1. Intrahypothalamic injection of either dopamine or 5-hydroxytryptamine (5-HT) in a dose volume of 1 microliters caused a fall in core temperature in lightly restrained rats maintained at an ambient temperature of 17 +/- 1 degree C. 2. Haloperidol (6.5 n-mole), a dopamine antagonist, prevented the hypothermic effect of dopamine (65 n-mole), but was ineffective against the response to either intrahypothalamic 5-HT (114 n-mole) or oxotremorine (6.0 n-mole). 3. Methysergide (14 n-mole) and cryproheptadine (17 n-mole) blocked the effect of both 5-HT and dopamine. However, these same doses failed to antagonise the effect of oxotremorine. 4. Rats placed on 0.65 m below a 250 W infra-red lamp responded to the imposed heat load vasodilation of tail skin blood vessels, as indicated by an increased tail skin temperature. 5. Rats tested 2 weeks after bilateral intrahypothalamic injection of 5,6-dihydroxytryptamine (42 n-mole in 2 microliters) showed a significant reduction in their tail skin temperature response and were less able to withstand the imposed heat load. 6. Three serial sections (0.8 mm thick) were prepared from the preoptic area of the rat brain, one anterior, one posterior and one corresponding to the previously defined dopamine-sensitive site. 7. Pretreatment with 5,6-dihydroxytryptamine significantly reduced the 5-HT concentration in the dopamine sensitive site, but had no effect on the concentration of dopamine. This pretreatment blocked dopamine but not 5-HT-induced hypothermia. 8. The 5-hydroxyindoleacetic acid (5HIAA) concentration in the hypothalamus of the normal rat exposed to a heat load was found to be significantly elevated, whereas there was no change in the 5HIAA concentration in the cortex. 9. Slices of rat preoptic hypothalamus and hippocampus were incubated with [3H]5-HT (0.2-2 microM). These slices accumulated 5-HT with properties characteristic of a neuronal uptake process. 10. Perfusion with either dopamine (greater than 50 microM) or apomorphine (greater than 200 microM) enhanced the release of [3H]5-HT from the prelabelled hypothalamic slices, but failed to stimulate release from hippocampal slices. 11. The release of [3H]5-HT from preoptic slices by dopamine and apomorphine was antagonised by the dopamine antagonists haloperidol (2 microM) and (+) isomer of butaclamol (1 microM), the (-) isomer of butaclamol was inactive. 12. These results support the hypothesis of a dopamine-<em>5HT</em> link in the hypothalamic thermoregulatory pathways of the rat.

Long-term antidepressant treatment success should be viewed as the result of the cumulative effects of treatment at each stage of major depressive disorder (MDD), and as a balance between efficacy and tolerability/safety. Depression is a heterogeneous disorder and different mechanisms of action of different antidepressants probably capitalize on this response heterogeneity. Results from clinical trials with agomelatine, a melatonergic receptor agonist (MT(1)/MT(2)) and <em>5HT</em>(2C) receptor antagonist, have shown that it is efficacious in both the acute phase and the continuation phase of treatment of depression. Agomelatine's efficacy is observed in different depressive symptom clusters (core depression symptoms, sleep symptoms, anxiety, retardation, somatic symptoms, and work and activities). Active comparator trials show at least comparable efficacy with other antidepressants (paroxetine, venlafaxine, sertraline, fluoxetine) and efficacy has also been demonstrated in severe depression and in treating anxiety symptoms associated with major depression. The tolerability profile shows some clinically significant advantages especially in the lower incidence of treatment emergent sexual dysfunction and of weight gain, two adverse events experienced by patients as most bothersome. Transient aminotransferase elevations without clinical signs of liver damage have been observed more frequently than with placebo (1.1% versus 0.7%), and a hepatic monitoring schedule is therefore recommended.

To study the mechanisms of antiepileptic action of zonisamide (ZNS), we determined the effects of ZNS on extracellular, total levels and re-uptake activity of serotonin (5-HT) in rat striatum and hippocampus. After acute administrations, plasma ZNS concentrations associated with anticonvulsive action (effective concentrations) increased the total levels of 5-HT, its metabolise (5-hydroxyindoleacetic acid: 5-HIAA) and precursor (5-hydroxytryptophan: 5-HTP). After chronic administration of ZNS, effective plasma concentrations also increased the extracellular and total levels of 5-HT, 5-HIAA, and 5-HTP. On the other hand, after both acute and chronic administrations of ZNS, a supra-effective ZNS concentration either decreased or did not affect the total levels of these substances. Therefore, the stimulatory effects of ZNS on the 5-HT system were reduced by an increase in ZNS concentration to supra-effective concentrations. ZNS concentrations of 30-1000 microM did not affect hippocampal <em>5HT</em> re uptake activity in vitro. These results suggest that ZNS has biphasic effects on the 5-HT system, in that effective concentrations of ZNS enhance and supra-effective concentrations of ZNS reduce the function of the 5-HT system. These biphasic effects of ZNS on the 5-HT system may be involved in the mechanisms of action of the antiepileptic and psychotropic effects, and side effects of ZNS.

We identified a population of presumed dopaminergic amacrine cells and populations of presumed serotonergic bipolar and amacrine cells in the retina of the turtle Pseudemys scripta elegans by a combination of autoradiographic, fluorescence, and immunocytochemical techniques. Antisera directed against the dopamine-synthesizing enzyme, tyrosine hydroxylase (TOH), stained perikarya located at the border of inner nuclear (INL) and inner plexiform (IPL) layers. Processes emitted by these cells arborized in sublaminae 1, 3, and 5 of the IPL. Incubation of retinas in 10(-6) M 3H-dopamine yielded a labeling pattern identical to the staining pattern achieved with TOH antisera, but when the concentration of 3H-dopamine was increased 25-fold, both amacrine and bipolar cells are labeled. Following intraocular injection of dopamine, fluorescence micrography revealed both stained amacrine and bipolar cells. The bipolar cells had Landolt's clubs, pyriform perikarya located in the distal portion of the INL, and axons that coursed horizontally in the INL, then entered the IPL, and ramified in both its superficial and deeper layers. Although no fluorescent neuronal profiles were revealed following injection of serotonin (<em>5HT</em>), bipolar cells identical to those described were visualized with <em>5HT</em> antisera. The intensity of bipolar cell staining with <em>5HT</em> antisera was improved by preinjection of the eye with exogenous <em>5HT</em>. We suggest that the bipolar cell is serotonergic, but that it also can actively accumulate dopamine. The <em>5HT</em> antisera also stained a population of large amacrine cells whose processes ramified in IPL sublaminae 1, 4, and 5. The same populations of presumed serotonergic bipolar and amacrine cells were labeled following incubation of the eyecup in 10(-6) M 3H-<em>5HT</em>.

Inorganic lead produces cerebral dysfunction and clinically definable encephalopathies in man. To date there have been few studies on the biochemical changes in brain following exposure to inorganic lead. Studies correlating toxicity with behavioral and brain neurochemical changes following lead exposure have been hindered because adult laboratory animals are resistant to the central nervous system effects of lead poisoning. Such studies have been impeded by lack of suitable experimental models until Pentschew and Garro showed that brain lesions develop in neonatal rats when a pregnant rat newly delivered of her litter is placed on a 4% lead carbonate containing diet. Lead passes into the developing sucklings via maternal milk. Lead-poisoned new-borns have pronounced retardation of growth and during the fourth week of ilfe develop the severe signs of lead encephalopathy, namely, extensive histological lesions of the cerebellum, brain edema, and paraplegia. There is an approximate 85-fold increase in the lead concentration of both the cerebellum and cerebral cortex relative to controls, but edema and gross vascular changes are confined to the cerebellum. Ingested lead had little effect on RNA, DNA, and protein concentrations of developing rat cerebellum and cerebral cortex. However, there was a reduction of between 10 and 20% in the DNA content of the cerebellum around 3 weeks of age in the lead-exposed sucklings. This suggests a failure of cell multiplication in this part of the brain.A critical evaluation of this experimental approach indicated that under similar dietary conditions experimental lactating rats eat 30% less food than controls resulting in: (a) sustained loss in body weight of nursing mothers and that (b) offsprings who develop paraplegia and cerebellar damage do so after gaining access to lead containing diet. We have studied mothers' food consumption and body weight changes and blood, milk, and brain lead content; and newborns' body and brain weight changes, blood and brain lead content, and brain serotonin (<em>5HT</em>), norepinephrine (NE), dopamine (DA), and gamma-aminobutyric acid (GABA). We have found that a lactating mother rat eating 5% lead acetate (2.73% Pb) produced milk containing 25 ppm lead. When the mothers' diet is changed at day 16 from 5% PbAc to one containing 25 ppm Pb, and neonates allowed free access to the solid diet, the sucklings still have retarded body growth but do not develop paraplegia or grossly apparent vascular damage of the cerebellum. However, during the fourth week these animals exhibit a less severe form of "encephalopathy" consisting of hyperactivity, tremors, and stereotype behavior. Pair-fed controls coetaneous to experimental groups do not display such activities. There was no change in brain <em>5HT</em>, GABA, or NE, but a 15-20% decrease in brain DA. Change in DA relative to other monoamines suggests a relationship between CNS dysfunction due to lead and DA metabolism in the brain.The experimental design as discribed provides a model of CNS dysfunction due to lead exposure without debilitating histopathologies. It is possible that our findings on increased motor activity and changes in brain dopamine may correspond to early responses to lead exposure before recognized overt signs of toxicity.

Enterochromaffin (EC) cells in the gastrointestinal tract are known to contain 5-hydroxytryptamine (<em>5HT</em>). The probable ultrastructural localization of <em>5HT</em> in the dense core vesicles ( DCVs ) of EC cells is based on the use of histochemical techniques, such as argentaffinity and the potassium dichromate reaction. In the present paper we describe an immunocytochemical method for specifically localizing <em>5HT</em> in EC cells by electron microscopy. Pieces of mucosa from the pyloric region of the rabbit stomach were prepared for electron microscopy by fixation in 0.5% glutaraldehyde-picric acid-formaldehyde without osmication , and then embedded in LX-112. Thick sections (1 micron) were mounted on glass slides and processed for the fluorescence immunocytochemical localization of <em>5HT</em>. Thin sections (60-90 nm) were mounted on formvar-coated slot grids and processed for the ultrastructural immunocytochemical localization of <em>5HT</em>. Both the thick and thin sections were processed by an identical procedure, beginning with a 30-min incubation in anti-<em>5HT</em> antiserum diluted 1:1400, followed by an IgG-FITC-gold-labeled second antibody. Fluorescent EC cells were consistently observed in the thick sections of gastric mucosa. By carefully trimming and sectioning the adjacent block face, the identical EC cell could be identified by electron microscopy. A quantitative analysis revealed the number of gold particles in EC cells to be significantly greater over the cores of DCVs than over the non-core cytoplasm or over the nucleus. Absorption of the primary antiserum with <em>5HT</em> abolished all labeling, while absorption with a <em>5HT</em> precursor, 5-hydroxytryptophan, did not significantly reduce core labeling. Non-EC epithelial cells were not labeled. These results demonstrate that immunoreactive <em>5HT</em> in EC cells is stored in the cores of DCVs .

CP122,288, a conformationally restricted analogue of sumatriptan, is a highly potent inhibitor of neurogenic plasma protein extravasation (PPE) in rat and guinea pig at low doses where it has no <em>5HT</em>1B-mediated vascular actions. We have examined its effect on a model of trigeminovascular nociception to assess the relative importance of vasoconstrictor and serotonin (<em>5HT</em>)(1B/1D) agonist activity to the modulation trigeminal neuronal activation. For comparison to activate relevant <em>5HT</em> receptors, the clinically effective relatively lipophilic <em>5HT</em>(1B/1D) agonist eletriptan was studied in parallel. The superior sagittal sinus was isolated in the alpha-chloralose (60 mg/kg, i.p. and 15-20 mg/kg i.v. supplement every 2 h) anaesthetized cat. Animals were prepared for stimulation and then maintained for 24 h before stimulation and perfusion for Fos immunohistochemistry. Stimulation of the superior sagittal sinus (250 micros, 100 V, 0.3 Hz) resulted in Fos expression in cells in the trigeminal nucleus caudalis and superficial laminae of the dorsal horns of C(1-2). Administration of low dose CP122,288 (100 ng/kg) had no effect on Fos expression after sinus stimulation either when administered alone or in combination with mannitol; the latter to ensure access to the trigeminocervical complex. The number of cells in the superficial laminae of the trigeminal nucleus caudalis with stimulation being a median of 50 (quartile range: 47-53) and 48 (35-48) after CP122,288, and after CP122,288 and mannitol 45 (41-53). In comparison, the clinically effective <em>5HT</em>(1B/1D) agonist, eletriptan, reduced Fos expression in the trigeminocervical complex to a median of 24 (21-33). These data demonstrate that the potent inhibitor of neurogenic plasma protein extravasation (PPE) CP122,288 has no effect on Fos expression in central trigeminal neurons when administered at a dose which blocks PPE in rat and guinea pig, but has no vasoconstrictor <em>5HT</em>(1B/1D) activity, and while ensuring its access to central trigeminal neurons. The data suggest that activation of the <em>5HT</em>(1B/1D) receptor is important for the clinical action of this class of compounds and is consistent with the fact the CP122,288 is ineffective in the treatment of the acute attack of migraine.

The recovery of persistent inward currents (PICs) and motoneuron excitability after chronic spinal cord transection is mediated, in part, by the development of supersensitivity to residual serotonin (<em>5HT</em>) below the lesion. The purpose of this paper is to investigate if, like <em>5HT</em>, endogenous sources of norepinephrine (NE) facilitate motoneuron PICs after chronic spinal transection. Cutaneous-evoked reflex responses in tail muscles of awake chronic spinal rats were measured after increasing presynaptic release of NE by administration of amphetamine. An increase in long-lasting reflexes, known to be mediated by the calcium component of the PIC (CaPIC), was observed even at low doses (0.1-0.2 mg/kg) of amphetamine. These findings were repeated in a reduced S2 in vitro preparation, demonstrating that the increased long-lasting reflexes by amphetamine were neural. Under intracellular voltage clamp, amphetamine application led to a large facilitation of the motoneuron CaPIC. This indicates that the increases in long-lasting reflexes induced by amphetamine in the awake animal were, in part, due to actions directly on the motoneuron. Reflex responses in acutely spinal animals were facilitated by amphetamine similar to chronic animals but only at doses that were ten times greater than that required in chronic animals (0.2 mg/kg chronic vs. 2.0 mg/kg acute), pointing to a development of supersensitivity to endogenous NE in chronic animals. In summary, the increases in long-lasting reflexes and associated motoneuron CaPICs by amphetamine are likely due to an increased release of endogenous NE, which motoneurons become supersensitive to in the chronic stages of spinal cord injury.

Fusaric acid is produced by several species of Fusarium, which commonly infect corn and other agricultural commodities. Since this mycotoxin may augment the effects of other Fusarium toxins, a gas chromatography/mass spectrometry method of analysis in feeds was developed. Fusaric acid was analyzed as the trimethylsilyl-ester from F. moniliforme-cultures, -contaminated corn screenings, and feeds toxic to livestock. The mycotoxin was found in all samples and ranged from 0.43 to 12.39 micrograms/g sample. Also, fusaric acid was tested for its neurochemical effects in the brain and pineal gland of rats. Animals were dosed intraperitoneally (100 mg/kg body weight) 30 min prior to the onset of the dark phase (lights out) and the effects were studied at 1.5, 3.5, and 5.5 h after treatment. Brain serotonin (<em>5HT</em>), 5-hydroxyindoleacetic acid (5HIAA), tyrosine (TYRO), and dopamine (DA) were increased (P < 0.05) by fusaric acid, and norepinephrine (NEpi) was decreased (P < 0.05). Analogously, DA in the pineal gland increased and NEpi decreased (P < 0.05). Pineal N-acetylserotonin (NAc<em>5HT</em>) was increased (P < 0.05), whereas pineal <em>5HT</em> and its two major metabolites 5HIAA and 5-hydroxytryptophol (<em>5HT</em>OL) decreased (P < 0.05). Elevated brain TYRO and brain and pineal DA, with decreased NEpi, may be consistent with fusaric acid's partial inhibitory effect on tyrosine-hydroxylase and its inhibitory effect on dopamine-beta-hydroxylase, respectively. Elevated pineal Nac<em>5HT</em> is consistent with decreased pineal <em>5HT</em> and the increased pineal DA, and support the dopaminergic stimulatory activity of the enzyme responsible for the conversion of <em>5HT</em> to NAc<em>5HT</em>. This is the first report of fusaric acid's in vivo effect on pineal DA, NEpi, <em>5HT</em>, and NAc<em>5HT</em> in rats, and a relation for the effects on TYRO, <em>5HT</em>, and 5HIAA in brain tissue. The results indicate fusaric acid alters brain and pineal neurotransmitters and may contribute to the toxic effects of Fusarium-contaminated feeds.

Doxazosin, an alpha1-adrenoceptor antagonist, is used for the treatment of benign prostatic hyperplasia (BPH) and hypertension. Alpha-adrenoceptor antagonists also inhibit growth and induce apoptosis in malignant prostatic cells. The apoptotic activity is independent of their capacity to antagonize alpha-adrenoceptors. The effect of doxazosin on the growth of prostate and bladder cancer cell lines was assessed and whether the growth inhibitory effect of doxazosin on prostate cancer cells is serotonin (5-hydroxtryptamine; <em>5HT</em>)-dependent was investigated.

METHODS

PC3 (androgen-independent prostate cancer) and HT1376 (grade III transitional cell carcinoma) cells were plated. The cells were incubated with doxazosin. After 72 h, cell viability was assessed (crystal violet assay). Studies were also performed after incubating the PC3 cells with <em>5HT</em> or <em>5HT</em>(1B) agonists for a short duration, followed by the addition of doxazosin. Cell viability was assessed at 72 h.

RESULTS

Doxazosin caused a dose-dependent inhibition of PC3 and HT1376 cell growth with a maximum inhibition of 80% (n=12, p < 0.0001) and 91% (n=12, p < 0.0001), respectively, at a concentration of 10(-4)M, at 72 h. Incubation of PC3 cells with <em>5HT</em> or <em>5HT</em>(1B) agonist, followed by addition of doxazosin, increased the percent of viable cells as compared to when the cells were treated with doxazosin alone.

CONCLUSIONS

Doxazosin significantly inhibited prostate (PC3) and bladder cancer (HT1376) cell growth. Furthermore, prior incubation of PC3 cells with <em>5HT</em> or <em>5HT</em>(1B) agonist increased cell viability as compared to treatment with doxazosin alone. These findings may be related to the similarity between subtype 1 serotonin and adrenergic receptors. The effect of alpha1-adrenoceptor antagonists on tumour cell growth merits further investigation.

We measured plasma parameters of the prothrombotic state, namely thrombin-antithrombin III complex (TAT), fibrinopeptide A (FPA). D-dimer (DD), von Willebrand factor (vWF), tissue-type plasminogen activator (tPA), beta-thromboglobulin (beta TG), platelet factor 4 (PF4) and serotonin (<em>5HT</em>) in a series of 51 adult patients with chronic uremia: 22 were on maintenance hemodialysis (MHD) and 29 on conservative dietary treatment. Serum tumor necrosis factor alpha (TNF) was determined as well. Uremics presented significantly higher levels of TAT, FPA, DD, vWF, TNF, beta TG and <em>5HT</em> than normal controls. Patients on conservative treatment showed lower levels of TAT, DD, TNF and beta TG than patients on MHD. Our results provide evidence that a prothrombotic state exists in chronic uremia and that MHD patients have a higher degree of hypercoagulation. Both hemodialysis procedure and uremia-related factors are likely to contribute to the hemostatic derangement.

BACKGROUND

Selective drugs are required to test the hypothesis whether antipsychotic effects may be induced or modulated by <em>5HT</em>(2A) receptor antagonism. M100907 (previously known as MDL 100,907) is a highly selective <em>5HT</em>(2A) antagonist in clinical development.

OBJECTIVE

To test if the suggested clinical dose of 20 mg M100907 daily induces high <em>5HT</em>(2A) receptor occupancy in patients with schizophrenia.

METHODS

The <em>5HT</em>(2A) receptor occupancy was determined in two patients with schizophrenia treated with M100907, 20 mg once a day. Positron emission tomography (PET) with (11)C-labeled M100907, was performed prestudy and under steady state conditions. Clinical ratings were performed weekly.

RESULTS

Clinical treatment with M100907, 20 mg daily induced a very high <em>5HT</em>(2A) receptor occupancy in the frontal cortex of both patients (>90%). M100907 was well tolerated. One patient improved minimally and one patient became minimally worse during treatment.

CONCLUSIONS

The results confirm that an oral dose of 20 mg per day ensures adequate <em>5HT</em>(2A) receptor occupancy for clinical proof of concept. The sample is too small to allow conclusions about the clinical effect.

Asenapine is a new atypical antipsychotic agent currently under development for the treatment of schizophrenia and bipolar disorder. It has high affinity for various receptors including antagonism at <em>5HT</em>(2A), <em>5HT</em>(2B), <em>5HT</em>(2C), <em>5HT</em>(6) and <em>5HT</em>(7) serotonergic receptor subtypes, alpha(1A), alpha(2A), alpha(2B) and alpha(2C) adrenergic and D(3) and D(4) dopaminergic receptors. As with other atypicals, asenapine exhibits a high <em>5HT</em>(2A):D(2) affinity ratio. Although similar to clozapine in its multi-target profile, it shows no appreciable affinity for muscarinic receptors. Asenapine has shown efficacy in alleviating both positive and negative symptoms of schizophrenia compared with placebo. Although promising, further studies are required in order to determine whether it has advantages over placebo and other antipsychotics in alleviating cognitive impairment associated with schizophrenia. It has also shown long-term efficacy comparable with olanzapine in bipolar I disorder. Asenapine is generally well tolerated and appears to be metabolically neutral. It has low propensity to cause weight gain and prolactin elevation. There were no concerns in the studies about its effects on the cardiovascular system and QTc prolongation. The incidence of extrapyramidal symptoms with asenapine however has been found to be higher than that with olanzapine. It may be a useful alternative to aripiprazole in schizophrenia and bipolar disorder in patients who are at high risk of metabolic abnormalities.

The different coping responses to three types of aversive events - future threats, acute events and chronic stress - may be modulated by <em>5HT</em> projections. Dysfunction in these coping mechanisms could cause, respectively: generalised anxiety disorder, panic, and depression. This theory proposes that dorsal raphe nucleus projections to <em>5HT</em>(2) and <em>5HT</em>(1D) receptors mediate anticipatory anxiety and normally motivate avoidance of threats. The brain aversion system may be held in check by dorsal raphe nucleus <em>5HT</em> projections to mediate behavioural inhibition during anticipatory anxiety. Proximal aversive stimuli such as pain and asphyxia elicit the fight-flight reflex mediated by the amygdala-hypothalamic-periaqueductal grey brain aversion system. Panic attacks may thus be due to spontaneous activation of this system. Median raphe projections to <em>5HT</em>(1A) receptors have been implicated in adaptation to chronic stress-resilence. There is good evidence that <em>5HT</em>(1A) function breaks down in depression and causes the depressed state. Experimental tests of this theory suggest that viewing anxiety, panic, and depression as dysfunctions in neurochemically and anatomically specific coping systems is heuristically useful.

BACKGROUND

Serotonin (<em>5HT</em>), a naturally occurring vasoactive substance, is released from platelets into plasma under various pathological conditions. Recently, anticancer drugs that act by selectively disrupting tumour blood flow have been found to increase plasma <em>5HT</em> concentrations in mice. Two such antivascular agents, flavone acetic acid (FAA) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA), have completed Phase I clinical trial and raise the important question of whether suitable surrogate markers for antivascular effects can be identified.

METHODS

<em>5HT</em> is unstable to storage, precluding routine clinical assay, but the <em>5HT</em> metabolite, 5-hydroxyindoleacetic acid (5HIAA) accumulates in plasma following <em>5HT</em> release and is a more suitable marker because of its greater stability. We have developed an automated procedure for the assay of the low concentrations of 5HIAA found in humans by combining solid-phase extraction with high-performance liquid chromatography (HPLC).

RESULTS

Efficient separation of 5HIAA from possible interfering substances in human plasma, including a variety of pharmaceutical agents, was achieved on C18 columns using cetyltrimethylammonium bromide (CETAB) as an organic modifier. Adequate precision, accuracy and sensitivity were achieved by electrochemical detection (ECD) at +400 mV. Analysis of plasma from two patients treated with DMXAA in a Phase I trial demonstrated DMXAA-induced elevation of plasma 5HIAA with a time course similar to that previously described in mice.

CONCLUSIONS

Measurement of changes in plasma 5HIAA provides a new approach to the monitoring of therapies with an antivascular effect. The assay is sensitive to dietary sources of <em>5HT</em>, which should be minimised.

Although empirical and neural studies show that serotonin (<em>5HT</em>) plays many functional roles in the brain, prior computational models mostly focus on its role in behavioral inhibition. In this study, we present a model of risk based decision making in a modified Reinforcement Learning (RL)-framework. The model depicts the roles of dopamine (DA) and serotonin (<em>5HT</em>) in Basal Ganglia (BG). In this model, the DA signal is represented by the temporal difference error (δ), while the <em>5HT</em> signal is represented by a parameter (α) that controls risk prediction error. This formulation that accommodates both <em>5HT</em> and DA reconciles some of the diverse roles of <em>5HT</em> particularly in connection with the BG system. We apply the model to different experimental paradigms used to study the role of <em>5HT</em>: (1) Risk-sensitive decision making, where <em>5HT</em> controls risk assessment, (2) Temporal reward prediction, where <em>5HT</em> controls time-scale of reward prediction, and (3) Reward/Punishment sensitivity, in which the punishment prediction error depends on <em>5HT</em> levels. Thus the proposed integrated RL model reconciles several existing theories of <em>5HT</em> and DA in the BG.

Little is known about the cells or mechanisms of O2 chemoreception in vertebrates other than mammals. The purpose of this study, therefore, was to identify O2-sensitive chemoreceptors in a fish. Putative O2-sensitive chemoreceptors were dissociated from the gills of channel catfish, Ictalurus punctatus, and cultured. A population of cells was identified with morphology and a histochemical profile similar to mammalian carotid body Type I (glomus) cells and pulmonary neuroepithelial cells. These cells stain with neutral red and appear to be the branchial neuroepithelial cells. Immunocytochemical staining showed that these cells contain neuron-specific enolase (NSE), tyrosine hydroxylase (TH) and 5-hydroxytryptamine (<em>5HT</em>). Patch-clamp experiments showed that these cells have a O2-sensitive, voltage-dependent outward K+ current like mammalian O2 sensors. Two kinds of electrophysiological responses to hypoxia (P(O2) < 10 Torr) were observed. Some cells showed inhibition of outward current in response to hypoxia, whereas other cells showed potentiation. Neurochemical content and electrophysiological responses to hypoxia indicate that these cells are piscine O2-sensitive chemoreceptors.

Diphenyl diselenide [(PhSe)2] is an organoselenium compound which presents pharmacological antioxidant, anti-inflammatory, antinociceptive and antidepressant properties. The present study was designed to investigate the anxiolytic effect of (PhSe)2 in rats, employing the elevated plus maze task. The involvement of <em>5HT</em> and GABA receptors in the anxiolytic-like effect was also evaluated. (PhSe)2 (5, 25 and 50 micromol/kg, i.p.) did not affect locomotor activity as evaluated in the open open-field test, and learning and memory when assessed in the inhibitory foot-shock avoidance task. However, (PhSe)2 at the 50 micromol/kg dose produced signs of an anxiolytic action, namely a decreased number of fecal boli in the open-field arena and an increased time spent in as well as an increased number of entries to the open arms of the elevated plus maze test. To evaluate the role of GABA and <em>5HT</em> receptors in the anxiolytic-like effect of (PhSe)2, a selective GABAA receptor antagonist bicuculline, (0.75 mg/kg, i.p.), a non-selective <em>5HT</em>2A/2C receptor antagonist, ritanserin (2 mg/kg, i.p.), a selective <em>5HT</em>2A receptor antagonist, ketanserin (1 mg/kg, i.p.), and a selective <em>5HT</em>1A receptor antagonist, WAY100635 (0.1 mg/kg, i.p.) were used. All the antagonists used were able to abolish the anxiolytic effect of (PhSe)2 suggesting that GABAA and <em>5HT</em> receptors may play a role in the pharmacological property of this selenocompound in the central nervous system.

Abrupt withdrawal of benzodiazepine treatment in generalized anxiety patients was found to induce a rebound anxiety state in addition to minor physical symptoms. Controlled clinical trials suggest that the newer high potency benzodiazepines (alprazolam, clonazepam and bromazepam) have novel psychiatric indications and greater anxiolytic effect than the classical benzodiazepines. Alprazolam, a triazolobenzodiazepine, was superior to placebo in the treatment of panic disorder, for which medium or low potency benzodiazepines are generally inefficacious. Clonazepam, an anticonvulsant which increases <em>5HT</em> synthesis, was more efficacious than lithium in reducing manic symptoms. Bromazepam, a new potent benzodiazepine, was superior to diazepam in the treatment of generalized anxiety disorder.

Hamsters repeatedly exposed to cocaine during adolescence display high levels of offensive aggression compared to saline-treated littermates. The escalated offensive phenotype observed in adolescent cocaine-treated animals is modulated by serotonin (5-HT) signaling and can be suppressed by inhibiting 5-HT type 3 receptors, suggesting that these receptors might play an important role in the aggression-stimulating effects of adolescent cocaine exposure. The current study examined this hypothesis and extended earlier studies investigating the relationship between <em>5HT</em>(3) receptor neural signaling and the offensive response patterns of aggressive, adolescent cocaine-treated animals compared to non-aggressive, saline-treated littermates. Adolescent cocaine-treated hamsters and saline-treated littermates were tested for offensive aggression after the administration of either the 5-HT(3) antagonist 3-tropanylindole-3-carboxylate methiodide (tropisetron) or the 5-HT(3) agonist 1-(m-chlorophenyl)-biguanide hydrochloride (mCPBG). Tropisetron significantly reduced the high levels of offensive responding observed in adolescent cocaine-treated animals, whereas treatment with the 5-HT(3) receptor agonist mCPBG failed to affect the escalated offensive response. Conversely, tropisetron failed to affect very low, baseline levels of aggressive responding seen in adolescent saline-treated animals, while 5-HT(3) receptor activation via mCPBG triggered highly escalated levels of offensive aggression in these animals. Together, these data support a stimulatory role for 5-HT(3) neural signaling in offensive aggression.

For many patients suffering from major depressive disorder, available treatments are unsatisfactory due to long delays before the onset of effects, low response rates, poor tolerability, and high recurrence rates. Evidence now suggests that major depressive disorder is a complex syndrome fed by multiple pathways and therefore that modulating serotonergic and noradrenergic neurotransmission, while important, is insufficient. To this effect, data have shown consistently over the last 50 years that patients suffering from depression experience a wide range of circadian rhythm disturbances, and that temporary remission of symptoms can be reached with chronotherapeutic interventions. Agomelatine, a melatonergic antidepressant with an innovative pharmacological profile, is both a melatonergic receptor agonist and a <em>5HT</em>(2C) receptor antagonist. Its antidepressant activity has been demonstrated in animal models and placebo-controlled trials as well as in comparator studies. Clinically and statistically significant improvements in the core symptoms of depression, as well as a rapid onset of benefits, low relapse rates upon discontinuation, and high tolerability have been noted. It is likely that the antidepressant activity of agomelatine results, at least in part, from the resynchronization of the circadian rhythms that are disturbed in many depressed patients. In a recent study, for example, treatment with agomelatine significantly improved the amplitude of the circadian rest-activity/ sleep-wake cycle and decreased depression and anxiety symptoms compared with treatment with sertraline. Together, these data suggest that agomelatine, through its innovative mechanism of action, may result in a more complete and sustained remission for chronically depressed patients.

Cannabinoid receptor activation is involved in homeostatic regulation of the body. These receptors are activated by cannabinoids, that include the active constituents of Cannabis sativa, as well as endocannabinoids (eCBs). The eCBs are endogenously synthesized from the omega-6 and omega-3 polyunsaturated fatty acids (PUFAs). The consumption of omega-3 fatty acids shifts the balance towards a higher proportion of omega-3 eCBs, whose physiological functions warrants further investigation. Herein, we review the discovery of omega-3 fatty acid derived eCBs that are generated from long chain omega-3 PUFAs - docosahexaenoyl ethanolamide (DHA-EA or synaptamide), docosahexanoyl-glycerol (DHG), eicosapentaenoyl ethanolamide (EPA-EA) and eicosapentanoylglycerol (EPG). Furthermore, we outline the lesser known omega-3 eCB-like molecules that arise from the conjugation of omega-3 fatty acids with neurotransmitters serotonin and dopamine - DHA-serotonin (DHA-<em>5HT</em>), DHA-dopamine (DHA-DA), EPA-serotonin (EPA-<em>5HT</em>) and EPA-dopamine (EPA-DA). Additionally, we describe the role of omega-3 eCBs and their derivatives in different disease states, such as pain, inflammation and cancer. Moreover, we detail the formation and potential physiological roles of the oxidative metabolites that arise from the metabolism of omega-3 eCBs by eicosanoid synthesizing enzymes - cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 epoxygenase (CYP450). In summary, we outline the novel findings regarding a growing class of signaling molecules that can control the physiological and pathophysiological processes in the body.

Glucose-induced insulin secretion is inhibited by 5-hydroxytryptamine (<em>5HT</em>). In the present studies the specificity of <em>5HT</em> inhibition of release and the potential biochemical mechanisms involved were investigated. Dose-dependent inhibition of 15 mM glucose-induced secretion was induced by a prior 3 h incubation with <em>5HT</em>. At the highest <em>5HT</em> concentration (500 microM) employed, both first and second phase responses to 15 mM glucose were reduced 50-60%. In addition, this level (500 microM) of <em>5HT</em> virtually abolished 10 mM glucose-induced secretion. In contrast, secretion in response to the protein kinase C activator phorbol 12-myristate 13-acetate (500 nM) was immune to 500 microM <em>5HT</em> pre-treatment. Glucose usage rates were comparable in both control and 500 microM <em>5HT</em>-pretreated islets. However, the generation of inositol phosphates and the efflux of 3H-inositol from 3H-inositol-prelabeled islets in response to stimulatory glucose were impaired in parallel with insulin secretion. Based on these observations the following conclusions were reached: (1) <em>5HT</em> impairs glucose-induced insulin release by altering glucose-induced activation of phospholipase C. (2) Biochemical events distal to phospholipase C remain intact despite this proximal biochemical lesion. (3) Amperometric analysis of <em>5HT</em> release from <em>5HT</em>-pretreated islets must take into consideration its profound adverse impact on glucose-induced insulin secretion.

Epilepsy is a syndrome of episodic brain dysfunction characterized by recurrent unpredictable, spontaneous seizures. Cerebellar dysfunction is a recognized complication of temporal lobe epilepsy and it is associated with seizure generation, motor deficits and memory impairment. Serotonin is known to exert a modulatory action on cerebellar function through <em>5HT</em>(2C) receptors. 5-HT(2C) receptors are novel targets for developing anti-convulsant drugs. In the present study, we investigated the changes in the 5-HT(2C) receptors binding and gene expression in the cerebellum of control, epileptic and Bacopa monnieri treated epileptic rats. There was a significant down regulation of the 5-HT content (p<0.001), 5-HT(2C) gene expression (p<0.001) and 5-HT(2C) receptor binding (p<0.001) with an increased affinity (p<0.001). Carbamazepine and B. monnieri treatments to epileptic rats reversed the down regulated 5-HT content (p<0.01), 5-HT(2C) receptor binding (p<0.001) and gene expression (p<0.01) to near control level. Also, the Rotarod test confirms the motor dysfunction and recovery by B. monnieri treatment. These data suggest the neuroprotective role of B. monnieri through the upregulation of 5-HT(2C) receptor in epileptic rats. This has clinical significance in the management of epilepsy.