A method of expressing platelet aggregation response after incubation relative to the response before incubation has been used in preference to using direct measurements, and some reasons are given for this choice. The effect of pre-incubating human platelets with reserpine has been compared with the effect of pre-incubation with 5-hydroxytryptamine (<em>5HT</em>). Reserpine inhibited <em>5HT</em>-induced aggregation more slowly than <em>5HT</em> and on this basis their actions could be distinguished. It was found that the aggregation response of human platelets to <em>5HT</em> without pre-incubation (R) is inversely proportional to the natural <em>5HT</em> content of whole blood, and an explanation has been suggested.A decrease in the aggregation response of human platelets to <em>5HT</em> without pre-incubation (R) with increasing age has been noted, and is commented upon with reference to the release of amines from blood platelets. Platelets in plasma obtained from control subjects and incubated with methysergide and from migrainous patients taking methysergide both have reduced aggregation responses to <em>5HT</em>. Platelets incubated with clonidine (St155) do not have reduced aggregation responses. A potentiating effect was noted after 20 minutes' incubation, but platelets from migraine patients taking St155 behaved normally. Tyramine affected the response of platelets to <em>5HT</em>, giving results similar to those reported for reserpine. The differences between the aggregation responses to <em>5HT</em> of platelets from migraine patients and normal control subjects are discussed.

Mood disturbances and depression are supposed to have a negative impact on patients' outcome in malignant tumour disease. On the other hand, poor prognosis in cancer patients is associated with chronic immune challenge which is paralleled by enhanced degradation of the essential amino acid tryptophan and thus decreased plasma tryptophan concentrations. Because tryptophan is precursor for the biosynthesis of the neurotransmitter serotonin (= 5-hydroxytryptamine, <em>5HT</em>), low tryptophan concentrations will lead to decreased availability of serotonin which finally increases the susceptibility for the development of mood disturbances and depression in the patients. Thus, the development of depression in cancer patients may result from chronic cellular immune stimulation. In conclusion, a more aggressive tumour rather than depression will be responsible for worse outcome of cancer patients and will be associated with a more drastic challenge of the immune system, as a side effect leading to neurotransmitter disturbances.

N-Palmitoyl-5-hydroxytryptamines (Pal-<em>5HT</em>), a cannabinoid, has recently been reported to express anti-allergic and anti-inflammatory actions in RBL-2H3 cells, and ameliorate glutamate-induced cytotoxicity in HT-22 cells. In this study, we examined the effect of Pal-<em>5HT</em> on deficits of learning and memory induced by scopolamine in mice. Memory performance was evaluated using Morris water maze test and passive avoidance test. Activities of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT), level of oxidative stress markers, and expression of brain-derived neurotrophic factor (BDNF), phosphorylation of cAMP response element-binding protein (p-CREB) were determined. Loss of neuronal cells in hippocampus was evaluated by histological examinations. Pal-<em>5HT</em> significantly improved the amnesia in the behavioral assessment. Pal-<em>5HT</em> regulated cholinergic function by inhibiting scopolamine-induced elevation of AChE activity and decline of ChAT activity. Pal-<em>5HT</em> suppressed oxidative stress by increasing activities of glutathione peroxidase (GPx), glutathione reductase (GR) or NAD(P)H quinine oxidoreductase-1 (NQO-1) and lowering MDA level. Additionally, it prevented against scopolamine-induced expression of iNOS and COX-2. Moreover, Pal-<em>5HT</em> suppressed the death of neuronal cells in CA1 and CA3 regions, while it restored expression of p-CREB and BDNF in hippocampus. Taken together, Pal-<em>5HT</em> is suggested to ameliorate deficits of memory and learning through regulation of cholinergic function, activation of antioxidant systems as well as restoration of BDNF and p-CREB expression. From these, Pal-<em>5HT</em> may be a potential candidate to prevent against neurodegeneration related to the memory deficit.

Although atypical antipsychotics have been associated with improvements in cognitive function in schizophrenia, the neurochemical basis for such effects is not well understood. Candidate neurotransmitter systems primarily involve dopamine and serotonin. The current study explored this issue by examining the cognitive abilities, social function and quality of life in patients with schizophrenia who were medicated with atypical antipsychotics. Comparisons were done for matched schizophrenia patients who were on antipsychotics with (i) an affinity for multiple receptors (olanzapine, clozapine, quetiapine) versus those that have preferential affinity for dopamine receptors (risperidone, amisulpride); and patients on medication with (ii) a high affinity for serotonin (<em>5HT</em>-2A) receptors (risperidone, olanzapine, clozapine) versus those with a low (or no) affinity for <em>5HT</em>-2A receptors (quetiapine, amisulpride). No differences emerged between groups on any cognitive or social variable when the groups were compared for the dopaminergic properties of antipsychotic medication. By contrast, differences did emerge when patients were compared on the <em>5HT</em>-2A affinity of their antipsychotic medications. Patients on low <em>5HT</em>-2A-affinity antipsychotics exhibited a better performance on a measure of selective attention and adjustment to living. These findings accord with the notion that serotonergic mechanisms are important determinants of both the cognitive and the social effects of the atypical antipsychotics.

The coupling of serotonin receptors to Ca2+ channels was studied in a subpopulation of acutely isolated rat dorsal root ganglion (DRG) cell bodies (type 1 DRG cells), which have membrane properties similar to C-type nociceptive sensory neurons. In these cells, serotonin (<em>5HT</em>) inhibited high-threshold Ca2+ channel current and decreased action potential duration. The inhibitory effects of <em>5HT</em> and the <em>5HT</em>1A agonist 8-OH-DPAT were shown to be antagonized by the <em>5HT</em>1A antagonists spiperone and pindolol, respectively, indicating involvement of a <em>5HT</em>1A receptor. Several observations suggest that <em>5HT</em>1A receptors couple to N- and L-type Ca2+ channels by two different signaling pathways in type 1 DRG cells. The inhibition of Ca2+ channel currents produced by 10 microM <em>5HT</em> occurred in two phases, an initial slowing of current activation rate (kinetic slowing), which was complete within 10 s, and a simultaneous reduction in steady state current amplitude (steady state inhibition), which peaked in approximately 1 min. The kinetic slowing, but not steady state inhibition, was reversed by a positive prepulse to +70 mV (prepulse). Blockade of N-type Ca2+ channels selectively reduced the kinetic slowing and its reversal by prepulses. Chelation of intracellular Ca2+ or blockade of L-type Ca2+ channels selectively reduced the steady state inhibition. Recordings using the cell-attached patch configuration suggest that steady state inhibition required a component that was diffusible in the cytosol, while kinetic slowing occurred via a membrane delimited pathway. The application of <em>5HT</em> to the cell body outside the patch pipette reduced macroscopic Ca2+ channel currents in 33% of small-diameter DRG cells tested, indicating the participation of a cytosolic diffusible component. Application of <em>5HT</em> (a membrane impermeant compound) outside the patch pipette produced steady state inhibition only, whereas similar application of membrane permeant <em>5HT</em>1A agonists, 8-OH-DPAT or 5-methoxy-N,N-dimethyl-tryptamine, produced kinetic slowing and steady state inhibition. Together these data suggest that <em>5HT</em>1A receptors couple negatively to Ca2+ channels via two pathways: a membrane-delimited pathway that couples to N-channels and actuates voltage-sensitive kinetic slowing and a pathway dependent on a cytosolic diffusible component and free intracellular Ca2+, which couples to L channels and actuates steady state inhibition.

The effects of acetaminophen (APAP) in vitro, or ex vivo following APAP ingestion, on human platelet aggregation, 14C-<em>5HT</em> secretion, and thromboxane B2 (TxB2) formation were assessed. APAP added in vitro to citrated platelet-rich plasma (PRP) inhibited aggregation, secretion, and TxB2 formation induced by collagen, epinephrine, arachidonate, and the ionophore A23187, but had no effect on the responses induced by the endoperoxide analog U44069. Arachidonate-induced responses were inhibited by lower concentrations of APAP than were the responses to the other agonists. In PRP obtained 1 hour after ingestion of 650 mg or 1000 mg APAP, arachidonate-induced TxB2 formation was inhibited by 40-99% in five subjects tested, whereas inhibition of collagen- or epinephrine-induced TxB2 formation was less consistent. Aggregation and secretion responses were not altered by APAP ingestion in 4 of the 5 subjects, but were inhibited in the remaining subject, who had the highest plasma APAP levels. In contrast to aspirin and indomethacin, APAP-induced inhibition of collagen-stimulated TxB2 formation could be partially overcome with increasing collagen concentrations. No such partial correction occurred with epinephrine, however. In washed platelet suspensions labeled with 3H-arachidonate, both APAP and aspirin inhibited the formation of labeled PGD2 and PGE2, as well as TxB2. These results suggest that APAP acts in human platelets as a reversible inhibitor of cyclo-oxygenase, as found previously in other tissues, and that recent APAP ingestion can, on occasion, produce inhibition of platelet functional responses measured in vitro.

Twenty-four hour rhythmicity of serum prolactin and median eminence and anterior pituitary content of dopamine (DA), serotonin (<em>5HT</em>), gamma-aminobutyric acid (GABA), taurine and somatostatin were examined in 2 months-old and 18-20 months-old Wistar male rats. The concentration of prolactin was higher in aged rats, with peaks in both groups of rats at the early phase of the activity span. Median eminence DA content of young rats attained its maximum at the middle of rest span and decreased as prolactin levels augmented while the lowest values of adenohypophysial DA were observed at the time of prolactin peak. DA rhythmicity disappeared in aged rats. GABA content of median eminence and adenohypophysis was lower in aged rats, with maximal values of median eminence GABA at light-dark transition in young rats and at the second half of activity span in aged rats. Serum prolactin correlated positively with median eminence GABA in young rats and negatively with pituitary GABA in young and aged rats. Median eminence somatostatin peaked at the beginning of the activity phase (young rats) or at the end of the rest phase (aged rats). Prolactin levels and somatostatin content correlated significantly in young rats only. Median eminence and pituitary <em>5HT</em> and taurine content did not change with age. The results indicate disruption of prolactin regulatory mechanisms with aging in rats.

N-feruloylserotonin (N-f-<em>5HT</em>) isomers, isolated from seeds of Leuzea carthamoides (Wild) DC, inhibited dose-dependent oxidative burst in human whole blood and isolated neutrophils in vitro, which were measured by luminol- and/or isoluminol-enhanced chemiluminescence in the following rank order of stimuli: PMA>> OpZ>> calcium ionophore A23187. In isolated neutrophils that were stimulated with PMA, N-f-<em>5HT</em> isomers were effective against extracellular and intracellular reactive oxygen species. Liberation of ATP, analysis of apoptosis, and recombinant caspase-3 activity revealed that N-f-<em>5HT</em> isomers, used in concentrations up to 100 μM, did not alter the viability and integrity of isolated neutrophils. Western blot analysis documented that in concentrations of 10 and 100 μM, N-f-<em>5HT</em> isomers significantly decreased PMA-induced phosphorylation of PKC α/β II. The results suggest that N-f-<em>5HT</em> isomers are an effective, naturally occurring substance with a potent pharmacological effect on the oxidative burst of human neutrophils. It should be further investigated for its pharmacological activity against oxidative stress in ischemia-reperfusion, inflammation and other pathological conditions.

Although metabotropic glutamate receptor (mGluR) modulation has been studied extensively in neurons, it has not been investigated in astrocytes. We studied modulation of glutamate-evoked calcium rises in primary astrocyte cultures using fura-2 ratiometric digital calcium imaging. Calcium plays a key role as a second messenger system in astrocytes, both in regulation of many subcellular processes and in long distance intercellular signaling. Suprachiasmatic nucleus (SCN) and cortical astrocytes showed striking differences in sensitivity to glutamate and to mGluR agonists, even after several weeks in culture. Kainate-evoked intracellular calcium rises were inhibited by concurrent application of the type I and II mGluR agonists quisqualate (10 micro;M), trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylate (100-500 micro;M), and (2S-1'S-2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I) (10 micro;M). Inhibition mediated by L-CCG-I had long-lasting effects (>45 min) in approximately 30% of the SCN astrocytes tested. The inhibition could be mimicked by the L-type calcium channel blocker nimodipine (1 micro;M) as well as by protein kinase C (PKC) activators phorbol 12,13-dibutyrate (10 micro;M) and phorbol 12-myristate 13-acetate (500 nM), and blocked by the PKC inactivator (+/-)-1-(5-isoquinolinesulfonyl)-2-methylpiperazine (200 micro;M), suggesting a mechanism involving PKC modulation of L-type calcium channels. In contrast, mGluRs modulated serotonin (<em>5HT</em>)-evoked calcium rises through a different mechanism. The type III mGluR agonist L-2-amino-4-phosphonobutyrate consistently inhibited <em>5HT</em>-evoked calcium rises, whereas in a smaller number of cells quisqualate and L-CCG-I showed both inhibitory and additive effects. Unlike the mGluR-kainate interaction, which required a pretreatment with an mGluR agonist and was insensitive to pertussis toxin (PTx), the mGluR modulation of <em>5HT</em> actions was rapid and was blocked by PTx. These data suggest that glutamate, acting at several metabotropic receptors expressed by astrocytes, could modulate glial activity evoked by neurotransmitters and thereby influence the ongoing modulation of neurons by astrocytes.

Lurasidone is a new second-generation antipsychotic approved in October 2010 by the Food and Drug Administration for the treatment of schizophrenia. Like other second-generation antipsychotics, lurasidone is a powerful antagonist of D(2) dopamine and <em>5HT</em>(2A) serotonin receptors, but differs from the other second-generation antipsychotics in its action profile for certain receptors. Lurasidone is the second-generation antipsychotic with the greatest affinity for <em>5HT</em>(7) receptors and has a high affinity for <em>5HT</em>(1A) serotonin receptors, compatible with favorable effects on cognitive function and an antidepressant action. By contrast, lurasidone has a low affinity for and α(1) α(2C)-adrenergic and <em>5HT</em>(2C) serotonin receptors, and no affinity for histaminergic H(1) or muscarinic M(1) receptors, suggesting a better tolerability profile than the other second-generation antipsychotics. Lurasidone has demonstrated its efficacy in several short-term trials in acute schizophrenia, promptly and significantly reducing total Positive and Negative Syndrome Scale and Brief Psychiatric Rating Scale scores compared with placebo. Several long-term studies are in progress to assess its efficacy in the maintenance treatment of schizophrenic patients. The efficacy of lurasidone with regard to cognitive functions and depressive symptoms seems good, but requires further work. Lurasidone differs from the other second-generation antipsychotics by having a good tolerability profile, in particular for cardiometabolic tolerability. However, it seems to have a significant although moderate link with the occurrence of akathisia, extrapyramidal symptoms, and hyperprolactinemia at the start of treatment. This tolerance profile greatly broadens the scope of second-generation antipsychotics and so supports the view of some authors that the term "second-generation antipsychotic" is now outdated. Other therapeutic perspectives of lurasidone are assessed here, in particular bipolar depression.

Gepirone (BMY 13805), a buspirone analog, was used to determine the antianxiety mechanism of the arylpiperazine class of drugs. Because of the weak effects of these drugs on conflict behavior, isolation-induced aggressive mice were used as the antianxiety model. Gepirone, like buspirone, potently inhibited attacks against group housed intruder mice (ED50 = 4.5 mg/kg i.p.) without causing sedation or ataxia. Inhibition of aggression was potentiated by co-administration of 0.25 mg/kg methiothepin or 2.5 mg/kg methysergide. Gepirone had variable effects on dopamine metabolism and reduced 5-hydroxytryptamine (<em>5HT</em>) metabolism about one third after a dose of 2.5 mg/kg. In contrast to buspirone, which markedly increased dopaminergic impulse flow, gepirone inhibited the firing of most cells recorded from the substantia nigra zona compacta in doses of 2.3-10 mg/kg i.v. and the effects were reversible by administration of haloperidol. The common metabolite of buspirone and gepirone, 1-(2-pyrimidinyl)-piperazine, caused increased firing rates only. Gepirone potently inhibited serotonergic impulse flow recorded from the dorsal raphe nucleus (88.3% after 0.04 mg/kg) and this effect was partially reversed by serotonergic antagonists. Both buspirone and gepirone displaced [3H]-<em>5HT</em> from the <em>5HT</em>1a binding site in the hippocampus with IC50 values of 10 and 58 nM, respectively. Non-alkyl substituted aryl-piperazines displaced [3H]-<em>5HT</em> from both <em>5HT</em>1a and <em>5HT</em>1b binding sites. Thus, although gepirone may be a weak postsynaptic <em>5HT</em> agonist, its primary effect is to decrease <em>5HT</em> neurotransmission. In support of this conclusion was the observed potentiation of antiaggressive effects by blocking <em>5HT</em> receptors wit small doses of methiothepin or methysergide, which would exacerbate the decreased release of <em>5HT</em> caused by gepirone. These results are in harmony with reports that decreased serotonergic activity has anxiolytic-like effects in animal models of anxiety.

Research with antidepressants has emphasized the importance of a delayed deamplification of the linked serotonin (<em>5HT</em>)/norepinephrine (NE) receptor coupled adenylate cyclase system in brain. The basic phenomena of regulation of receptor number and function of the beta adrenoceptor linked adenylate cyclase system in brain are well established, with NE regulating beta adrenoceptors in the high agonist affinity conformation (linked to adenylate cyclase and down-regulated by antidepressants), and with <em>5HT</em> regulating those receptors in the low agonist affinity conformation. The biochemical effector systems of NE and <em>5HT</em> are discussed and it is concluded that the final common pathway of signal transduction is protein kinase mediated phosphorylation of cellular proteins. Glucocorticoid receptors are located in the perikarya of aminergic cell bodies and may exert their effects by modifying the genomic expression of the diffusely projecting stress-responsive monoamine systems. The molecular neurobiology of beta adrenoceptors, with its implication for genetic and immunologic investigations, is briefly discussed and further research on stimulus-transcription coupling and regulation of gene expression in brain is suggested as an exciting new direction in central receptor research relevant to the psychopharmacology of affective and other disorders.

BACKGROUND

The most effective pharmacological treatments for depression inhibit the transporters that reuptake serotonin (Selective Serotonin Reuptake Inhibitors - SSRIs) and noradrenaline (Noradrenaline Reuptake Inhibitors - NaRIs) into the presynaptic terminal. There is evidence to suggest that noradrenaline and serotonin enhancing drugs work through separate mechanisms to produce their clinical antidepressant action. Although most of the current evidence suggests there is little difference in overall efficacy between SSRIs and NaRIs, there are patients who respond to one class of compounds and not another. This suggests that treatment response could be predicted by genetic and/or clinical characteristics. Firstly, this study aims to investigate the influence of a polymorphism (SLC6A4) in the <em>5HT</em> transporter in altering response to SSRI medication. Secondly, the study will investigate whether those with more severe depression have a better response to NaRIs than SSRIs.

METHODS

The GenPod trial is a multi-centre randomised controlled trial. GPs referred patients aged between 18-74 years presenting with a new episode of depression, who did not have any medical contraindications to antidepressant medication and who had no history of psychosis or alcohol/substance abuse. Patients were interviewed to ascertain their suitability for the study. Eligible participants (with a primary diagnosis of depression according to ICD10 criteria and a Beck Depression Inventory (BDI) score>> 14) were randomised to receive one of two antidepressant treatments, either the SSRI Citalopram or the NaRI Reboxetine, stratified according to severity. The final number randomised to the trial was 601. Follow-up assessments took place at 2, 6 and 12 weeks following randomisation. Primary outcome was measured at 6 weeks by the BDI. Outcomes will be analysed on an intention-to-treat basis and will use multiple regression models to compare treatments.

CONCLUSIONS

The results of the trial will provide information about targeting antidepressant treatment for individual patients; in turn this may increase prescribing efficacy, thereby speeding recovery and reducing the cost to the NHS. It will also help to understand the different roles that noradrenaline and serotonin might play in the biology of depression. The trial is expected to report in the autumn of 2008.

BACKGROUND

ISRCTN 31345163.

1. Injection of lipopolysaccharides (LPS) or endotoxin into mice and rats induces a prolonged increase in serotonin (5-hydroxytryptamine: <em>5HT</em>), predominantly in the liver. 2. The <em>5HT</em> increase reflects the accumulation of platelets in the sinusoidal and perisinusoidal Disse spaces (spaces between endothelial cells and hepatocytes) in the liver. 3. Most of the platelets which accumulated in these spaces still retained their intact structure and a large amount of <em>5HT</em>. 4. Interleukin-1 and/or tumor necrosis factor also induce the platelet response. 5. Kupffer's cells play a key role in this platelet response. 6. Anti-platelet drugs currently used, except for anti-inflammatory steroids, were ineffective in preventing the platelet response. 7. This platelet response is different from the well known platelet aggregation. 8. The possible involvement of this platelet response in insulin-independent hypoglycaemia, disseminated intravascular coagulation, septic shock, hepatitis, Shwartzman type reactions or self-defense mechanisms is discussed.

Serotonergic (5-HT) and dopaminergic activities have been examined in Lewy Body Dementia (LBD) and compared with Parkinson's disease (PD) and Alzheimer's disease (AD). In the neocortex the LBD subgroup experiencing hallucinations was distinguished from the other categories by an increase in the 5HIAA:<em>5HT</em> ratio measured in frontal cortex and by the serotonergic (5-HIAA or 5-HIAA:5-HT): cholinergic (choline acetyltransferase) ratio in frontal and temporal cortex. In the neostriatum (caudate nucleus), loss of dopamine and increased HVA:dopamine ratio correlated with the reduction in substantia nigra neurons in LBD but not PD, despite the greater loss of neurones and dopamine and the higher dopamine turnover ratio in PD. LBD patients experiencing severe Parkinsonism as a result of neuroleptic treatment tended to have lower neuron counts, in combination with higher turnover ratios, than the remainder. Qualitative differences between LBD and PD included decreased cortical 5-HT turnover in PD compared with the increase in LBD. There were no significant changes in any parameter in AD, with the exception of a reduction in temporal cortex 5HIAA. The results suggest that although the neurochemical pathology of LBD and PD involves similar systems, the nature of the derangements differs sufficiently between the diseases to account for differences in symptomatology.

BACKGROUND

Aripiprazole (OPC-14597) is a novel atypical antipsychotic drug with a low incidence of side effects. The therapeutic action of aripiprazole has been attributed to its unique agonist/antagonist effects at D(2) dopamine receptors; however, aripiprazole also has significant in vitro affinity at 5-HT(1A) receptors.

OBJECTIVE

The 5-HT(1A) agonist property of aripiprazole has so far not been evaluated in any in vivo assay.

METHODS

Thirteen male Sprague Dawley rats trained to discriminate the 5-HT(1A) agonist LY 293284 (75 nmol/kg) from saline, using a fixed ratio (FR) 50 schedule of food-reinforcement in a two-lever operant-conditioning task, were used to evaluate the behavioral effect of aripiprazole at 5-HT(1A) receptors.

RESULTS

Aripiprazole fully mimicked LY 293284 in a drug-discrimination assay with an ED(50) of 1.39 micromol/kg (0.62 mg/kg). In combination tests, aripiprazole did not block the LY 293284 cue but at 8.92 micromol/kg (4 mg/kg) significantly reduced the response rate by lowering the threshold for induction of the 5-HT syndrome produced by the training dose of LY 293284. Moreover, the selective <em>5HT</em>(1A) receptor antagonist WAY 100635 was able to block the substitution of aripiprazole in LY-293284 trained rats.

CONCLUSIONS

Although the efficacy of aripiprazole against the positive symptoms of schizophrenia may be related to its dopamine receptor interactions, it seems possible that its atypical profile may derive, at least in part, from its 5-HT(1A) agonist effect, rather than from unusual D(2) receptor properties.

Serotonergic neurons in the dorsal raphe nucleus, the major source of forebrain serotonin projections, synthesize a terminal autoreceptor that inhibits serotonin release-the 5-HT(1B) autoreceptor. Overexpression of this autoreceptor is hypothesized to contribute to anxiety. Antidepressants decrease (while learned helplessness increases) 5-HT(1B) mRNA in dorsal raphe neurons, and viral-mediated overexpression of 5-HT(1B) here increases anxiety behavior after stress. However, 5-HT(1B) mRNA levels in dorsal raphe are substantially elevated in unstressed rats in two models of stress resistance. Thus, the role of dorsal raphe 5-HT(1B) autoreceptors in anxiety is complex. Therefore, we tested whether different stressors differentially affect dorsal raphe 5-HT(1B) mRNA [via in situ hybridization histochemistry] and anxiety behavior (using the elevated plus maze). Rats were assigned to a stressor (either forced swim, water restraint, dry restraint, or electric tail shock) or a control condition, then were tested and sacrificed 24 h later. Overall, controls exhibited less anxiety than stressed rats as indicated by a higher ratio of open arm to total arm entries (OTR). The stressors did not differentially affect the OTR, nor did any alter dorsal raphe 5-HT(1B) mRNA levels. There was, however, a significant positive correlation between the OTR and <em>5HT</em>(1B) mRNA intensity in controls (r=.64; P=.006), but not in stressed rats (r=.16, P=.36), providing further evidence that elevated dorsal raphe 5-HT(1B) levels are associated with reduced anxiety in animals that have not been exposed to stress.

Depression is highly prevalent in community and primary care samples. According to the findings of the Sequential Treatment Alternatives to Relieve Depression study, after multiple clinical interventions, approximately one-third of patients never fully experienced remission from depression. This somber finding invites consideration of novel antidepressant options, which may in the near future include agomelatine. Agomelatine is a melatonergic agonist and a <em>5HT</em>(2c) antagonist (i.e., it has a unique mechanism of action). The melatonergic function appears to improve sleep patterns, whereas the serotonergic antagonism results in the release of norepinephrine and dopamine. Given the current information, the overall side-effect profile of agomelatine appears relatively mild. For example, agomelatine has no discontinuation syndrome, exhibits infrequent sexual dysfunction, and is generally weight neutral. The drug appears to be relatively safe in overdose. On a cautionary note, however, one percent of patients experience elevated hepatic transaminases while on treatment. Overall, agomelatine may be a unique pharmacological addition in the clinical war on depression in both psychiatric and primary care settings-if further evaluation in clinical trials supports reasonable risk.

The antiplatelet and antithrombotic activity of SL65.0472 (7-fluoro-2-oxo-4-[2-[4-(thieno [3,2-c]pyrin-4-yl) piperazin-1-yl]ethyl]-1,2-di-hydroquinoline-acetamide), a mixed 5-HT1B/5-HT2A receptor antagonist was investigated on <em>5HT</em>-induced human platelet activation in vitro, and in rat, rabbit and canine platelet dependent thrombosis models. SL65.0472 inhibited 5-HT-induced platelet shape change in the presence of EDTA (IC50 values = 35, 69 and 225 nM in rabbit, rat and human platelet rich plasma (PRP)), and also inhibited aggregation induced in human PRP by 3-5 microM 5-HT + threshold concentrations of ADP (0.5-1 microM) or collagen (0.3 microg/ml) with mean IC50 values of 49 +/- 13 and 48 +/- 6 nM respectively. SL65.0472 inhibited thrombus formation when given both intravenously 5 min and orally 2 h prior to assembly of an arterio-venous (A-V) shunt in rats as from 0.1 and 0.3 mg/kg respectively. It was active in a rabbit A-V shunt model with significant decreases in thrombus weight as from 0.1 mg/kg i. v. and at 10 mg/kg p.o. The delay to occlusion in an electric current-induced rabbit femoral artery thrombosis model was increased by 251% (p <0.05) after 20 mg/kg p.o. SL65.0472 (30 microg/kg i.v.) virtually abolished coronary cyclic flow variations (7.2 +/- 1.0/h to 0.6 +/- 0.6/h, p <0.05) and increased minimum coronary blood flow (1.2 +/- 0.8 ml/min to 31.8 +/- 8.4 ml/min, p <0.05) in a coronary artery thrombosis model in the anaesthetised dog. Finally, SL65.0472 significantly increased the amount of blood lost after rat tail transection at 3 mg/kg p.o. Thus the anti-5-HT2A component of SL65.0472 is reflected by its ability to inhibit 5-HT-induced platelet activation, and platelet-rich thrombus formation.

OCD was considered a rare, treatment refractory disorder of psychological origin, up until 20 years ago. Research in the last two decades has altered the perspectives regarding OCD. It is now clear that OCD is a prevalent disorder--about 2% of the population suffer from OCD--and that it is amenable both to psychological (cognitive-behavioural approach) and pharmacological intervention (with serotonergic medication). The biochemical and neuroanatomical (the frontal basal-thalamo cortical circuit) pathophysiology of OCD is also beginning to emerge. OCD is unique with regards to its specific response to serotonergic medication that blocks reuptake. Clomiprimine, fluoxetine, fluvoxemine, paroxetine, sertraline and citalopram were all found to be effective treatments for OCD based on large, multicentre, double-blind, placebo-controlled studies. As only serotonergic medications appear to be effective in OCD, the serotonergic hypothesis has been formulated and tested. Indeed, pharmacological challenges with specific serotonin agonists such as mCPP and sumatriptan, which were associated with transient exacerbation of OCD symptoms, are in line with the specific role of <em>5HT</em> in the pathogenesis of OCD. However, this serotonergic hypothesis, while necessary, is not sufficient. It is clear that the dopaminergic and autoimmune mechanism are also implicated in the pathogenesis of OCD. Further studies are required to understand the relevance of the serotonergic and non-serotonergic systems in OCD, and to highlight the various possible subtypes of this intriguing disorder.

Serotonergic agonists such as m-chlorophenylpiperazine (m-CPP) and fenfluramine may induce migraine attacks. This has led to opposing theories concerning the role of 5-hydroxytryptamine (<em>5HT</em>) in triggering migraine attacks; is there hyperfunction or hypofunction of the central serotonergic system. Our review of the literature strongly suggests that m-CPP and fenfluramine provoke migraine attacks by stimulating, directly or indirectly, the <em>5HT</em>2C/<em>5HT</em>2B receptors, although there is no total agreement with this interpretation. Central <em>5HT</em> hypersensitivity in migraine patients, probably due to <em>5HT</em> neuronal depletion, is proposed on the basis of review of electrophysiological tests and neuroendocrine challenge paradigms.

Contextual fear conditioning involves forming a context representation and associating it to a shock, both of which involved the dorsal hippocampus (DH) according to our recent findings. This study tested further whether the two processes may rely on different neurotransmitter systems in the DH. Male Wistar rats with cannula implanted into the DH were subjected to a two-phase training paradigm of contextual fear conditioning to separate context learning from context-shock association in two consecutive days. Immediately after each training phase, different groups of rats received bilateral intra-DH infusion of the GABA(A) agonist muscimol, <em>5HT</em>(1A) agonist 8-OH-DPAT, NMDA antagonist APV or muscarinic antagonist scopolamine at various doses. On the third day, freezing behavior was tested in the conditioning context. Results showed that intra-DH infusion of muscimol impaired conditioned freezing only if it was given after context learning. In contrast, scopolamine impaired conditioned freezing only if it was given after context-shock training. Posttraining infusion of 8-OH-DPAT or APV had no effect on conditioned freezing when the drug was given at either phase. These results showed double dissociation for the hippocampal GABAergic and cholinergic systems in memory consolidation of contextual fear conditioning: forming context memory required deactivation of the GABA(A) receptors, while forming context-shock memory involved activation of the muscarinic receptors.

The goal of the present study was to examine how social subordination stress and <em>5HT</em>T polymorphisms affect the development of brain serotonin (<em>5HT</em>) systems during the pubertal transition in female rhesus monkeys. We also examined associations with developmental changes in emotional reactivity in response to a standardized behavioral test, the Human Intruder (HI). Our findings provide the first longitudinal evidence of developmental increases in <em>5HT</em>1A receptor and <em>5HT</em>T binding in the brain of female primates from pre- to peripuberty. The increase in <em>5HT</em>1A BP(ND) in these socially housed female rhesus monkeys is a robust finding, occurring across all groups, regardless of social status or <em>5HT</em>T genotype, and occurring in the left and right hemispheres of all prefrontal regions studied, as well as the amygdala, hippocampus, hypothalamus, and raphe nuclei. <em>5HT</em>T BP(ND) also showed an increase with age in raphe, anterior cingulate cortex, and dorsolateral prefrontal cortex. These changes in brain <em>5HT</em> systems take place as females establish more adult-like patterns of social behavior, as well as during the HI paradigm. Indeed, the main developmental changes in behavior during the HI (increase in freezing and decrease in submission/appeasement) were related to neurodevelopmental increases in <em>5HT</em>1A receptors and <em>5HT</em>T, because the associations between these behaviors and <em>5HT</em> endpoints emerge at peripuberty. We detected an effect of social status on <em>5HT</em>1A BP(ND) in the hypothalamus and on <em>5HT</em>T BP(ND) in the orbitofrontal cortex, with subordinates showing higher BP(ND) than dominants in both cases during the pubertal transition. No main effects of <em>5HT</em>T genotype were observed for <em>5HT</em>1A or <em>5HT</em>T BP(ND). Our findings indicate that adolescence in female rhesus monkeys is a period of central <em>5HT</em> reorganization, partly influenced by exposure to the social stress of subordination, that likely functions to integrate adrenal and gonadal systems and shape the behavioral response to emotionally challenging social situations.

Learning from mistakes and prospectively adjusting behavior in response to reward feedback is an important facet of performance monitoring. Dopamine (DA) pathways play an important role in feedback learning and a growing literature has also emerged on the importance of serotonin (<em>5HT</em>) in reward learning, particularly during punishment or reward omission (negative feedback). Cognitive impairments resulting from psychostimulant exposure may arise from altered patterns in feedback learning, which in turn may be modulated by DA and <em>5HT</em> transmission. We analyzed long-term, off-drug changes in learning from positive and negative feedback and associated striatal DA transporter (DAT) and frontocortical <em>5HT</em> transporter (SERT) binding in rats pretreated with methamphetamine (mAMPH). Specifically, we assessed the reversal phase of pairwise visual discrimination learning in rats receiving single dose- (mAMPHsingle) vs. escalating-dose exposure (mAMPHescal). Using fine-grained trial-by-trial analyses, we found increased sensitivity to and reliance on positive feedback in mAMPH-pretreated animals, with the mAMPHsingle group showing more pronounced use of this type of feedback. In contrast, overall negative feedback sensitivity was not altered following any mAMPH treatment. In addition to validating the enduring effects of mAMPH on early reversal learning, we found more consecutive error commissions before the first correct response in mAMPH-pretreated rats. This behavioral rigidity was negatively correlated with subregional frontocortical SERT whereas positive feedback sensitivity negatively correlated with striatal DAT binding. These results provide new evidence for the overlapping, yet dissociable roles of DA and <em>5HT</em> systems in overcoming perseveration and in learning new reward rules.