline, produced a biphasic effect, first a decrease followed by an increase with higher doses, similar effects were obtained with a mean duration of gripping-induced IEs. These findings correlate with the pharmacological observations in narcoleptic dogs and humans in which serotonin-reuptake inhibitors improve cataplexy, particularly in long-term treatment that could change the serotonin receptor levels. Polysomnographic recordings showed an increase in the awakening time and a decrease in the slow wave and rapid eye movement sleep concomitant with a decrease in immobilities after use of +/-DOI, this being stronger with the highest dose. Taken together, our results show that postsynaptic serotonin receptors are involved in the modulation in gripping-induced IEs caused by the changes in the organization of the sleep-wake cycle in taiep rats. It is possible that specific agonists, without side effects, could be a useful treatment in human narcoleptic patients.

Perimenopausal Depression

Perimenopausal Depression

Recent Findings and Current Status of Augmentation Strategies

Augmentation strategies have become popular in patients with a partial response or residual symptoms. In a survey conducted by the American Society of Consultant Pharmacists, 65% of 169 psychiatrists indicated that they would augment treatment as the next step in a partial responder in contrast to non-responders in whom they would switch to another drug (J.C. Nelson, unpublished data). This decision is based on common sense and practicality rather than empirical evidence. Many clinicians and patients think that if a patient achieves at least a partial response to a medication, it makes sense to continue that drug and add a second. To some extent, the patient preferences for treatment shown in the Systematic Treatment Alternatives to Relieve Depression (STAR*D) study reflect this approach. This discussion will update clinicians on the use of augmentation agents for the treatment of major depressive disorder (MDD).Lithium augmentation has been used since it was first described by de Montigny and colleagues in 1981. This strategy is based on a rational neurochemical hypothesis that lithium has a synergistic effect when added to a tricyclic antidepressant (TCA). Lithium increases serotonin turnover and the TCA increases postsynaptic serotonin receptor sensitivity. Recent debates have focused on whether lithium is as effective combined with selective serotonin reuptake inhibitors (SSRIs) as it is combined with a TCA. The rapid effects sometimes observed with lithium augmentation of TCAs does not seem to occur with SSRIs, conceivably because SSRIs do not increase postsynaptic serotonin receptor sensitivity.

Does trazodone have a role in palliating symptoms?

Trazodone is a unique antidepressant, which blocks the postsynaptic serotonin (5-HT) receptors, 5-HT(2A) and 5-HT(2C), and weakly inhibits presynaptic 5-HT transporters. Trazodone is well-absorbed by the mouth and is metabolized by three cytochromes: CYP1A2, CYP2D6, and CYP3A4. Clinical benefits include reduced insomnia in those depressed and/or on antidepressants. Pain may be relieved by mechanisms similar to venlafaxine. Delirium unresponsive to neuroleptics has been reported to respond to trazodone. Drug interactions are a risk due to cytochrome metabolism. Trazodone has a unique pharmacology, which may be an advantage in palliating symptoms; however, little evidence is available through cohort or randomized trials to give guidance to its use.

La place des antipsychotiques atypiques dans le traitement des syndromes dépressifs

Depression is a frequent symptom in psychiatry, either isolated (major depression) or entangled with other psychiatric symptoms (psychotic depression, depression of bipolar disorders). Many antidepressant drugs are available with different pharmacological profiles from different classes: tricyclic antidepressants, monoamine oxydase inhibitors, selective serotonin reuptake inhibitors (SSRI). However, there are some limitations with these drugs because there is a long delay before relief for symptoms, some patients with major depression are resistant to treatment, there is a risk to induce manic symptoms in patients with bipolar disorders and these drugs have no effect on the psychotic symptoms frequently associated to major depression. The leading hypothesis for the search of more efficient new antidepressants has been the amine deficit hypothesis: noradrenaline and/or serotonin deficit and more recently dopamine deficit. Moreover, a dopamine deficit has been also hypothesized as the central mechanism explaining the negative symptoms of schizophrenia. These symptoms are the consequence of a deficit of normal behaviours and include affective flattening, alogia, apathy, avolition and social withdrawal. There is thus a great overlap between symptoms of depression and negative symptoms of schizophrenia. Atypical antipsychotics, in contrast with conventional neuroleptics, have been shown to decrease negative symptoms, most probably through the release of dopamine in prefrontal cortex, thus improving psychomotor activity, motivation, pleasure, appetite, etc. The dopamine deficit in cortical prefrontal areas was thus an unifying hypothesis to explain both some symptoms of depression and negative symptoms of schizophrenia. Studies in animal confirm this view and show that the association of an atypical antipsychotic drug and an SSRI (olanzapine plus fluoxetine) increases synergistically the release of dopamine in prefrontal areas. Moreover, most of the atypical antipsychotics have a large action spectrum, beyond the only dopamine receptors: their effects on the serotonin receptors--particularly the 5-HT2A and 5-HT2C receptors--suggest that their association to SSRI could be a promising treatment for depression. Indeed, SSRI act mainly by increasing the serotonin level in the synapse, thus leading to a non specific activation of all pre- and post-synaptic serotonin receptors. Among them, 5-HT2A/2C receptors have been involved in some of the unwanted effects of SSRI: agitation, anxiety, insomnia, sexual disorders, etc. The inhibition of these receptors could be thus beneficial for patients treated with SSRI. Amisulpride is an unique atypical antipsychotic that selectively blocks dopamine receptors presynaptically in the frontal cortex, possibly enhancing dopaminergic transmission. The antidepressant effect of amisulpride was shown in dysthymia in many clinical studies versus placebo, tricyclic antidepressants, SSRI or others. However, a shorter delay for symptom relief was not demonstrated for amisulpride as compared to comparative antidepressants. Other atypical antipsychotics (clozapine, olanzapine), which act on a large variety of receptors, have shown antidepressant effects--mainly in association with SSRI--in different psychiatric diseases: treatment-resistant major depression, major depression with psychotic symptoms and depression of bipolar disorders, with no increase of manic symptoms in this latter case. Moreover, the delay for symptom relief was greatly shortened. More comparative double-blind studies are required to confirm and to precise the antidepressant effects of atypical antipsychotics. Nevertheless, these studies suggest that atypical anti-psychotics could be of great value in depressive conditions reputed for their resistance to treatment with usual antidepressants. Particularly, new strategies emerge that combine atypical antipsychotics and antidepressants for greater efficacy and more rapid relief of depression symptoms.

Neurobiologie et pharmacothérapie de la phobie sociale

Resume Bien que Marks ait propose des 1970 une classification des phobies comprenant la phobie sociale, l’apparition de l’entite diagnostique phobie sociale est encore plus recente. Elle a lieu en 1980 avec le DSM III, 3e edition de la nomenclature de l’American Psychiatric Association, qui etablit des criteres operationnels pour son diagnostic. De ce fait, les recherches visant a identifier les facteurs genetiques, familiaux et temperamentaux, les correlats neurochimiques et neuroendocriniens ainsi que les structures cerebrales s’inscrivant dans la pathogenie de ce trouble en sont a leur debut. Neanmoins, elles ont permis d’apprecier l’intervention des influences genetiques, du milieu familial, et de traits temperamentaux, comme l’inhibition comportementale face a l’inconnu, dans le risque d’apparition d’une phobie sociale. Elles ont egalement contribue a mettre en evidence des perturbations du fonctionnement des systemes de neurotransmission monoaminergique dans la phobie sociale. Parallelement, les progres realises dans l’analyse des relations structure-fonction, et notamment l’apport recent de la neuro-imagerie, ont souligne l’importance des voies cortico-limbiques dans la physiopathologie de la phobie sociale, avec la participation de regions et structures cerebrales comme le cortex prefrontal, l’hippocampe, l’amygdale et le striatum. Ceci n’a rien de surprenant si l’on considere leur role essentiel dans la signification attribuee aux informations emanant de l’environnement, les processus emotionnels, mnesiques et de conditionnement contextuel, ainsi que dans la programmation des comportements dont on peut supposer l’alteration a la lumiere des symptomes caracteristiques de la maladie. La demarche pharmacotherapique aujourd’hui proposee repose sur l’efficacite demontree d’agents medicamenteux, au premier rang desquels figurent les inhibiteurs selectifs de la recapture de la serotonine dont l’emploi peut aujourd’hui prevaloir sur celui d’autres produits egalement actifs, comme les inhibiteurs de la monoamine oxydase non selectifs et irreversibles ou les benzodiazepines, de par la simplicite de leur utilisation et leur tres bonne tolerance.

No effect of MDMA (ecstasy) on cell death and 5-HT 2A receptor density in organotypic rat hippocampal cultures

MDMA (3,4 Methylenedioxy-methamphetamine) binds and blocks the presynaptic serotonin reuptake transporters and postsynaptic serotonin 5-HT 2A receptors, with highest affinity for the first. Whether 5-HT 2A receptor density decreases due to MDMA's direct effect on postsynaptic serotonin receptors is at present not known. This study analyzes whether direct stimulation of the postsynaptic 5-HT 2A receptor by MDMA in organotypic hippocampal cultures results in cell death and downregulation of this receptor. Fifty or 100 μM MDMA was added to 1 week old cultures, made of 11 day old rat pups. Fluorojade and immunostaining for MAP2 and 5-HT 2A to determine neurodegeneration, and changes in receptor density, respectively, resulted in no significant differences. MDMA's neurotoxicity and regulation of post-synaptic 5-HT 2A receptors thus seems to require the presence of intact serotonergic terminals.

Serotonin agonists and antagonists in obstructive sleep apnea: therapeutic potential.

Obstructive sleep apnea hypopnea syndrome (OSAHS) is a prevalent disorder associated with substantial cardiovascular and neurobehavioral morbidity. Yet this is a disorder for which there are no widely effective pharmacotherapies. The pathophysiology of obstructive sleep apnea namely, normal respiration in waking with disordered breathing only in sleep, suggests that this disorder should be readily amenable to drug therapy. Over the past 10 years, we have gained tremendous insight into the neurochemical mechanisms involved in state-dependent control of respiration. It is apparent from this work that there are many potential avenues for pharmacotherapies, including several seemingly conflicting directions for serotonergic therapies. Serotonin delivery is reduced to upper airway dilator motor neurons in sleep, and this contributes, at least in part, to sleep-related reductions in dilator muscle activity and upper airway obstruction. The dilator motor neuron post-synaptic serotonin receptors are 5-HT(2A) and 5-HT(2C) subtypes, and in adults the presynaptic 5-HT receptor in motor nuclei is 5-HT(1B), an inhibitory receptor. Serotonin receptors are also found within central respiratory neuronal groups, and these receptor subtypes include 5-HT(1A) (inhibitory) and 5-HT(2) receptors. Peripherally, stimulation of 5-HT(2A), 5-HT(2C) and 5-HT(3) receptor subtypes have an inhibitory effect on respiration via action at the nodose ganglion. Many of these receptor subtypes and their signal transduction pathways may be affected by oxidative stress in obstructive sleep apnea. These alterations will make finding drug therapies for sleep apnea more challenging, but not insurmountable. Future directions are suggested for elucidating safe, well-tolerated serotonergic drugs for this disorder. Tryptophan was one of the first serotonergic drugs tested for OSAHS. This drug was withdrawn from the market as a result of reports linking tryptophan use with eosinophilic myalgia syndrome and life-threatening pulmonary hypertension. Newer drugs with serotonergic activity tested in persons with sleep-disordered breathing include buspirone, fluoxetine and paroxetine. Trials are presently being conducted to evaluate the effects of 5-HT(2A) and 5-HT(3) antagonists on OSAHS. Many of the drugs tested have not shown significant improvement in sleep apnea. However, with continued effort to elucidate the pharmacology of neurochemical control of state-dependent changes in respiratory control, the availability of pharmacological therapy for this disorder is not too far away.

Genes May Play Key Role In Impulsive Aggression in BPD

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessGenes May Play Key Role In Impulsive Aggression in BPDChristine LehmannChristine LehmannSearch for more papers by this authorPublished Online:17 Jan 2003https://doi.org/10.1176/pn.38.2.0020Recent research suggests that people with borderline personality disorder may be genetically predisposed to the disorder and impulsive aggression.“Impulsive acts of verbal and/or physical aggression are associated with domestic violence, workplace violence, and crimes involving physical assaults. Impulsive aggression has also been associated with personality disorders and is a major research focus because of the dire social consequences,” said Antonia New, M.D., an assistant professor of psychiatry at Mount Sinai School of Medicine/Bronx VA Medical Center.New presented the research at a conference on borderline personality disorder last month in Bethesda, Md. The conference was organized by the Treatment and Research Advancements Association for Personality Disorder.Twin studies have shown that the genetic contribution to borderline personality disorder is about 60 percent. The genetic contribution to impulsive aggression is estimated to be between 20 percent and 62 percent, said New.She looked for candidate genes in the serotonergic system based on previous findings from studies that have consistently shown a decreased neuroendocrine response to serotonergic agents in impulsive aggression. In one study involving the serotonergic agent d,l-fenfluramine, there was a decreased prolactin response in patients with impulsive aggression, suggesting abnormal functioning of serotonin receptors, according to New.However, a decreased prolactin response to fenfluramine was found most often in people with personality disorder who had attempted suicide and engaged in self-destructive behaviors, according to a study by New and other researchers published in the March 1997 Psychiatry Research. New told Psychiatric News that suicide attempts and self-injurious behaviors represent self-directed aggression.In addition, the results of a brain imaging study by New and colleagues at Mount Sinai/Bronx VA showed that regions of the brain that inhibit aggression were not activated by a serotonergic agent, meta-chloropiperazine, in impulsive aggressive patients with personality disorders in contrast to normal controls (see story on Original article: page 29). The study was published in the July 2002 Archives of General Psychiatry.New hypothesized that multiple genes and environmental factors contributed to the susceptibility involved in the complex behavior of impulsive aggression. “In this model, each gene provides a small contribution toward the susceptibility to impulsive aggression.”She studied two candidate serotonin genes in large samples of patients with personality disorders. The first study looked at HTR1B, a gene with a presynaptic receptor that regulates and synthesizes serotonin. The study, published in the July 1, 2001, issue of Biological Psychiatry, had a sample size of about 90 subjects with personality disorders.“Previous studies of mice found that the ones lacking HTR1B displayed more aggressive behaviors than the mice with HTR1B,” said New.She did not find a similar association between HTR1B and impulsive aggression in human subjects. She found, however, that subjects with a G-allele variant of the gene had a higher number of suicide attempts compared with subjects with a C-allele variant of the gene.An unpublished second study by New looked at HTR2A, a gene with a postsynaptic serotonin receptor that is widely distributed in the neocortex of the brain. The study involved nearly 140 subjects with personality disorders, she said.“The results showed that subjects with an unexpressed variant of the gene had higher rates of self-injurious acts than subjects with an expressed variant of the gene,” said New.“These preliminary findings show how subtle genetic variations of a serotonin receptor gene can increase or decrease susceptibility to behaviors associated with borderline personality disorder,” said New.She emphasized that the gene candidate association findings are preliminary and need to be replicated.“We plan to look at brain responses to provocation in patients with impulsive aggression to determine whether there are a smaller number of underlying genes that create susceptibility. This means that when we do candidate gene studies, genotyping of patients, and relating those genotypes to brain imaging results, we are more likely to find a reproducible finding,” said New. ▪ ISSUES NewArchived

Pre- and postsynaptic responses to 1-(1-naphthylpiperazine) following adaptation to stress in rats

In view of a role of pre- and postsynaptic serotonin (5-hydroxytryptamine; 5-HT) receptors in adaptation to stress, effects of 1-(1-naphthylpiperazine) (1-NP) were compared in unrestrained and repeatedly restrained adapted rats. In the first part of the study, effects of various doses (1.0–15 mg/kg ip) of 1-NP were monitored on brain 5-HT metabolism (presynaptic response) and on the activity (postsynaptic response) of rats in an activity cage to which the rats were habituated before the drug administration. The drug injected at doses of 2.5–15.0 mg/kg increased motor activity and decreased brain 5-hydroxyindoleacetic acid (5-HIAA) concentration in a dose-dependent manner. In the second part of the study, rats were restrained on wire grids 2 h/day for 5 days. First-day episode of 2-h restraint decreased 24-h cumulative food intake, water intake and growth rate. The decreases attenuated following second-, third- and fourth-day episodes of 2-h restraint were not observed following fifth-day episode of 2-h restraint stress, suggesting adaptation to the stress schedule has occurred. Serotonergic and motor responses to 1-NP in unrestrained and repeatedly restrained adapted rats were compared by injecting the drug at a dose of 5 mg/kg, a dose that above results suggested would not produce maximal effects on 5-HT metabolism or motor activity. Administration of 1-NP at a dose of 5 mg/kg increased motor activity and decreased brain 5-HIAA concentration in unrestrained and repeatedly restrained adapted rats. Increases of motor activity were much greater in repeatedly restrained adapted than unrestrained rats. Decreases of 5-HIAA concentration were comparable in the two groups. The results are discussed in the context of an increase in the effectiveness of postsynaptic 5-HT-1A and 5-HT-1B receptors and a decrease in the effectiveness of presynaptic 5-HT-1A (somatodendritic) and 5-HT-1B (terminal) receptors following adaptation to stress. It is suggested that these changes of receptor responsiveness might help coping with stress demand to produce adaptation to stress.

Chronic clomipramine alters presynaptic 5-HT 1B and postsynaptic 5-HT 1A receptor sensitivity in rat hypothalamus and hippocampus, respectively

Clomipramine is a tricyclic antidepressant drug with a high affinity for the serotonin (5-HT) uptake site or transporter. Electrophysiological experiments have provided evidence that repeated administration of clomipramine induces an increase in the sensitivity of postsynaptic 5-HT 1A receptors in the hippocampus. We have studied the effects of clomipramine, administered to rats at a dose of 10 mg/kg/day for 28 days by osmotic minipumps, on presynaptic 5-HT 1A and 5-HT 1B autoreceptors in the hypothalamus, and on postsynaptic 5-HT 1A receptors in the hippocampus, by using in vivo microdialysis to measure 5-HT and cyclic adenosine monophosphate (cAMP) levels. Postsynaptic 5-HT 1A receptor sensitivity in the hypothalamus was determined by means of a neuroendocrine challenge procedure. Although the sensitivity of presynaptic 5-HT 1A autoreceptors, as measured by the effect of a subcutaneous (s.c.) injection of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.2 mg/kg or 50 μg/kg) to reduce 5-HT levels, did not change, there was a reduction in sensitivity of presynaptic 5-HT 1B receptors, as measured by the effect of an injection of the 5-HT 1B/1D antagonist GR 127935 (5 mg/kg, s.c.) to increase 5-HT levels. This effect probably accounted for the increase in basal 5-HT levels observed in the hypothalamus after chronic clomipramine administration. Postsynaptic 5-HT 1A receptor sensitivity in the hippocampus, measured by the effect of 8-OH-DPAT to increase cAMP levels in the dialysate, was increased after chronic clomipramine. Animals that had received daily intraperitoneal injections of 10 mg/kg clomipramine for 28 days did not show a change in postsynaptic 5-HT 1A receptor sensitivity in the hypothalamus as measured by the ability of 8-OH-DPAT (50 μg/kg, s.c.) to stimulate secretion of corticosterone. Taken together with the results of previous experiments involving the cerebral cortex, these in vivo results show that chronic clomipramine exerts effects on both pre- and postsynaptic serotonin receptors, but that these effects are highly region-specific.

Serotonin Syndrome in a Child After a Single Dose of Fluvoxamine

Serotonin syndrome, a potentially fatal iatrogenic complication of psychopharmacologic therapy, is most commonly reported with combinations of serotonergic medications. Serotonin syndrome is characterized by alterations in cognition, behavior, autonomic, and central nervous system function as a result of increased postsynaptic serotonin receptor agonism. We present the first reported case of serotonin syndrome after a single dose of fluvoxamine in a pediatric patient after ingestion of a single supratherapeutic dose of fluvoxamine. [Gill M, LoVecchio F, Selden B: Serotonin syndrome in a child after a single dose of fluvoxamine. Ann Emerg Med April 1999;33:457-459.]

Involvement of serotonin and dopamine in the mechanism of action of novel antidepressant drugs: a review.

Several hypotheses regarding the physiopathology of major depression exist. Attention has been focused on cerebral monoaminergic systems, the dysfunction of which is thought to underlie various aspects of depressive symptomatology. There is extensive literature describing the involvement of serotonergic and dopaminergic systems in the mechanism of action of antidepressant drugs. However, a unitary analysis of the data in terms of interaction between different monoaminergic systems is still lacking. In this article, studies reporting the biochemical, behavioral, and clinical effects of tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), selective blockers of presynaptic dopamine (DA) receptors, and antagonists of serotonin-2 (5-hydroxytryptamine-2 [5-HT2]) receptors were reviewed. Analysis of the current literature indicates that long-term treatment with antidepressants causes adaptive changes of the serotonergic and dopaminergic systems. In particular, long-term administration of TCAs enhances the responsiveness of postsynaptic serotonin receptors to iontophoretically applied serotonin and potentiates the behavioral responses to both direct and indirect dopaminergic agonists. Repeated administration of SSRIs and MAOIs increases serotonergic transmission by desensitizing the inhibitory 5-HT1A somatodendritic and terminal 5-HT1B/1D autoreceptors. Selective blockers of DA autoreceptors exert their antidepressant effect by enhancing DA release. A similar mechanism of action could be hypothesized for 5-HT2 receptor antagonists. There is general agreement that the clinical effect of antidepressant drugs, which becomes evident only after long-term treatment, is caused by their ability to induce adaptive changes of the monoaminergic systems. Increases in both serotonergic and dopaminergic function have been consistently found after long-term treatment with various classes of antidepressant drugs. Recent studies have focused on the functional interaction between the serotonergic and dopaminergic systems to explain the mechanism of the antidepressant action of SSRIs and 5-HT2 antagonists.