Serotonergic ergoline derivatives

Novel classes of 13- and 14-tertbutyl-ergoline derivatives were prepared, and characterised in vitro for their affinity for adrenergic, dopaminergic and serotonergic binding sites. This study particularly examines the importance of the presence and the position of the tert-butyl group in conferring either significant 5-HT1A or 5-HT2 affinity and selectivity respectively.     

Serotonergic regulation of adrenocortical function

Serotonin (5-HT) plays a pivotal role in the regulation of the hypothalamo-pituitary-adrenal axis. In particular, 5-HT is involved in the stimulation of ACTH secretion during stress. Recent data indicate that, at the adrenal level, 5-HT acts as a local regulator of corticosteroid secretion. The presence of 5-HT in the adrenal gland has been demonstrated immunohistochemically and biochemically in various species including frog, mouse, rat and human. In the mouse, 5-HT has been detected in nerve fibers while, in the frog and rat, 5-HT appears to be sequestered in chromaffin cells. In man, 5-HT is stored in perivascular mast cells. In vivo and in vitro studies have shown that 5-HT stimulates mineralo- and glucocorticoid secretion from adrenal cells. In rat, the type of receptor involved in the corticotropic effect of 5-HT is still controversial. In the frog and the human, the effect of 5-HT on the adrenal cortex is mediated through a 5-HT4 receptor subtype positively coupled to adenylyl cyclase and calcium influx. Clinical studies indicate that 5-HT4 receptor agonists stimulate aldosterone secretion in healthy volunteers and in patients with aldosterone disorders. The 5-HT4 receptor agonist cisapride and angiotensin II exert additive effects on aldosterone secretion. In contrast, cisapride has no influence on ACTH-induced aldosterone release. Collectively, these findings suggest that intra-adrenal 5-HT stimulates the secretory activity of adrenocortical cells through a paracrine mode of communication involving a 5-HT4 receptor type. Serotonergic control of corticosteroid production may be involved in the physiological control of the activity of the adrenal cortex, in particular during inflammatory stress. 5-HT may also be implicated in the pathophysiology of aldosterone disorders.     

Serotonergic modulation of acetylcholine release from cortex of freely moving rats

The modulation of acetylcholine (ACh) release by 5-HT3 receptor activation was studied using in vivo microdialysis. Spontaneous and K+-stimulated ACh release were measured in frontoparietal cortex and hippocampus of freely moving rats. Two consecutive exposures to high K+ produced ACh release of similar magnitude. In the cortex, serotonin (5-HT) failed to alter spontaneous ACh release, but caused a concentration-dependent decrease of K+-evoked ACh release. Phenylbiguanide (PBG) and m-chlorophenylbiguanide, two selective 5-HT3 agonists, mimicked the 5-HT responses, but 8-hydroxy-2-(di-n-propylamino)tetralin, a selective 5-HT1A agonist, was without effect. However, PBG failed to modify K+-evoked ACh release from the hippocampus. Systemic and local administration of a highly selective 5-HT3 antagonist, tropisetron ((3-alpha-tropanyl)1H-indole-carboxylic acid ester) blocked the effect of both 5-HT and PBG. The inhibition of ACh release by PBG was sensitive to tetrodotoxin. These observations provide direct evidence that, in rat cortex, 5-HT modulates in-vivo release of ACh through activation of 5-HT3 receptors.     

Serotonergic functioning in depressed abused children: clinical and familial correlates

BACKGROUND: The goal of this study was to examine serotonergic functioning and concomitant clinical and familial correlates in depressed abused children. METHODS: L-5-Hydroxytryptophan (L-5-HTP) (0.8 mg/kg) was administered intravenously to 10 depressed abused (MDD-AB), 10 depressed nonabused (MDD-NA), and 10 normal control nonabused (NC-NA) children. The children in the two nonabused cohorts represent a small matched subset of children from a larger interlocking study of the psychobiology of depression. Blood samples for prolactin and cortisol were collected from 30 min before to 2.5 hours after L-5-HTP infusion. RESULTS: The MDD-AB children secreted significantly more prolactin post-L-5-HTP than the children in the other two groups. There were no differences in baseline prolactin or any of the cortisol measures. Total prolactin post-L-5-HTP was significantly correlated with clinical ratings of aggressive behavior (rho = .48). In addition, children with a family history positive for suicide attempt (MDD-AB: n = 7; MDD-NA: n = 5; NC-NA: n = 2) secreted significantly more prolactin post-L-5-HTP than children with no family history of suicide. CONCLUSIONS: Dysregulation in the serotonergic system in abused children appears to be related to both familial and experiential factors.     

Serotonergic function and negative and depressive symptomatology in schizophrenia and major depression

BACKGROUND: Serotonergic abnormalities are found in both major depressive disorder (MDD) and schizophrenia. Depressive symptoms commonly occur alongside the negative or defect symptoms in schizophrenia and antiserotonergic drugs may be particularly effective in their treatment. We wished to explore whether these symptoms could be distinguished biologically by directly comparing serotonergic function in these two illnesses. METHOD: Fifteen patients with MDD and 13 patients with schizophrenia underwent testing with the specific serotonin releasing agent D-fenfluramine (D-FEN). Prolactin and cortisol responses were measured to ascertain central serotonergic function. Individual patient results were compared with their own carefully matched control to correct for the effect of age, sex, weight and menstrual cycle, before the two patient groups were then compared. RESULTS: Prolactin responses differed significantly between the two patient groups, being lower in MDD patients and higher in schizophrenia patients than their individually matched controls. Cortisol responses did not differ. Within the schizophrenia group, increased serotonergic function correlated positively with depressive symptoms, but there was no such correlation with defect symptoms. Depressive scores were negatively correlated with the presence of negative symptoms in the schizophrenic group. CONCLUSIONS: Schizophrenia and MDD have distinct and opposite neuroendocrine responses to D-FEN. There is no evidence that depressive symptoms in these two conditions have a common serotonergic basis. Moreover, these responses distinguished between negative and depressive symptoms in our schizophrenic group.     

Serotonergic innervation of the hypothalamic suprachiasmatic nucleus and photic regulation of circadian rhythms

Converging lines of evidence have firmly established that the hypothalamic suprachiasmatic nucleus (SCN) is a light-entrainable circadian oscillator in mammals, critically important for the expression of behavioral and physiological circadian rhythms. Photic information essential for the daily phase resetting of the SCN circadian clock is conveyed directly to the SCN from retinal ganglion cells via the retinohypothalamic tract. The SCN also receives a dense serotonergic innervation arising from the mesencephalic raphe. The terminal fields of retinal and serotonergic afferents within the SCN are co-extensive, and serotonergic agonists can modify the response of the SCN circadian oscillator to light. However, the functional organization and subcellular localization of 5HT receptor subtypes in the SCN are just beginning to be clarified. This information is necessary to understand the role 5HT afferents play in modulating photic input to the SCN. In this paper, we review evidence suggesting that the serotonergic modulation of retinohypothalamic neurotransmission may be achieved via at least two different cellular mechanisms: 1) a postsynaptic mechanism mediated via 5HT1A or 5ht7 receptors located on SCN neurons; and 2) a presynaptic mechanism mediated via 5HT1B receptors located on retinal axon terminals in the SCN. Activation of either of these 5HT receptor mechanisms in the SCN by specific 5HT agonists inhibits the effects of light on circadian function. We hypothesize that 5HT modulation of photic input to the SCN may serve to set the gain of the SCN circadian system to light.     

Serotonergic repression of mitogen-activated protein kinase control of the calcitonin gene-related peptide enhancer

We have investigated the mechanisms underlying regulation of the calcitonin gene-related peptide (CGRP) cell-specific enhancer. Recently, we reported that this enhancer is inhibited by serotonin type-1 (5-HT1) agonists, similar to currently used antimigraine drugs. We have now tested whether this repression involves a mitogen-activated protein (MAP) kinase pathway. We first demonstrate that the CGRP enhancer is strongly (10-fold) activated by a constitutively active MAP kinase kinase (MEK1), yielding reporter activities 100-fold above the enhancerless control. The involvement of a MAP kinase pathway was confirmed by down-regulation of reporter activity upon cotransfection of a dominant negative Ras. Activation of the enhancer by MEK1 was blocked in a dose-dependent manner by the 5-HT1 receptor agonist CGS 12066A (CGS). Since it is not known whether the CGRP enhancer factors are immediate targets of MAP kinases, we then used EIk-1- and c-Jun-dependent reporter genes that are directly activated by the ERK (extracellular signal-regulated kinases) and JNK (c-Jun N-terminal kinase) MAP kinases. CGS treatment repressed the activation of both of these reporters, suggesting that at least two MAP kinases are the immediate targets of CGS-mediated repression. We further demonstrate that 5-HT1 agonists inactivate ERK by dephosphorylation, even in the presence of constitutively activated MEK1. This inactivation appears to be due to a marked increase in the level of MAP kinase phosphatase-1. These results have defined a novel and general mechanism by which 5-HT1 receptor agonists can repress MAP kinase activation of target genes, such as CGRP.     

Serotonergic and noradrenergic markers of post-traumatic stress disorder with and without major depression

Some studies have suggested that disorders in the peripheral and central metabolism of serotonin (5-HT) and noradrenaline (NE) may play roles in the pathophysiology of post-traumatic stress disorder (PTSD). This study examines (1) the availability of plasma total tryptophan, the precursor of 5-HT, and tyrosine, the precursor of NE; and (2) the platelet 5-HT transporter and alpha 2-adrenoceptor (alpha 2-AR) binding sites in patients with PTSD and healthy volunteers. High-performance liquid chromatography (HPLC) was employed to measure plasma tryptophan and tyrosine as well as amino acids known to compete with the same cerebral transport system; that is, valine, leucine, phenylalanine, and isoleucine. The maximum number of binding sites (Bmax) and their affinity (Kd) for binding to [3H]-paroxetine and [3H]-rauwolscine, a selective alpha 2-AR antagonist, were determined. [3H]-paroxetine and [3H]-rauwolscine binding Kd values were significantly higher in patients with PTSD than in healthy volunteers. [3H]-rauwolscine binding Kd values were significantly higher in patients with PTSD and concurrent major depression (MD) than in PTSD patients without MD and healthy volunteers. Plasma tyrosine concentrations and the ratio of tyrosine/valine + leucine + isoleucine + phenylalanine + tryptophan were significantly higher in PTSD patients with MD than in those without MD and healthy volunteers. The results show that PTSD is accompanied by lower affinity of paroxetine binding sites and that PTSD with concurrent MD is accompanied by lower affinity of alpha 2-ARs and increased plasma tyrosine availability to the brain. The results suggest that (1) serotonergic mechanisms, such as defects in the 5-HT transporter system, may play a role in the pathophysiology of PTSD; and (2) that catecholaminergic mechanisms, such as increased precursor availability and lowered affinity of alpha 2-ARs, may play a role in the pathophysiology of PTSD with concurrent MD.     

Serotonergic agents in the treatment of acute neuroleptic-induced akathisia: open-label study of buspirone and mianserin

It has been suggested that dopamine/serotonin (5-HT) imbalance, with relative enhancement of serotonergic activity, might be one of the possible pathophysiological mechanisms underlying neuroleptic-induced akathisia. On the basis of preclinical data, which imply that the partial 5-HT1A agonist buspirone possesses anti-5-HT activity, in the present open-label study we examined the putative antiakathitic effect of buspirone in 10 neuroleptic-treated patients with acute neuroleptic-induced akathisia. Buspirone (up to 30 mg/day in divided doses) was administered for a trial period of 4 days (first part of the study). No significant changes in neuroleptic-induced akathisia as rated using the Barnes Akathisia Scale were detected during buspirone treatment. Buspirone was effective in only two neuroleptic-induced akathisia patients and caused worsening of akathisia in the other two patients. According to the study design, eight buspirone non-responders were switched to the 5-HT2A/2C antagonist mianserin (15 mg/day) for the other 4 days of treatment (second part of the study). Seven mianserin-treated patients improved and five revealed complete disappearance of neuroleptic-induced akathisia. It seems that the 5-HT1A partial agonist buspirone is of limited value in the treatment of acute neuroleptic-induced akathisia. It contrast, it appears that low-dose mianserin is therapeutically effective in acute neuroleptic-induced akathisia.     

Serotonergic neurons differentially modulate the efficacy of two motor neurons innervating the same muscle fibers in Aplysia

Feeding behavior in Aplysia shows substantial plasticity. An important site for the generation of this plasticity is the modulation of synaptic transmission between motor neurons and the buccal muscles that generate feeding movements. We have been studying this modulation in the anterior portion of intrinsic buccal muscle 3 (I3a), which is innervated by two excitatory motor neurons and identified serotonergic modulatory neurons, the metacerebral cells (MCCs). We have shown previously that serotonin (5-HT) applied selectively to the muscle potently modulates excitatory junction potentials (EJPs) and contractions. All the effects of 5-HT were persistent, lasting many hours after wash out. We examined whether the release of endogenous 5-HT from the MCC could produce effects similar to the application of 5-HT. Stimulation of the MCCs did produce similar short-term effects to the application of 5-HT. MCC stimulation facilitates EJPs, potentiates contractions, and decreases the latency between the onset of a motor neuron burst and the onset of the evoked contraction. The effects of MCC stimulation reached a maximum at quite low firing frequencies, which were in the range of those previously recorded during feeding behavior. The maximal effects were similar to those produced by superfusion with approximately 0.1 microM 5-HT. Although the effects of MCC stimulation on EJPs were persistent, they were less persistent than the effects of 0.1 microM 5-HT. Mechanisms that may account for differences in the persistence between released and superfused 5-HT are discussed. Thus activity in the MCCs has dramatic short-term effects on the behavioral output of motor neurons, increasing the amplitude and relaxation rate of contractions evoked by both B3 and B38 and shifting the temporal relationship between B38 bursts and evoked contractions.     

Serotonergic and cholinergic involvement in habituation of activity and spontaneous alternation of rats in a maze.

Studied the effects of drug administration to 220 male Sprague-Dawley rats on spontaneous alternation (SA) in a -maze which Ss were permitted to freely explore for 8-min sessions. Results show that SA was not affected by administration of methysergide or the serotonin (5-HT) depletors DL-chloroamphetamine (PCA) and DL-p-chlorophenylalanine (PCPA). However, either LSD, or d-amphetamine in combination with methysergide, PCA, or PCPA interfered with SA. Scopolamine also disrupted SA, but pretreatment with 5-hydroxytryptophan or amphetamine blocked this action. Amphetamine reversal of the scopolamine-induced disruption of SA did not occur in Ss depleted of 5-HT or pretreated with methysergide. Amphetamine disrupted habituation of exploratory activity alone or after PCPA or PCA. PCPA or PCA alone did not affect habituation. Scopolamine interfered with habituation of activity. Methysergide caused an increase in the initial activity level, while LSD produced a dose-dependent decrease. (34 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Serotonergic dysfunction in addiction: effects of alcohol, cigarette smoking and heroin on platelet 5-HT content

A total of eight different hydroxy carotenoids were produced in transformants of the non-carotenogenic bacterium Escherichia coli. They include the acyclic 1-hydroxyneurosporene, 1-hydroxylycopene, 1,1'-dihydroxylycopene and demethylspheroidene as well as the cyclic 3-hydroxy-beta-zeacarotene, 7,8-dihydrozeaxanthin, 3 or 3'-7,8-dihydro-beta-carotene and 1'-hydroxy-gamma-carotene. Most of these uncommon carotenoids are found only in trace amounts in natural sources. For the synthesis of all the carotenoids mentioned above, E. coli was transformed with a combination of up to three compatible plasmids, which contained several carotenogenic genes from Erwinia uredovora and two Rhodobacter species. Their function in the pathway leading to the individual carotenoids was outlined. Finally, growth conditions were optimized for production of the hydroxy carotenoids in amounts which are suitable for their isolation and purification.     

Serotonergic neurons are present and innervate blood vessels in the olfactory bulb of the laboratory shrew, Suncus murinus

The distribution and characteristics of serotonin-immunoreactivity in the olfactory bulb of the laboratory shrew (Suncus murinus, insectivore) was studied immunohistochemically. Serotonergic neurons were found only in the subependymal layer of the main olfactory bulb. These neurons were 8-12 microm in size and bipolar in shape. These serotonergic neurons had smooth nerve fibers which innervate blood vessels located mainly in the subependymal layer of the main olfactory bulb. On the other hand, other serotonergic nerve fibers with varicosities, which must be extrinsic, were detected in most olfactory layers except the olfactory nerve layer. This result suggests that intrinsic serotonergic neurons may control blood vessels and varicose serotonergic nerve fibers may act to modulate the olfactory transmission.     

Two Types of Aggression Are Differentially Related to Serotonergic Activity and the A779C TPH Polymorphism.

The authors investigated whether different types of aggression relate to the A779C tryptophan hydroxylase (TPH) polymorphism and to serotonergic activity in volunteers. A factor analysis of the Buss-Durkee Hostility Inventory yielded 2 factors representing Neurotic Hostility (NH) and Aggressive Hostility (AH). The authors used a neuroendocrine challenge with Citalopram in 48 volunteers and increased cortisol concentrations only in those with high levels of AH. Finally, an association study with 58 volunteers revealed that the A779C TPH polymorphism significantly relates to AH, with the highest aggression levels for the genotype AA and the lowest aggression levels for the genotype CC, but not to NH. Results are discussed with respect to inconsistent findings in the literature, which may be explained by this distinction of types of aggression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evidence That GABA Mediates Dopaminergic and Serotonergic Pathways Associated With Locomotor Activity in Juvenile Chinook Salmon (Oncorhynchus tshawytscha).

The authors examined the control of locomotor activity in juvenile salmon (Oncorhynchus tshawytscha) by manipulating 3 neurotransmitter systems--gamma-amino-n-butyric acid (GABA), dopamine, and serotonin--as well as the neuropeptide corticotropin releasing hormone (CRH). Intracerebroventricular (ICV) injections of CRH and the GABAA agonist muscimol stimulated locomotor activity. The effect of muscimol was attenuated by administration of a dopamine receptor antagonist, haloperidol. Conversely, the administration of a dopamine uptake inhibitor (4′,4″-difluoro-3-alpha-[diphenylmethoxy] tropane hydrochloride [DUI]) potentiated the effect of muscimol. They found no evidence that CRH-induced hyperactivity is mediated by dopaminergic systems following concurrent injections of haloperidol or DUI with CRH. Administration of muscimol either had no effect or attenuated the locomotor response to concurrent injections of CRH and fluoxetine, whereas the GABAA antagonist bicuculline methiodide potentiated the effect of CRH and fluoxetine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Serotonergic function, two-mode models of self-regulation, and vulnerability to depression: What depression has in common with impulsive aggression.

Evidence from diverse literatures supports the viewpoint that two modes of self-regulation exist, a lower-order system that responds quickly to associative cues of the moment and a higher-order system that responds more reflectively and planfully; that low serotonergic function is linked to relative dominance of the lower-order system; that how dominance of the lower-order system is manifested depends on additional variables; and that low serotonergic function therefore can promote behavioral patterns as divergent as impulsive aggression and lethargic depression. Literatures reviewed include work on two-mode models; studies of brain function supporting the biological plausibility of the two-mode view and the involvement of serotonergic pathways in functions pertaining to it; and studies relating low serotonergic function to impulsiveness, aggression (including extreme violence), aspects of personality, and depression vulnerability. Substantial differences between depression and other phenomena reviewed are interpreted by proposing that depression reflects both low serotonergic function and low reward sensitivity. The article closes with brief consideration of the idea that low serotonergic function relates to even more diverse phenomena, whose natures depend in part on sensitivities of other systems. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Telehealth systems

A 20 year old woman with acute myocardial infarction exhibited a huge aneurysm of the left main coronary artery that was occluded by a large intraluminal thrombus. After exclusion of other vascular or systemic diseases, atypical Kawasaki syndrome was diagnosed. Other major symptoms usually required for this diagnosis were absent. As patients with Kawasaki syndrome in childhood are surviving longer, acute coronary symptoms may occur in young adults, and coronary aneurysms might be the only symptom of atypical Kawasaki syndrome.