The harmful effects of exposure to benzo[alpha]pyrene (B[alpha]P), which is a neurotoxic pollutant, on mammalian neurodevelopment and/or behaviour as yet remain widely unclear. In the present investigation, we evaluated the impact of the lactational exposure to B[alpha]P on postnatal development of pups and behaviour of young mice. The neurobiological effects of B[alpha]P during lactation were also evaluated on pups' brain. Here, we found that lactational exposure to B[alpha]P at 2 and 20mg/kg affects the neuromaturation of pups by significantly decreasing their reflex as highlighted in surface righting reflex and negative geotaxis tests. However, we noted a significant increase in muscular strength of lactationally B[alpha]P mg/kg-exposed pups, which was probably due to the impact of the exposure to this toxic compound on body weight gain. At the pup stage, lactational exposure to B[alpha]P also provoked a neurobiological change, which was assessed by determination of neuronal receptor gene expression. Indeed, a significant reduction in gene expression of <em>5HT</em>(1A) receptors in pups exposed to B[alpha]P through lactation was found in comparison to controls. Additionally, attenuation in the expression of MOR(1) mRNA was observed, but statistically significant only in animals receiving the higher dose. Neither the expression levels of ADRA(1D) nor GABA(A) mRNA were altered. Interestingly, the harmful effects of lactational exposure to B[alpha]P on behaviour and cognitive function were still found despite a long post-weaning period. Young mice whose mothers were exposed to B[alpha]P displayed a disinhibition behaviour towards the aversive spaces of the elevated plus maze. Furthermore, a significant increase of spontaneous alternation in the Y-maze was observed, but only in young mice whose mothers were orally exposed to the lower dose of B[alpha]P. Our results suggest a close link between the neurobiological change highlighted in pups' brain and the different behavioural disturbances observed during postnatal development period until young adult stage.

A large body of evidence corroborates the notion that deficiencies of serotonergic system are likely involved in the pathogenesis of both depression and anxiety. Activation of beta(3) adrenoceptors has been shown to increase brain tryptophan content suggesting an elevation of brain serotonin (<em>5HT</em>) synthesis. SR58611A is a selective beta(3) adrenergic agent possessing a profile of antidepressant activity in routine rodents' experimental models of depression. The present study was undertaken to evaluate in rodents the antidepressant properties of SR58611A and to assess its putative anxiolytic value in experimental models of depression and anxiety. Compared to the control group, SR58611A (0.1, 1, 5 or 10 mg/kg) caused a dose-dependent reduction in immobility of Wistar male rats in the forced swim test. The maximum dose appeared to be equivalent to an effective dose of clomipramine (50 mg/kg). In addition, acute injection of SR58611A induced in rats a dose-dependent decrease in grooming response to a novel environment (novelty-induced grooming test). For any dose, the effect was lower than that of diazepam (1 mg/kg). Chronic treatment with SR58611A resulted also in an increased social interaction time in the social interaction test without affecting motor activity of rats. Furthermore, similarly to diazepam a chronic treatment with the highest doses of SR58611A was followed by increased exploratory behavior in Swiss male mice exposed to the elevated plus maze test. These effects are mediated by beta(3) adrenoceptors since i.p. pretreatment with the selective beta(3) adrenoceptor antagonist SR59230A (5 mg/kg) blocked the effects of SR58611A. Finally, also the <em>5HT</em> antagonist methysergide (2 mg/kg) prevented the antidepressant and anxiolytic-like activity of SR58611A indicating that <em>5HT</em> transmission is strictly involved in its action.

Cyclandelate inhibits calcium-induced contraction of vascular smooth muscle cells, platelet aggregation induced by thrombin, platelet-activating-factor and adenosine, and also suppresses a provoked <em>5HT</em> release from platelets. This pharmacological profile suggests that cyclandelate may have a potential prophylactic effect in migraine. To test this hypothesis, a double-blind multicentre study was performed in 214 patients to investigate the efficacy and tolerability of cyclandelate compared to placebo and propranolol. After a 4-week baseline period, eligible patients (randomization 3:2:3) were treated for 12 weeks with daily doses of 1.200 mg cyclandelate (n = 81), placebo (n = 55) or 120 mg propranolol (n = 78). The number of migraine attacks >> or = 50% responders) and the migraine duration/month were compared based on the difference between baseline and the last 4 weeks of prophylactic treatment. The percentage of patients with a reduction in migraine attacks of>> or = 50% treated with cyclandelate (37.0%) or propranolol (42.3%) was not significantly superior to placebo (30.9%; p>> 0.025). The mean duration of migraine in hours (h) per month decreased in both active treatment groups (cyclandelate: 36.8 h, p = 0.046; propranolol: 34.4 h, p = 0.039) compared to placebo (13.7 h) without reaching statistical significance (alpha/2 = 0.025). The clinical efficacy of cyclandelate and propranolol was comparable. Adverse experiences were reported by 13 patients (16.0%) treated with cyclandelate, by 5 patients (9.1%) treated with placebo and by 19 patients (24.4%) treated with propranolol. These were drug-related in 7.1% (n = 6) of patients treated with cyclandelate and in 9% (n = 7) of patients treated with propranolol. In summary, cyclandelate has a comparable efficacy to that of propranolol, an established drug of first choice in the prophylaxis of migraine. Both drugs were better than placebo, but not significantly so. Both active treatments were well tolerated.

<AbstractText>Studies have reported a lack of association between improvements in gastric emptying (GE) and upper gastrointestinal (UGI) symptoms with promotility drugs. However, GE test methods were suboptimal in some studies. We assessed improvements in GE and UGI symptoms in patients given promotility agents in studies with optimal or moderate test methods (scintigraphy or breath test, solid meal, >2 hours duration) compared to studies with suboptimal GE test methods.</AbstractText><p><div><b>METHODS</b></div>With an expert librarian, we completed an extensive search of publications in the Ovid MEDLINE (1946 to present), EMBASE (1988 to January 2018), and EBM Reviews Cochrane Central Register of Controlled Trials, without restrictions on language or year. Two independent reviewers evaluated the following inclusion criteria: randomized, blinded, parallel, or crossover trials of <em>5HT</em>₄ agonists, D₂ receptor antagonist, or ghrelin agonists; trials that measured change in GE (T_1/2) or composite UGI symptoms; trials of patients with functional dyspepsia and gastroparesis; and trials of GE test methods. Standardized mean differences (units expressed as SD) were used to standardize symptom assessments that were not uniform across studies. Random effects model was used to analyze data and meta-regression was used to evaluate the association between change in GE and UGI symptoms.</p><p><div><b>RESULTS</b></div>Of 899 studies considered, 22 studies assessed change in GE; 23 evaluated UGI symptoms; and 14 evaluated GE and UGI symptoms. Promotility agents significantly accelerated GE (T_1/2) in all studies (mean reduction in T_1/2, 16.3 minutes; 95% confidence interval, -22.1 to -10.6 minutes) and in studies that used optimal GE test methods (mean reduction in T_1/2, 23.6 minutes; 95% confidence interval, -32.3 to -14.9 minutes). Promotility agents also significantly reduced UGI symptoms (mean reduction, 0.25 SD; 95% confidence interval, -0.37 to -0.13 SD). Meta-regression found no significant association between change in GE and UGI symptoms. However, when only studies with optimal GE test methods were evaluated, there was a significant positive association between improvement in GE and UGI symptoms (P = .02).</p><AbstractText>In a meta-analysis of published trials, we found promotility agents to significantly accelerate GE (when optimal test methods were used) and to produce significant improvements in UGI symptoms.</AbstractText>

BACKGROUND

Zingiber officinale (ZO, family Zingiberaceae) has been reported for its antiemetic activity against cancer chemotherapy induced emesis in animal models and in clinics. Current study was designed to investigate ZO for potential usefulness against cisplatin induced vomiting in pigeon and its effects on central and peripheral neurotransmitters involved in the act of vomiting.

METHODS

Zingiber officinale acetone fraction (ZO-ActFr) was investigated for attenuation of emesis induced by cisplatin in healthy pigeons. Neurotransmitters DA, <em>5HT</em> and their metabolites DOPAC, HVA and 5HIAA were analyzed using High Performance Liquid Chromatography system coupled with electrochemical detector in area postrema, brain stem and intestine. Antiemetic effect of ZO-ActFr was correlated with central and intestinal neurotransmitters levels in pigeon.

RESULTS

Cisplatin (7 mg/kg i.v.) induced emesis without lethality upto the observation period. ZO-ActFr (25, 50 & 100 mg/kg) attenuated cisplatin induced emesis ~ 44.18%, 58.13% (P < 0.05) and 27.9%, respectively; the reference drug, metoclopramide (MCP; 30 mg/kg), produced ~ 48.83% reduction (P < 0.05). ZO-ActFr reduced (P < 0.05 - 0.001) 5-hydroxytryptamine (<em>5HT</em>) concentration in the area postrema, brain stem and intestine at 3(rd) hour of cisplatin administration, while at the 18(th) hour ZO treatments attenuated the dopamine upsurge (P < 0.001) caused by cisplatin in the area postrema and <em>5HT</em> concentration (P < 0.01 - 0.001) in the brain stem and intestine. ZO treatments alone did not altered the basal neurotransmitters and their metabolites in the brain areas and intestine.

CONCLUSIONS

The behavioral study verify the antiemetic profile of ZO against cisplatin induced emesis in the pigeon, where central and peripheral neural evidences advocate the involvement of serotonergic mechanism at initial time point (3(rd) hr), while the later time point (18(th) hr) is associated with serotonergic and dopaminergic component in the mediation of its antiemetic effect.

OBJECTIVE

Mephedrone is a stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Although mephedrone does not damage dopamine nerve endings it increases the neurotoxicity of amphetamine, methamphetamine and MDMA. The effects of mephedrone on serotonin (<em>5HT</em>) nerve endings are not fully understood, with some investigators reporting damage while others conclude it does not. Presently, we investigate if mephedrone given alone or with methamphetamine or MDMA damages <em>5HT</em> nerve endings of the hippocampus.

METHODS

The status of <em>5HT</em> nerve endings in the hippocampus of female C57BL mice was assessed through measures of <em>5HT</em> by HPLC and by immunoblot analysis of serotonin transporter (SERT) and tryptophan hydroxylase 2 (TPH2), selective markers of <em>5HT</em> nerve endings. Astrocytosis was assessed through measures of glial fibrillary acidic protein (GFAP) (immunoblotting) and microglial activation was determined by histochemical staining with Isolectin B4.

RESULTS

Mephedrone alone did not cause persistent reductions in the levels of <em>5HT</em>, SERT or TPH2. Methamphetamine and MDMA alone caused mild reductions in <em>5HT</em> but did not change SERT and TPH2 levels. Combined treatment with mephedrone and methamphetamine or MDMA did not change the status of <em>5HT</em> nerve endings to an extent that was different from either drug alone.

CONCLUSIONS

Mephedrone does not cause toxicity to <em>5HT</em> nerve endings of the hippocampus. When co-administered with methamphetamine or MDMA, drugs that are often co-abused with mephedrone by humans, toxicity is not increased as is the case for dopamine nerve endings when these drugs are taken together.

Prenatal <em>5HT</em> depletion causes a significant decrease in the level of nociceptive sensitivity during the second phase of the formalin test behavioral response. These experiments were designed to test whether blocking <em>5HT</em>2A/2c receptors in the CA1 region of the hippocampus and dentate gyrus would decrease nociceptive behaviors induced by a peripheral noxious stimulus formalin as an animal model of unremitting human being. The <em>5HT</em>2A/2c receptor antagonist ritanserin (2, 4 and 8 microg/0.5 microl) was injected into the CA1 area and dentate gyrus of behaving rats 5 min before subcutaneous injection of formalin irritant. Nociceptive behaviors in both phases of the formalin test were significantly decreased by ritanserin (4 and 8 microg/0.5 microl) and ritanserin had no effect at 2 microg/0.5 microl. These results support the hypothesis that the hippocampal formation may modify the processing of incoming nociceptive information and that <em>5HT</em>2A/2c receptor-sensitive mechanisms in the hippocampus may play a role in nociception and/or the expression of related behaviors.

Bronchial hyperresponsiveness (BHR) is a major characteristic of bronchial asthma. The pathogenesis of BHR remains to be fully elucidated, but is considered to be closely linked to airway inflammation. Animal models might provide us with useful data for a better understanding of the interrelationship between these phenomena. In the present study we investigated the effect of a single and chronic exposure to inhaled antigen on bronchial responsiveness and airway morphology in actively sensitized Brown Norway rats. Immunization to ovalbumin (OA) did not cause airway inflammation, but induced a small, transient decrease in bronchial responsiveness to 5-hydroxytryptamine (<em>5HT</em>) on Day 10, which returned to baseline on Day 16. By 24 h after a single exposure to aerosolized OA, a significant decrease in the provocative concentration of <em>5HT</em> causing a 50% increase in lung resistance (PC50RL <em>5HT</em>) was observed, compared with immunized, saline-exposed animals (7.7 +/- 0.8 versus 10.8 +/- 1.0 micrograms/kg). This was accompanied by the influx of neutrophils and few eosinophils in bronchoalveolar lavage fluid. Repeated daily or intermittent exposure to aerosolized OA enhanced airway inflammation, characterized by the presence of neutrophils, eosinophils, and lymphocytes in bronchoalveolar lavage fluid. Histologic analysis revealed patchy inflammatory infiltrates, located predominantly around bronchi and bronchioli. Despite these inflammatory changes, bronchial responsiveness was not significantly different from that of control animals. We therefore conclude that the induction of airway inflammation is not always associated with BHR.

Dose-dependent increases in threshold for operant fear/escape responses of rats submitted to aversive stimulation of the dorsolateral periaqueductal gray (dPAG) were recorded following intraperitoneal injection of three chemically unrelated but selective <em>5HT</em>2C receptor agonists (Ro 60-0175, Org 12962 and Ro 60-0332) and fluoxetine. The decreased sensitivity of rats to the acute panic-like aversion elicited by stimulation of this limbic periventricular region was detected at dosages devoid of impairing effects on the latencies needed for operant brain stimulation interruption. In this paradigm which has been validated as a simulation of acute anxiety with relevance to panic disorder, the selective activation of <em>5HT</em>2C receptors by Ro 60-0175, Org 12962 or Ro 60-0332 induces effects analogous to those observed following benzodiazepine receptor activation by antipanic agents such as clonazepam or alprazolam or following non-selective and indirect <em>5HT</em> receptor activation by fluoxetine. Potency and efficacy of <em>5HT</em>2C receptor agonists were intermediate between those of clonazepam and fluoxetine, indicating authentic antiaversive properties and suggesting antipanic potential for these <em>5HT</em>2C receptor agonists. In addition, these data suggest that the <em>5HT</em>2C receptor subtype may play a major role in the therapeutic properties of selective serotonin reuptake inhibitors. It is also speculated that serotonin/benzodiazepine interactions existing in the brain may functionally involve the <em>5HT</em>2C receptor subtypes and that the anxiogenic action reported under certain circumstances for <em>5HT</em> mimetics are not mediated by <em>5HT</em>2C receptor subtypes.

Nicotine has been definitively shown to be critically involved in the neural bases of tobacco addiction. However, nicotine releases a wide variety of neurotransmitters. Nicotine-induced dopamine release has been shown to play a key role in facilitating nicotine self-administration. Other transmitter systems may also play important roles in the pharmacological effects of nicotine and may provide important leads for combating nicotine self-administration. Clozapine, an antipsychotic drug, which blocks a variety of different transmitter receptors including serotonin <em>5HT</em>(2) and histamine H(1) receptors, has been found to decrease smoking. Previously we found that the serotonin <em>5HT</em>(2) antagonist, ketanserin, significantly reduced nicotine self-administration. In the current study, we assessed histamine H(1) receptor interaction with nicotine self-administration. Young adult female Sprague-Dawley rats were fitted with IV catheters and trained to self-administer nicotine (0.03mg/kg/infusion). Acute doses of 40mg/kg of pyrilamine, a histamine H(1) antagonist, significantly reduced nicotine self-administration. We also found that repeated injections (20mg/kg) or chronic infusion via osmotic minipumps (50mg/kg/day) of pyrilamine also significantly decreased nicotine self-administration. The peripherally restricted H(1) antagonist ebastine was ineffective in reducing nicotine self-administration, pointing to central H(1) receptor blockade as key for the effectiveness of pyrilamine. H(1) antagonists may be a promising avenue to explore for new treatments to aid smoking cessation.

The atypical antipsychotic drug clozapine is effective in treatment-refractory schizophrenia. The intracellular signaling pathways that mediate clozapine action remain unknown. A potential candidate is the mitogen-activated protein kinase extracellular signal-regulated kinase (MAPK-ERK) cascade that links G-protein-coupled receptor and ErbB growth factor signaling systems, thereby regulating synaptic plasticity and connectivity, processes impaired in schizophrenia. Here, we examined how clozapine differentially modulated phosphorylation of the MAPK isoforms, ERK1/ERK2 in primary murine prefrontal cortical neurons compared to the typical antipsychotic drug haloperidol. While clozapine and haloperidol acutely decreased cortical pERK1 activation, only clozapine but not haloperidol stimulated pERK1 and pERK2 with continued drug exposure. This delayed ERK increase however, did not occur via the canonical dopamine D(2)-Gi/o-PKA or serotonin <em>5HT</em>(2A)-Gq-phospholipase-C-linked signaling pathways. Rather, epidermal growth factor (EGF) receptor signaling mediated clozapine-induced ERK activation, given dose-dependent reduction of pERK1 and pERK2 stimulation with the EGF receptor inhibitor, AG1478. Immunocytochemical studies indicated that clozapine treatment increased EGF receptor (Tyr1068) phosphorylation. In vivo mouse treatment studies supported the in vitro findings with initial blockade, subsequent activation, and normalization of the cortical ERK response over 24 h. Furthermore, in vivo clozapine-induced ERK activation was significantly reduced by AG1478. This is the first report that clozapine action on prefrontal cortical neurons involves the EGF signaling system. Since EGF receptor signaling has not been previously linked to antipsychotic drug action, our findings may implicate the EGF system as a molecular substrate in treatment-resistant schizophrenia.

In order to approach the uptake of 14C-<em>5HT</em> by platelets as a first-order process, experimental conditions were selected in which accumulation of the amine either by diffusion or by other passive nonsaturable processes could be excluded. These conditions included an incubation period of 14C-<em>5HT</em> with human or rat platelets of 4 min or 30 s, respectively and the use of substrate concentrations around the calculated apparent Km values (0.25 - 2.0 muM). While the apparent Km values were rather similar for human and rat platelets, Vmax was about 5 times higher in rat than in human platelets. The kinetic model adopted in this study was used to evaluate the relative potency and the type of inhibiton of 14C-<em>5HT</em> uptake exhibited by imipramine, chlorimipramine and (+)-fenfluramine. All 3 compounds inhibited 14C-<em>5HT</em> uptake by platelets. Chlorimipramine was about 10 times more effective than imipramine both in rat and in human platelets. Both drugs were more potent inhibitors on human than on rat platelets. (+)-Fenfluramine was almost as active as imipramine on rat but 30 times less potent than imipramine on human platelets. Both imipramine and chlorimipramine inhibited 14C-<em>5HT</em> uptake by an apparent non-competitive mechanism, whereas (+)-fenfluramine appeared to act as a competitive inhibitor. No differences were found in this respect between human and rat platelets. Pharmacological or therapeutic doses of these drugs usually result in plasma concentrations similar to those found in this study to effectively inhibit platelet 14C-<em>5HT</em> uptake.

Aplysia motoneurons cocultured with a presynaptic sensory neuron exhibit homosynaptic depression when stimulated at low frequencies. A single bath application of serotonin (<em>5HT</em>) leads within seconds to facilitation of the depressed synapse. The facilitation is attributed to mobilization of neurotransmitter-containing vesicles from a feeding vesicle store to the depleted, readily releasable pool by protein kinase C (PKC). Here, we demonstrate that the calpain inhibitors, calpeptin, MG132, and ALLN, but not the proteasome inhibitors, lactacystin and clasto-lactacystin beta-lactone, block <em>5HT</em>-induced facilitation of depressed synapses. Likewise the <em>5HT</em>-induced enhancement of spontaneous miniature potentials (mEPSPs) frequency of depressed synapses is significantly reduced by calpeptin. In contrast, neither the facilitation of nondepressed synapses nor the enhancement of their mEPSPs frequency is affected by the inhibitor. The data suggest that action potentials-induced calcium influx activate calpains. These, in turn, play a role in the refilling processes of the depleted, releasable vesicle store.

Serotonin (5-hydroxytryptamine; <em>5HT</em>) kinetics and platelet activation by <em>5HT</em> were studied in patients with essential hypertension (n = 45), and in matched normotensive subjects (n = 45). Platelet response to <em>5HT</em> and plasma beta-thromboglobulin increased with age in men, both normotensives and hypertensives. Beta-thromboglobulin and 5-hydroxyindoleacetic acid (5HIAA) excretion were higher in hypertensive men than in women. In women, no changes in platelet activity or 5HIAA excretion were found. <em>5HT</em> plasma concentrations increased with blood pressure. Platelet <em>5HT</em> uptake (Vmax and KM) were the lowest in hypertensive men greater than or equal to 60 years of age. This may indicate that <em>5HT</em> uptake in vivo in normotensives is far below maximum (VNT much less than Vmax), whereas in hypertensive men it may be close to maximum (VHT approximately Vmax). This could reflect significantly higher <em>5HT</em> plasma concentrations in vivo hypertensives than in normotensives. The reduced uptake (which was found only in hypertensive men) may indicate an insufficient compensation of the enhanced <em>5HT</em> release from aggregating platelets in older men, in whom platelet activity is enhanced in vivo. It is concluded that the defect in platelet <em>5HT</em> uptake in hypertensives--along with the enhanced platelet aggregation--may contribute to a critical increase in <em>5HT</em> plasma concentrations locally. An increase in <em>5HT</em> concentrations leads to biochemical changes (higher 5HIAA excretion) as well as to an enhanced stimulation by <em>5HT</em>. This may be of clinical relevance especially in older men, in whom <em>5HT</em>2-receptor mediated responses are enhanced.

The partial agonist buspirone has a REM (rapid eye movement) suppressing effect on human sleep probably via a <em>5HT</em>(1A) receptor in the pontine area. Eptapirone is a new <em>5HT</em>(1A) agonist with a greater intrinsic effect than buspirone. The objective of this study was to examine the effects of eptapirone on sleep architecture, particularly REM sleep, in normal volunteers and compare it with buspirone and placebo. This was a randomized, double-blind placebo-controlled four-way crossover study in 12 healthy volunteers. Volunteers were screened to ensure that they had normal overnight sleep EEG (electroencephalogram) and were extensive CYP 2D6 metabolizers. Sleep was recorded on pairs of nights on four occasions, with medication being taken before the second night. Treatments were eptapirone 1.5mg at 10 AM, eptapirone 1.5mg at 11 PM, buspirone 20mg at 11 PM and placebo. Standard measures of sleep were derived and compared among the four treatments using ANOVA. REM sleep was significantly suppressed supporting the proposition that activation of post-synaptic <em>5HT</em>(1A) receptors reduces REM sleep. Sleep fragmentation increased by both drugs. REM sleep suppression was significantly greater with morning eptapirone than with buspirone. Wakefulness in sleep was significantly greatest after morning eptapirone. REM sleep effects were greatest after evening eptapirone, suggesting a greater effect on central serotonin receptors than that of buspirone.

BACKGROUND

The investigation of the environmental contribution for developmental neurotoxicity is very important. Many environmental chemical exposures are now thought to contribute to the development of neurological disorders, especially in children. Results from animal studies may guide investigations of human populations toward identifying environmental contaminants and drugs that produce or protect from neurotoxicity and may help in the treatment of neurodevelopmental disorders.

OBJECTIVE

To study the protective effects of omega-3 polyunsaturated fatty acid on brain intoxication induced by propionic acid (PPA) in rats.

METHODS

24 young male Western Albino rats were enrolled in the present study. They were grouped into three equal groups; oral buffered PPA-treated group given a nuerotoxic dose of 250 mg/Kg body weight/day for 3 days; omega-3 - protected group given a dose of 100 mg/kg body weight/day omega-3 orally daily for 5 days followed by PPA for 3 days, and a third group as control given only phosphate buffered saline. Tumor necrosis factor-α, caspase-3, interlukin-6, gamma amino-buteric acid (GABA), serotonin, dopamine and phospholipids were then assayed in the rats brain's tissue of different groups.

RESULTS

The obtained data showed that PPA caused multiple signs of brain toxicity as measured by depletion of gamaaminobyteric acid (GABA), serotonin (<em>5HT</em>) and dopamine (DA) as three important neurotransmitters that reflect brain function. A high significant increase of interlukin-6 (Il-6), tumor necrosis factor-α (TNF-α) as excellent markers of proinflammation and caspase-3 as a proapotic marker were remarkably elevated in the intoxicated group of rats. Moreover, brain phospholipid profile was impaired in PPA-treated young rats recording lower levels of phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylcholine (PC).

CONCLUSIONS

Omega-3 fatty acids showed a protective effects on PPA - induced changes in rats as there was a remarkable amelioration of most of the measured parameters (i.e. higher GABA, <em>5HT</em>, DA, PE, PS and PC) and lower Il-6, TNF-α and caspase-3.

OBJECTIVE

Genes involved in <em>5HT</em> transmission have been supposed to contribute to the biologic vulnerability for bulimia nervosa (BN). Because a long (L) and a short (S) variant of the promoter region of the <em>5HT</em> transporter gene have been identified, we tested whether the <em>5HT</em>T gene-linked polymorphic region (<em>5HT</em>TLPR) could represent a susceptibility factor for BN and/or could be related to nutritional parameters, harm avoidance personality dimension, and psychiatric comorbidity.

METHODS

A total of 219 white women (125 bulimics and 94 healthy control subjects) underwent a blood sample collection for <em>5HT</em>TLPR genotyping and a clinical evaluation assessing comorbidity for axis I and II psychiatric disorders, harm avoidance personality dimension, and body composition (only patients).

RESULTS

The distribution of the <em>5HT</em>TLPR genotypes did not significantly differ between patients and control subjects, although the L allele was significantly more frequent in the former. Bulimic individuals carrying at least one copy of the S allele had significantly lower mean body mass index and body fat mass values and significantly higher mean harm avoidance score than patients with the LL genotype. No significant association was found between the <em>5HT</em>TLPR genotype and comorbid axis I and II psychiatric disorders.

CONCLUSIONS

These findings support the view that polymorphic variants of the <em>5HT</em>T promoter region do not play a part in predisposing to BN, whereas they seem to predispose bulimic individuals to nutritional impairment and increased harm avoidance.

Disturbances in serotonin (<em>5HT</em>) neurotransmission have been indicated as biological substrates in several neuropsychiatric disorders including autism. Blood <em>5HT</em> concentrations, elevated in about one-third of autistic subjects, are regulated through the action of peripheral <em>5HT</em>-associated proteins. We have measured the activity of two platelet <em>5HT</em>-associated proteins: <em>5HT</em> transporter (<em>5HT</em>T) and monoamine oxidase B (MAOB), and indirectly studied the activity of <em>5HT</em>(2A) receptor (<em>5HT</em>(2A)r) in 15 hyperserotonemic (HS) and 17 normoserotonemic (NS) autistic subjects, and 15 healthy controls (C). While mean velocities of <em>5HT</em>T kinetics did not significantly differ among the groups, significant elevation in the mean velocity of MAOB kinetics was observed in NS subjects and was even more pronounced in HS subjects in comparison to controls. Also, a decrease in adenosine 5'-diphosphate-induced platelet aggregation of borderline significance was observed in NS subjects, compared to C subjects. The results suggest a possibility of upregulation of monoaminergic synthesis/degradation and, probably consequential, downregulation of <em>5HT</em>(2A)r in autistic subjects.

Dietary inositol is incorporated into neuronal cell membranes as inositol phospholipids where it serves as a key metabolic precursor in G protein-coupled receptors. In the brain, several subtypes of adrenergic, cholinergic, serotonergic and metabotropic glutamatergic receptors are coupled to the hydrolysis of phosphoinositides (PI) with myo-inositol (MI) crucial to the resynthesis of PI and the maintenance and effectiveness of signalling. Despite a mode of action that remains illusive, MI has demonstrated therapeutic efficacy in obsessive-compulsive disorder (OCD), putative OCD-spectrum disorders, as well as panic and depression. Behavioural and biochemical studies indicate that this efficacy does not involve simply the replenishing of the membrane PI pool. In addition to its precursory role in cell signalling, inositol lipids alter receptor sensitivity, can direct membrane trafficking events, and have been found to modulate an increasing array of signalling proteins. These effects may afford MI an ability to modulate the interaction between neurotransmitters, drugs, receptors and signalling proteins. This paper reviews the neuromolecular and genetic aspects of OCD in terms of the PI-linked <em>5HT</em> receptor subtypes and relates these to the behavioural and therapeutic effects of MI. Since OCD often is poorly responsive to current drug treatment, understanding the neuropharmacology of MI holds great promise for understanding the neuropathology of this and other MI-responsive disorders.

Rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the ascending nigro-striatal pathway have been shown to rotate in response to dopamine (DA) agonists that are not considered to have postsynaptic DA stimulant properties in intact animals, suggesting a relative loss of DA receptor selectivity in the denervated striatum. The present experiments assessed the possibility that this loss of selectivity may extend to serotonin (<em>5HT</em>) agonist drugs. The <em>5HT</em>-1a agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), at doses of 0.3-3 mg/kg SC, induced robust contralateral rotational behavior (RB) in 6-OHDA-lesioned rats that had been preselected on the basis of high responsiveness to the atypical DA agonists 3-PPP and SKF 38393. Rats with unilateral dorsal raphe lesions induced by 5,7-dihydroxytryptamine (5,7-DHT) showed contralateral RB in response to similar doses of 8-OH-DPAT but with a different behavioral pattern. The putative <em>5HT</em>-1b agonist RU 24969 produced contralateral RB in 5,7-DHT-lesioned rats while showing a much weaker effect in 6-OHDA-lesioned rats. Striatal DA levels were depleted by 99% in representative 6-OHDA-lesioned rats but striatal <em>5HT</em> levels were unaffected. The effects of 8-OH-DPAT in 6-OHDA-lesioned rats were therefore not attributable to destruction of ascending <em>5HT</em>-containing neurons. These effects may result from indirect actions, mediated by 5-HT neurons or neuronal receptors, that result from asymmetry of brain DA systems.(ABSTRACT TRUNCATED AT 250 WORDS)

The sulfates of norepinephrine, dopamine (DA), and serotonin (5-hydroxytryptamine [<em>5HT</em>]) are present in the cerebrospinal fluid (CSF) of laboratory animals and humans. The amounts of sulfated amines in human CSF always greatly exceed the amounts of the free amines. The enzyme responsible for sulfation, phenol sulfotransferase (PST) (EC 2.8.2.1), has been detected in the brain tissue of several species, including humans. PST in the human brain has a high affinity for the amines but it is a low-capacity enzyme. Accordingly, sulfation appears to be of greater significance in the economy of the amines under quiescent conditions than during conditions of increased release of transmitter. Recent evidence suggests that a fraction of the conjugated amines in CSF enters from plasma because in the African green monkey, DA sulfate and <em>5HT</em> sulfate cross the blood-CSF barrier after i.v. injection. In addition, in humans there are no increases in the concentration of amine sulfates from lumbar to ventricular CSF that would also be compatible with a partly peripheral origin for the amine sulfates. However, it appears that at least a portion of the amine sulfates in CSF originate in the central nervous system because the ratios of [CSF amine sulfates]/[plasma sulfates] are never as high after i.v. injection as under basal conditions.

Although the selective toxicity of 5,7-dihydroxytryptamine (5,7-DHT) is thought to depend on the drug's transport into serotonin (<em>5HT</em>) neurons via the <em>5HT</em> transporter, few studies have critically examined this postulation. We therefore evaluated if 5,7-DHT-induced reductions in <em>5HT</em> concentrations and synthesis rate in rat brain are blocked by pretreatment with <em>5HT</em>-selective reuptake inhibitors. Rats pretreated with desipramine (DMI) (to prevent norepinephrine depletion) received intracerebroventricular injections of 5,7-DHT (5, 50, 100, 200 microg/rat) 30 min after fluoxetine (20 mg/kg ip). Forty-eight hours later, they received m-hydroxybenzylhydrazine 30 min before sacrifice. The concentrations of <em>5HT</em> and 5-hydroxytryptophan (<em>5HT</em>P, an index of <em>5HT</em> synthesis) were measured in hypothalamus, cortex and brainstem. Each 5,7-DHT dose produced significant reductions in <em>5HT</em> and <em>5HT</em>P concentrations in all regions examined (5 microg reduced <em>5HT</em> but not <em>5HT</em>P), effects that were not blocked by fluoxetine. Two other <em>5HT</em> reuptake blockers (chlorimipramine, alaproclate) also failed to block the <em>5HT</em> and <em>5HT</em>P depleting actions of 5,7-DHT. Desipramine blocked 5,7-DHT-induced norepinephrine (NE) depletion. Pretreatment with the <em>5HT</em> receptor antagonist metergoline, or the <em>5HT</em>(1A) agonist 8-hydroxy-(di-n-propylamino)tetralin (to slow <em>5HT</em> neuronal firing rate) also failed to antagonize the <em>5HT</em> depleting action of 5,7-DHT. Together, the data strongly suggest that the mechanism by which 5,7-DHT depletes the brain of serotonin does not involve <em>5HT</em>-transporter-mediated concentration of neurotoxin in <em>5HT</em> neurons, may not involve <em>5HT</em> receptor interaction, and does not depend on the firing rate of the <em>5HT</em> neuron.

Platelet serotonin (<em>5HT</em>) uptake was studied in 13 pairs of monozygotic (MZ) twins, 13 pairs of dizygotic (DZ) twins, and 14 pairs of unrelated normal volunteers. Significant intraclass correlations (ICC) in the affinity (Km) of <em>5HT</em> uptake in the blood platelets of MZ and DZ twins and unrelated pairs were found. However, the ICC for maximum velocity (Vmax) was significant only in MZ and DZ twins. The ICC of the Vmax of <em>5HT</em> uptake of MZ twins was significantly greater than that of DZ twins and unrelated pairs. This suggests that the Vmax of <em>5HT</em> uptake in blood platelets is, in part, heritable. Thus, low platelet <em>5HT</em> uptake (Vmax) in major depression and other disorders may be genetically determined.

In order to evaluate the influence of dopaminergic transmission on regional brain utilization of serotonin (<em>5HT</em>), the effects of the destruction of the ascending dopamine (DA) pathways on regional brain <em>5HT</em> metabolism in the rat were examined. Complete unilateral lesions of the nigrostriatal DA pathways >> 90% DA loss) were made by infusing the neurotoxin 6-hydroxy-dopamine into either the left medial forebrain bundle (MFB) or the left substantia nigra (SN). At 6 weeks after the lesions, levels of <em>5HT</em> and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA), were determined bilaterally in the striatum, frontal cortex, and hypothalamus. In the striatum of the lesioned hemisphere, the <em>5HT</em> level decreased by more than 50%, while the ratio of 5HIAA:<em>5HT</em> (an index of <em>5HT</em> turnover) increased by more than 90%. In the same rats, cortical and hypothalamic <em>5HT</em>, 5HIAA, and <em>5HT</em> turnover were not changed as a result of the MFB or SN lesions. These results suggest that the loss of DA innervation in the striatum triggers an increase in <em>5HT</em> turnover and a net depletion of <em>5HT</em> in the striatum. To verify that the loss of DA was responsible for the observed striatal <em>5HT</em> changes, we examined the effect of intracerebral implantation of DA-containing pellets into one group of MFB-lesioned rats. The lesioned rats with placebo pellets did not differ from lesioned rats without pellets, whereas the implantation of DA pellets reversed the lesion-induced changes in the <em>5HT</em> levels and 5HIAA:<em>5HT</em> ratios.(ABSTRACT TRUNCATED AT 250 WORDS)