Elevated Serotonin Levels Research Articles

Preliminary Results of a Study of the Platelet Dense Granule and Serotonin Storage Pool in Autistic Children and Their Families.

Abstract 4456The etiology of autism is thought to be neurobiological, but the mechanisms involved are not known. One possible clue into this disorder can be found in multiple clinical studies which have established that at least 30-40% of individuals diagnosed with autism have significantly elevated levels of serotonin (5HT) in their blood. Serotonin transport by platelets and 5HT plasma levels have been found to be altered in patients with multiple neurobiological disorders, including bipolar disorder, schizophrenia, depression, aggression, autism, and migraine headache. Serotonin has numerous functions, including regulation of vasoconstriction, vasodilatation, and coagulation. A review of the literature reveals few studies of coagulopathy related to autism other than attempts to associate vaccination or infections with the etiology of autism. One recent study, of a limited number of individuals with autism spectrum disorders (ASD) and their families, reported a significant incidence of thrombophilia. All children evaluated (10/10) and 15 of 16 family members in the study were found to be at risk for thrombophilia disorders. We have been evaluating patients for PL dysfunction for many years and recently, have included ELISA tests to determine the 5HT concentration in PLs of patients suffering from migraine headache or syncope. All of our investigations to date have evaluated patients for a deficiency of the PL storage pool (DG SPD) including a decrease of PL DGs and their stored biochemical constituents; we have never conducted a study related to potentially increased numbers of DGs or the concentration of biochemicals contained in these granules. As at least one report exists in the literature suggesting the potential for thrombophilia in patients diagnosed with an autism spectrum disorder and their families, we decided to assess the platelet storage pool in autistic patients and their families as a potential model of platelet dysfunction due to elevated DGs and/or 5HT levels and/or as a potential biomarker for autism. As the major storage pool of 5HT in the circulation is known to exist in platelet PL DGs, it is possible that a PL DG storage pool could be an important mediator of ASD. Our hypothesis is that autistic children may have elevated numbers of DGs and increased levels of PL 5HT. Peripheral blood samples were obtained from children diagnosed with autism as well as their parents and siblings. Platelets were obtained via centrifugation and DG content determined by electron microscopy and an ELISA assay was utilized to determine PL 5HT concentration for all subjects. A questionnaire was also used to evaluate family bleeding history and drug therapy for the autistic children. At present, 4 families have been recruited for the study. Autistic children (n = 5) have an average of 5.42 ± 0.69 DG/PL and a mean 5HT concentration of 447.6.4 ± 85.6 ng/109 PL (PL 5HT normal range = 215-850 ng/109 PL). Their parents have an average of 5.00 ± 0.54 DG/PL and a mean 5HT concentration of 427.6.4 ± 82.66 ng/109 PL and one five year old sibling was found to have 8.17 DG/PL and 2233 ng/109 PL. Control subjects (n=21) have an average of 4.16 ± 0.09 DG/PL and a 5HT concentration of 589.6 ± 56.25 ng/109. There is no statistically significant difference between controls, parents or autistic subjects by ANOVA. Our preliminary data does not support our hypothesis. However, with serotonin being the immediate precursor of melatonin, we do not discount the fact that all of our subjects were receiving drug therapies including melatonin supplementation (n=2) or selective serotonin reuptake inhibitors (n=3) which diminish the PL 5HT concentration. Thus, the therapeutic regimens for these subjects could account for their normal 5HT levels. This project had been initiated just prior to the time of abstract submission; we are currently recruiting study participants and will present additional data at the meeting. Disclosures:No relevant conflicts of interest to declare.

Chronic treatment of astrocytes with therapeutically relevant fluoxetine concentrations enhances cPLA2 expression secondary to 5-HT2B-induced, transactivation-mediated ERK1/2 phosphorylation

We have recently shown that fluoxetine, a serotonin-specific reuptake inhibitor (SSRI), has low micromolar affinity for the 5-HT(2C) receptor (but not for 5-HT(2A) and 5-HT(2B) receptors) in primary cultures of mouse astrocytes. This was determined as phosphorylation (stimulation) of extracellular-regulated kinase 1 and 2 (ERK(1/2)) by transactivation-mediated phosphorylation of the epidermal growth factor (EGF) receptor, followed by conventional EGF receptor signaling (Li et al., Psychopharmacology 194:333-334, 2007). Paroxetine has an identical effect. The present study shows that chronic fluoxetine treatment with even higher affinity (EC(50) = 0.5-2.0 microM) upregulates Ca(2+)-dependent phospholipase A(2) (cPLA(2)), which releases arachidonic acid from the sn-2 position of membrane-bound phospholipid, without effect on secretory PLA(2) (sPLA(2)) and intracellular PLA(2) (iPLA(2)). This demonstration replicates the fluoxetine-induced cPLA(2) upregulation in rat brain shown by Rao et al. (Pharmacogenomics J 6:413-420, 2006) and provides the new information that upregulation (1) occurs in astrocytes, (2) is evoked by stimulation of 5-HT(2B) receptor, and (3) requires transactivation-mediated ERK(1/2) phosphorylation. Similar upregulation of cPLA(2) in intact brain in response to 5-HT(2)-mediated signaling by elevated serotonin levels and/or an SSRI during antidepressant treatment may explain the repeatedly reported ability of SSRIs to normalize regional decreases which occur in brain metabolism during major depression, since (1) arachidonic acid strongly stimulates glucose metabolism in cultured astrocytes (Yu et al., J Neurosci Res 64:295-303, 1993) and (2) plasma concentrations of arachidonic acid in depressed patients are linearly correlated with regional brain glucose metabolism (Elizabeth Sublette et al., Prostaglandins Leukot Essent Fatty Acids 80:57-64, 2009).

From Tryptophan to Hydroxytryptophan: Reflections on a Busy Life

Given the very difficult odyssey of my early years, who could have imagined the incredible and successful journey that constituted my life path after age 13? I was born into a Jewish family in Breslau, Germany, right before the rise of Nazism and Hitler's election. After Kristallnacht, when my father was taken to Buchenwald Concentration Camp, we had to leave Germany as soon as possible. The first opportunity came in May of 1939, when we boarded the SS St. Louis bound for Havana, Cuba. Almost all passengers were denied entrance into Cuba, and the ship had to go back to Europe, where I ended up in France. In December of 1939, during World War II, I was fortunate to be able to leave France. This time I made it to Cuba, where my father was already in residence. A year later, my entire family was allowed into the United States. I took advantage of all the educational resources in this land of opportunity. I graduated valedictorian of my high school class and earned a four-year scholarship to Rutgers University, where I obtained a Bachelor of Science degree. I went on to earn a Master's degree from the University of Connecticut and finally a PhD from the University of Illinois. Within two months after graduating from Illinois, I was hired as an assistant professor of nutritional biochemistry at Rutgers, where I enjoyed a most productive research and teaching career. My PhD research involved tryptophan and niacin metabolism in the chick, and upon arrival at Rutgers I continued amino acid studies with the goal of assessing the essential amino acid requirements for egg production. This research was crowned with success and was followed with amino acid requirement studies for maintenance and for growth in rabbits, and ultimately with a reevaluation of requirements in adult humans. An outgrowth of the maintenance requirements led to a series of investigations into the metabolism of histidine, histamine, and carnosine (a histidine-containing dipeptide). Histamine, we found, plays an important role in wound healing and stress management. Pyridoxal phosphate is the cofactor for the enzyme histidine decarboxylase required for histamine synthesis and similarly serves as a cofactor for hydroxytryptophan decarboxylase, the enzyme that is part of the pathway to serotonin synthesis. Investigations into these pathways led to interesting findings: brain concentrations of serotonin could be increased by supplementing the diet of rats with tryptophan and pyridoxine; the elevated brain serotonin levels had behavioral consequences. Alcohol craving, addiction, and withdrawal symptoms are affected by serotonin concentrations in the brain, and alleviation of these conditions can be achieved with simultaneous administration of serotonin and dopamine agonists. In the midst of our early amino acid studies, we serendipitously also became involved with lipid metabolism in relation to atherosclerosis and blood cholesterol in a chicken model. This work led to the recognition that soluble fibers, like pectin, had strong cholesterol-lowering properties that were beneficial in lowering the incidence of coronary plaque formation. The research success that I have enjoyed has been coupled with the gift of three accomplished children who are making important contributions as professionals in their fields of endeavor. My wife and I are also blessed with 10 wonderful grandchildren, our pride and joy!

An Unusual Presentation of Carcinoid Tumor

A 75-yr-old man presented to the operating room for a right ventricular (RV) mass excision and tricuspid valve (TV) replacement. The patient reported progressive worsening of dyspnea on exertion associated with lower extremity swelling, abdominal distension, diarrhea, and several episodes of hallucinations. The preoperative evaluation and workup revealed the presence of a carcinoid tumor of the mesentery. This was supported by elevated liver function tests and a urine 5hydroxyindole-acetic acid level of 78.9 (normal 0–10 mg/24 h) as well as elevated serum serotonin level of 1050 ng/mL (normal 90–195 ng/mL). Computed tomography of the abdomen and pelvis demonstrated a 3.2 cm × 2.3 cm mesenteric soft tissue mass in the right lower quadrant.

P19: The toxic effect of prolonged Ultram administration on cerebral cortex of albino rats: Toxicological and histological study

Ultram (Tramadol) is a widely used opioid analgesic effective in treating both acute and chronic pains and has acceptable adverse effects such as headache, nausea constipation and vertigo. The aim of the present study was to evaluate the cerebrocortical toxicity resulting from short term and long term Ultram administration to albino rats using biochemical and histological parameters. The study was carried out on 25 adult male albino rats divided into: control group received 0.5 ml/day saline orally by orogastric tube for 2 months, a short-term Ultram-treated group that received a dose of 30 mg/kg/day (1/10 LD50) for 1 month orally and a long-term Ultram–treated group that received the same dose for 2 months. The study revealed that Ultram administration caused a significant elevation of serotonin level in the cerebral cortical tissues of rats which was directly proportional to the duration of Ultram administration. Histologically, there were localized foci showing disorganization of the cortical layers in short term ultram treated group. While in long-term Ultram–treated one there were much disorganization of the cortical layers with vacuolated foci and cell loss. Ultrastructurally the neurons in the different layers of cerebral cortex associated with degenerative changes and damage of rough endoplasmic reticulum in the form of chromatolysis and degranulation which were more evident with the 2 months Ultram dosing than with 1 month. The correlation between the biochemical results and the histological findings proved that Ultram induced neuronal lesions could be mediated by the elevated cerebrocortical serotonin level which gives serious alarms for reconsidering the rush towards the excessive use of Ultram.

Prenatal dopamine and neonatal behavior and biochemistry

Depressed pregnant women ( N = 126) were divided into high and low prenatal maternal dopamine (HVA) groups based on a tertile split on their dopamine levels at 20 weeks gestation. The high versus the low dopamine group had lower Center for Epidemiological Studies-Depression Scale (CES-D) scores, higher norepinephrine levels at the 20-week gestational age visit and higher dopamine and serotonin levels at both the 20- and the 32-week gestational age visits. The neonates of the mothers with high versus low prenatal dopamine levels also had higher dopamine and serotonin levels as well as lower cortisol levels. Finally, the neonates in the high dopamine group had better autonomic stability and excitability scores on the Brazelton Neonatal Behavior Assessment Scale. Thus, prenatal maternal dopamine levels appear to be negatively related to prenatal depression scores and positively related to neonatal dopamine and behavioral regulation, although these effects are confounded by elevated serotonin levels.

Neurohumoral and psychoemotional features of arterial hypertension

87 participants of the study aged 30−60 years suffered from arterial hypertension of grade I-II, with low, moderate and high overall cardiovascular risk. Average age of patients was 47,7 ± 7,4 years old and average disease duration was 11,1 ± 9,4 years. Level of serotonin and adrenoreactivity by a method based on erythrocyte osmoresistance change under beta blockers influence were evaluated in all patients. Psychoemotional features were assessed by psychological testing. The performed study showed elevated adrenoreactivity and plasma serotonin level in more than 50% of cases. According to our study all patients suffering from arterial hypertension can be divided in 3 groups depending on psychoemotional status: 1 st group - patients with high aggressiveness; 2 nd group - patients with high situative and personal anxiety and high hostility; 3d group - patients without changes in psychoemotional status. Results of the study confirm the fact that psychoemotional status dysfunction is encountered in 67,8% while 32,2% of patients do not demonstrate significant changes of emotional profile

Brain Region-Specific Effects of Short-Term Treatment with Duloxetine, Venlafaxine, Milnacipran and Sertraline on Monoamine Metabolism in Rats

We examined brain region-specific changes in monoamines and metabolites, and their ratios, after short-term administration of antidepressants to rats. Serotonin noradrenaline reuptake inhibitors (SNRIs; duloxetine, venlafaxine, milnacipran) and a serotonin-selective reuptake inhibitor (SSRI; sertraline) elevated serotonin (5-HT) levels in the midbrain (MB). Duloxetine and venlafaxine increased 5-HT levels in the brainstem and 5-HT terminal areas, whereas milnacipran and sertraline increased levels in the brainstem only. Significant reductions in 5-HT turnover were observed in various forebrain regions, including the hippocampus and hypothalamus, after treatment with all of the tested drugs except for milnacipran. In addition, there was reduced 5-HT turnover in the dorsolateral frontal cortex (dlFC), the medial prefrontal cortex (mPFC), and both the dlFC and the mPFC after treatment with duloxetine, sertraline, and venlafaxine, respectively. Venlafaxine significantly increased dopamine (DA) levels in the nucleus accumbens (NAc) and the substantia nigra and decreased DA turnover in the NAc. Similar changes were observed after treatment with duloxetine and sertraline in the NAc, whereas milnacipran increased DA levels in the mPFC. Limited increases in noradrenaline levels were detected after treatment with duloxetine, venlafaxine, or sertraline, but not after treatment with milnacipran. These results show that SNRIs and SSRIs induced region-specific monoaminergic changes after short-term treatment.

Regulation of Monoamine Oxidase A by Circadian-Clock Components Implies Clock Influence on Mood

The circadian clock has been implicated in addiction and several forms of depression [1, 2], indicating interactions between the circadian and the reward systems in the brain [3-5]. Rewards such as food, sex, and drugs influence this system in part by modulating dopamine neurotransmission in the mesolimbic dopamine reward circuit, including the ventral tegmental area (VTA) and the ventral striatum (NAc). Hence, changes in dopamine levels in these brain areas are proposed to influence mood in humans and mice [6-10]. To establish a molecular link between the circadian-clock mechanism and dopamine metabolism, we analyzed the murine promoters of genes encoding key enzymes important in dopamine metabolism. We find that transcription of the monoamine oxidase A (Maoa) promoter is regulated by the clock components BMAL1, NPAS2, and PER2. A mutation in the clock gene Per2 in mice leads to reduced expression and activity of MAOA in the mesolimbic dopaminergic system. Furthermore, we observe increased levels of dopamine and altered neuronal activity in the striatum, and these results probably lead to behavioral alterations observed in Per2 mutant mice in despair-based tests. These findings suggest a role of circadian-clock components in dopamine metabolism highlighting a role of the clock in regulating mood-related behaviors.

Cortical enlargement in autism is associated with a functional VNTR in the monoamine oxidase A gene

Monoamine oxidase A (MAOA) is an enzyme expressed in the brain that metabolizes dopamine, norepinephrine, epinephrine, and serotonin. Abnormalities of serotonin neurotransmission have long been implicated in the psychopathology of autism. A polymorphism exists within the promoter region of the MAOA gene that influences MAOA expression levels so that "low activity" alleles are associated with increased neurotransmitter levels in the brain. Individuals with autism often exhibit elevated serotonin levels. Additional studies indicate that the "low activity" allele may be associated with lower IQ and more severe autistic symptoms. In this study we genotyped the MAOA promoter polymorphism in a group of 29 males (age 2-3 years) with autism and a group of 39 healthy pediatric controls for whom brain MRI data was available. We found a consistent association between the "low activity" allele and larger brain volumes for regions of the cortex in children with autism but not in controls. We did not find evidence for over-transmission of the "low activity" allele in a separate sample of 114 affected sib pair families. Nor did we find any unknown SNPs in yet another sample of 96 probands. Future studies will determine if there is a more severe clinical phenotype associated with both the "low activity" genotype and the larger brain volumes in our sample.

Effects of Diacylglycerol on Glucose, Lipid Metabolism, and Plasma Serotonin Levels in Lean Japanese

Diacylglycerol (DAG)-rich oil has been suggested to suppress postprandial hyperlipidemia and promote negative caloric balance by increasing energy expenditure (EE), due to small intestine physiochemical dynamics that differ from triacylglycerol (TAG). We studied the effect of DAG on postprandial glucose/insulin metabolism by loading of carbohydrate with oil. Further, to reveal the mechanism for increased EE by DAG, we measured plasma serotonin, which is mostly present in the small intestine and mediates peripheral sympathetic thermogenesis. Randomized crossover study with 2-week wash-out interval between differing fat ingestion. Seven male, lean, Japanese students ingested DAG or TAG oil with 40 g of carbohydrate. Measurements of metabolic parameters were performed before and at 2, 4, and 6 h after fat ingestion. Plasma serotonin levels and cholesterol concentration in each lipoprotein were measured using high-performance liquid chromatography (HPLC). The substitution of DAG for TAG decreased very-low-density lipoprotein-cholesterol (VLDL-C) by 45.6% at 2 h, and decreased serum insulin by 41.3% at 4 h after ingestion. The incremental area under the curve (IAUC) for VLDL-C was positively correlated with the IAUC for insulin. Concurrently, DAG elevated plasma serotonin levels by 47.3% at 2 h, while TAG did not influence. This study indicates that the substitution of DAG for TAG suppresses the postprandial increase in serum VLDL-C and insulin. This study also demonstrates that DAG ingestion increases plasma serotonin, proposing a possible mechanism for a postprandial increase in EE by DAG.

Tumeurs endocrines digestives : stratégie diagnostique

Carcinoid tumors account for less than 1% of all malignancies. The majority arise in the gastrointestinal system (GI carcinoids). The diagnosis of GI carcinoids is often made late, the protean symptoms are easy to overlook. Diagnosis, prognosis and treatment options are based on biochemical markers and imaging investigations. A high concentration of urinary 5-HIAA or an elevated serotonin level in plasma help to establish the diagnosis of GI carcinoid. Plasma chromogranin A has poor specificity (68%); its level depends on disease involvement and therapeutic response. Octreoscan is the best imaging technique to detect GI carcinoids, but CT scan and MRI are superior for the detection of metastasis. 18F-DOPA or 11C-5-HTP/PET, imaging fusion as of octreoscan or PET scan with CT or MRI, improve the results of metabolic imaging. Coronal contrast-enhanced CT or MRI angiogram can evaluate mesenteric vessel spread before surgery. Upper endoscopy or colonoscopy, can be performed to detect foregut carcinoid in MEN, or hindgut carcinoid. Echoendoscopy visualizes abdominal wall and local node involvement. Enteroscopy and capsule endoscopy localize 66% of midgut carcinoids. Although there have been considerable advances in diagnostic modalities, the diagnosis of carcinoid tumors is still, all too often, late.

Biochemical Markers in the Follow-up of Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) shares biochemical features with other neuroendocrine tumors but the particular characteristics are largely unexplored. We investigated the biochemical neuroendocrine profile of MTC and whether specific markers could be useful in follow-up. In addition to the standard tumor marker calcitonin, plasma carcino-embryonic antigen (CEA), plasma catecholamines, (platelet) serotonin, chromogranin A, tryptase, and urinary markers of catecholamine, histamine, and serotonin metabolism were prospectively determined in 46 patients with histologically proven MTC. Patients were divided according to the stage of disease: group 1, no evidence; group 2, stable disease (SD); and group 3, progressive disease (PD). Plasma dopamine was increased in the majority of the patients with SD and PD; however it did not correlate with extent of disease. Elevated plasma platelet levels of serotonin were only present in patients with multiple endocrine neoplasia 2 with SD or PD but did not differ between those groups. Histamine metabolites were elevated in 20% of patients with SD and PD. In addition to plasma calcitonin, only CEA and chromogranin A could differentiate between stable and progressive MTC. MTCs are capable of synthesizing catecholamines, serotonin, and histamine metabolites underscoring that MTCs have metabolic characteristics in common with other neuroendocrine tumors. Thus far, clinical usefulness and relevance seems limited. The most useful markers in the follow-up of MTC are plasma calcitonin and CEA.

A Sleep-Promoting Role for the Drosophila Serotonin Receptor 1A

Although sleep is an important process essential for life, its regulation is poorly understood. The recently developed Drosophila model for sleep provides a powerful system to genetically and pharmacologically identify molecules that regulate sleep. Serotonin is an important neurotransmitter known to affect many behaviors, but its role in sleep remains controversial. We generated or obtained flies with genetically altered expression of each of three Drosophila serotonin receptor subtypes (d5-HT1A, d5-HT1B, and d5-HT2) and assayed them for baseline sleep phenotypes. The data indicated a sleep-regulating role for the d5-HT1A receptor. d5-HT1A mutant flies had short and fragmented sleep, which was rescued by expressing the receptor in adult mushroom bodies, a structure associated with learning and memory in Drosophila. Neither the d5-HT2 receptor nor the d5-HT1B receptor, which was previously implicated in circadian regulation, had any effect on baseline sleep, indicating that serotonin affects sleep and circadian rhythms through distinct receptors. Elevating serotonin levels, either pharmacologically or genetically, enhanced sleep in wild-type flies. In addition, serotonin promoted sleep in some short-sleep mutants, suggesting that it can compensate for some sleep deficits. These data show that serotonin promotes baseline sleep in Drosophila. They also link the regulation of sleep behavior by serotonin to a specific receptor in a distinct region of the fly brain.

Hyperserotoninemia and Altered Immunity in Autism

One of the most consistent biological findings in autism is elevated whole blood serotonin (5-HT) levels found in about 1/3 of cases. Immune abnormalities are also commonly observed in this disorder. Given 5-HT's role as an immunomodulator, possible connections between 5-HT and immune abnormalities in autism are explored in this review. Areas of focus include hyperserotoninemia and cellular immune function, autoantibodies to 5-HT receptors, and 5-HT's role in autoimmunity. Further research is needed to determine the interactions between neuropsychiatric and immune dysfunction in autism and related disorders.

Desensitization of 5-HT 2A receptor function by chronic administration of selective serotonin reuptake inhibitors

We have previously shown that chronic treatment with selective serotonin reuptake inhibitors (SSRIs), fluvoxamine and paroxetine, attenuated m-chlorophenylpiperazine ( mCPP)-induced hypolocomotion in rats. The effect of these SSRIs on the response to mCPP is thought to be caused by the desensitization of 5-HT 2C receptor function. In the present study, we investigated whether chronic administration of SSRI could reduce another pharmacological response to mCPP in rats, i.e., the induction of the secretion of corticosterone. The mCPP-induced increase in the serum concentration of corticosterone was not blocked by the 5-HT 2C antagonist SB242084, but was blocked by the 5-HT 2A antagonist ketanserin. Chronic treatment with fluvoxamine and paroxetine attenuated the response to mCPP, while these SSRIs had no effects in control rats. These results suggest that the desensitization of 5-HT 2A receptor function occurs in the same way as that of 5-HT 2C receptor function through chronic treatment with either fluvoxamine or paroxetine as a consequence of prolonged exposure to elevated levels of serotonin. The hypersensitivity of 5-HT 2A receptors is observed in depressed patients, and chronic treatment with many antidepressants such as tricyclic antidepressants have been reported to reduce 5-HT 2A receptor density and/or efficacy. The desensitization of 5-HT 2A receptor function might contribute to the therapeutic mechanism of action of these SSRIs, as seen with other classes of antidepressants.

Boundary-limited serotonergic influences on pattern organization in rat sensory cortex

In neonatal rodents, elevated levels of cortical serotonin (5-HT) blur the normally segmented vibrissae-related pattern of thalamocortical afferents (TCAs) in the posteromedial barrel subfield (PMBSF) of primary somatosensory cortex. We employed 5-HT immunocytochemistry or anterograde transport of 1′1′-dioctadecyl-3,3,3′,3′ tetramethyl-indocarbocyanin (Di-I) to label TCA arbors to study the effects of 5-HT manipulations on space occupied by TCAs within the PMBSF and the total area labeled. In rats treated to increase cortical 5-HT from birth to postnatal day (P) 6, the percentage of PMBSF area occupied by terminal labeling was significantly higher from that in controls (79.0% versus 23.7%, P < 0.05) for the highest levels of cortical 5-HT and was raised, although not significantly, for lower levels of 5-HT. The TCA coverage was significantly correlated with treatment dose. In animals exposed to a selective 5-HT 1B agonist, 5-nonyloxytryptamine, or elevated endogenous 5-HT, the total areas of TCA aggregates in the PMBSF and those in visual cortex were similar to the controls. These results suggest that TCAs have a graded response to increasingly higher 5-HT concentrations. The lack of TCA expansion beyond normal cortical areas further implies that 5-HT-induced axon outgrowth is restricted at cortical boundaries.

Advances toward new antidepressants beyond SSRIs: 1-Aryloxy-3-piperidinylpropan-2-ols with dual 5-HT 1A receptor antagonism/SSRI activities. Part 5

A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT 1A receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1 H-Indol-4-yloxy)-3-(4-benzo[ b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinities at the 5-HT 1A receptor and serotonin reuptake site in vitro. In vivo evaluation of this series of compounds demonstrated elevated extracellular serotonin levels from the basal and quick recovery of neuron firing that was presumably suppressed by the initial acute activation of 5-HT 1A somatodendritic autoreceptors.

Long-term kindling of the basolateral amygdala impairs copulatory behavior in male rats

This experiment examined the consequences of long-term kindling of the basolateral amygdala on male sexual behavior and the frequency of both spontaneous wet dog shakes (WDS) and those induced by the 5-HT 2A receptor agonist DOI. Results demonstrated that following 60 stimulations of the left basolateral amygdala over a 4-week period, male Long–Evans rats exhibited decrements in every aspect of sexual behavior. Specifically, latencies to mount, intromit and ejaculate were all prolonged following long-term kindling, and ejaculation frequencies were significantly reduced. Furthermore, spontaneous peri-copulatory WDS were increased in kindled rats, suggesting a possible role of the 5-HT 2A receptor. However, countering this suggestion, there were no differences between sham and kindled rats on WDS induced by the 5-HT 2A receptor agonist DOI. These results suggest that kindled rats may exhibit elevated levels of endogenous serotonin during exposure to a female rat, which would attenuate copulatory behavior, while concurrently increasing WDS expression.

Protein Expression Profiling of the Drosophila Fragile X Mutant Brain Reveals Up-regulation of Monoamine Synthesis

Fragile X syndrome is the most common form of inherited mental retardation, associated with both cognitive and behavioral anomalies. The disease is caused by silencing of the fragile X mental retardation 1 (fmr1) gene, which encodes the mRNA-binding, translational regulator FMRP. Previously we established a disease model through mutation of Drosophila fmr1 (dfmr1) and showed that loss of dFMRP causes defects in neuronal structure, function, and behavioral output similar to the human disease state. To uncover molecular targets of dFMRP in the brain, we use here a proteomic approach involving two-dimensional difference gel electrophoresis analyses followed by mass spectrometry identification of proteins with significantly altered expression in dfmr1 null mutants. We then focus on two misregulated enzymes, phenylalanine hydroxylase (Henna) and GTP cyclohydrolase (Punch), both of which mediate in concert the synthetic pathways of two key monoamine neuromodulators, dopamine and serotonin. Brain enzymatic assays show a nearly 2-fold elevation of Punch activity in dfmr1 null mutants. Consistently brain neurochemical assays show that both dopamine and serotonin are significantly increased in dfmr1 null mutants. At a cellular level, dfmr1 null mutant neurons display a highly significant elevation of the dense core vesicles that package these monoamine neuromodulators for secretion. Taken together, these data indicate that dFMRP normally down-regulates the monoamine pathway, which is consequently up-regulated in the mutant condition. Elevated brain levels of dopamine and serotonin provide a plausible mechanistic explanation for aspects of cognitive and behavioral deficits in human patients.