The effect of the psychomotor stimulant, 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"), upon integrated cerebral function was measured in rats using the quantitative [14C]deoxyglucose autoradiographic technique. Animals were injected with MDMA (20 mg/kg sc) twice daily for 4 days. Fourteen days after the final administration, [3H]-paroxetine binding to <em>5HT</em> uptake sites was reduced by 89% in membranes prepared from tissue samples of frontal cortex. In the same rats [3H]-paroxetine binding autoradiography revealed heterogeneity in the regional distribution of 5-HT uptake site depletion within neocortex (0-92%) and hippocampus (30-95%). Despite these profound reductions in 5-HT uptake sites no significant alterations were found in glucose utilisation in any area of neocortex examined. However, significant increases in glucose use were found in subregions of the hippocampus, most notably within the pyramidal cell layer of CA2 and CA3 (25-35%). This study provides direct evidence that the loss of 5-HT innervation caused by exposure to MDMA results in lasting functional changes in hippocampus.

The disruption of prepulse inhibition (PPI) in rats by dopamine (DA) agonists is used to study the neural basis of strain differences in dopaminergic function. We reported that, compared to Long-Evans (LEH) rats, Sprague-Dawley (SDH) rats are more sensitive to the PPI-disruptive effects of the direct D1/D2 agonist apomorphine (APO) and the indirect DA agonist d-amphetamine (AMPH). This strain difference is heritable, with PPI drug sensitivity following a generational pattern (SDH>N2>F1>LEH) suggestive of additive effects of multiple genes. Here, we assessed the neurochemical bases for these heritable strain differences by measuring tissue levels of dopamine, serotonin (<em>5HT</em>) and their respective metabolites in several forebrain regions after vehicle, APO or AMPH administration. SDH rats were more sensitive than LEH rats to the PPI-disruptive effects of both APO (0.5 mg/kg) and AMPH (4.5 mg/kg). Several significant SDH vs. LEH strain differences in regional neurochemical levels were detected, as were drug effects on these chemicals. However, SDH, LEH and F1 rats did not exhibit differential drug sensitivity in any neurochemical indices measures. These findings suggest that inherited differences in the dopaminergic regulation of sensorimotor gating do not likely reflect differences in presynaptic forebrain dopaminergic or serotonergic processes.

Vasoactive intestinal peptide (VIP) is an octacosapeptide that occurs widely in the animal kingdom, is distributed in many organs and tissues, and has a broad range of biologic actions. We evaluated the ability of VIP to produce bronchodilation in anesthetized, mechanically ventilated, atropinized, closed chest cats. Boluses of VIP injected intravenously (0.1 to 10 micrograms X kg-1) reversed in a dose-dependent manner the increase in lung resistance (RL) and the decrease in dynamic lung compliance (Cdyn) induced by an intravenously administered infusion of 5-hydroxytryptamine (<em>5HT</em>) (5 to 30 micrograms X kg-1 X min-1). Distribution of bronchodilator activity was assessed by using RL as an index of central airways caliber and dynamic elastance (Edyn; the inverse of Cdyn) as an index of tone in peripheral airways and lung parenchyma. Although all levels of the tracheobronchial tree responded to VIP, the predominant site of action appeared to be in central airways. A similar distribution and magnitude of relaxant effects were observed after the intravenous administration of prostaglandin E2 (PGE2) (0.1 to 10 micrograms X kg-1). Prostaglandin E2 also was effective in reversing <em>5HT</em>-induced bronchoconstriction when given by ultrasonic nebulization, whereas VIP was not. Bronchodilation mediated by VIP persisted after pretreatment with indomethacin or propranolol. We conclude that VIP is a potent relaxant of feline airways smooth muscle in vivo and that this effect of the peptide occurs independent of prostaglandin production or beta adrenergic receptor activation.

The symptomatology of the fibromyalgia syndrome (FMS) often resembles an alteration in central nervous set points at least in three systems. The patients suffer under chronic pain in the region of the locomotor system, presumably reflecting a disturbed central processing of pain. Anxiety and depression often characterizes the clinical picture. Almost all of the hormonal feedback mechanisms controlled by the hypothalamus are altered. Characteristic for FMS patients are the elevated basal values of ACTH, follicle-stimulating hormone (FSH), and cortisol as well as lowered basal values of insulin-like growth factor 1 (IGF-1, somatomedin C), free triiodothyronine (FT3), and oestrogen. In FMS patients, the systemic administration of the relevant releasing hormones of corticotropin-releasing hormone (CRH), growth hormone-releasing hormone (GHRH), thyreotropin-releasing hormone (TRH), and luteinizing hormone-releasing hormone (LHRH) leads to increased secretion of ACTH and prolactin, whereas the degree to which TSH can be stimulated is reduced. The stimulation of the hypophysis with LHRH in female FMS patients during their follicular phase results in a significantly reduced LH response. All in all, the typical alterations in set points of hormonal regulation that are typical for FMS patients can be explained as a primary stress activation of hypothalamic CRH neurons caused by the chronic pain. In addition to the stimulation of pituitary ACTH secretion, CRH activates somatostatin on the hypothalamic level, which in turn inhibits the release of GH and TSH on the hypophyseal level. The lowered oestrogen levels could be accounted for both via an inhibitory effect of the CRH on the hypothalamic release of LHRH or via a direct CRH-mediated inhibition of the FSH-stimulated oestrogen production in the ovary. Serotonin (<em>5HT</em>), precursors like tryptophan (<em>5HT</em>P), drugs which release <em>5HT</em> or act directly on <em>5HT</em> receptors stimulate HPA axis, indicating a stimulatory serotonergic influence on HPA axis function. Therefore activation of the HPA axis may reflect an elevated serotonergic tonus in the central nervous system of FMS patients.

In blood platelets of man, both 5-hydroxytryptamine (<em>5HT</em>) and 80 nM of the Ca2+-ionophore A23187 led to rapid shape change reactions which were inhibited by prostaglandin E1 (PGE1), forskolin, 2-methyl-6-methoxy-8-nitroquinoline ( quin2 ) and chlortetracycline. The IC50-values of the inhibitors were similar in the <em>5HT</em>- and the A23187-experiments. Higher amounts of A23187 abolished the inhibitory actions of PGE1 and forskolin. Furthermore, <em>5HT</em> and A23187 enhanced adrenaline-induced platelet aggregation their effects showing similar time dependence. Ketanserin, an antagonist of <em>5HT</em>2 -receptors, and 8-(N,N-diethyl-amino)octyl-3,4,5-trimethoxybenzoate (TMB-8), an intracellular Ca2+-antagonist, counteracted the effects of <em>5HT</em> much more than those of A23187, whereas acetylsalicylate and indomethacin did not influence the actions of either <em>5HT</em> or A23187. In addition, <em>5HT</em> caused a concentration-dependent rise of intracellular free Ca2+ in platelets which was counteracted by ketanserin. PGE1 and forskolin reduced the resting Ca2+-levels. <em>5HT</em> did not affect either the basal or the PGE1-stimulated activity of adenylate cyclase, whereas the Ca2+-ionophore A23187 slightly raised the basal activity of the enzyme. In conclusion, the functional effects of <em>5HT</em>2 -receptor stimulation in human blood platelets (shape change reaction and enhancement of adrenaline aggregation) seem to be mediated by a rise of intracellular free Ca2+.

Substance P is thought to play an essential role in several forms of supraspinally mediated analgesia. The actions of substance P on synaptic transmission within descending analgesic pathways, however, are largely unknown. Here, we used whole-cell recordings from rat midbrain slices to examine the effects of substance P on GABAergic and glutamatergic transmission within the periaqueductal gray (PAG), a key component of a descending analgesic pathway that projects via the rostral ventromedial medulla (RVM) to the spinal cord dorsal horn. We found that substance P reversibly decreased the amplitude and increased the paired-pulse ratio of evoked IPSCs recorded from identified PAG-RVM projection neurons and from unidentified PAG neurons. Substance P had no effect on miniature IPSCs, implying an indirect mode of action. The effects of substance P were abolished by metabotropic glutamate type 5 and cannabinoid CB1 receptor antagonists, but unaltered by NMDA, GABA(B), mu,delta-opioid, adenosine A(1), and <em>5HT</em>(1A) receptor antagonists. Consistent with a role for endogenous glutamate in this process, substance P increased the frequency of action potential-dependent spontaneous EPSCs. Moreover, the effect of substance P on evoked IPSCs was mimicked and occluded by a glutamate transport inhibitor. Finally, these effects were dependent on postsynaptic G-protein activation and diacylglycerol lipase activity, suggesting the requirement for retrograde signaling by the endocannabinoid 2-arachidonoylglycerol. Thus, substance P may facilitate descending analgesia in part by enhancing glutamate-mediated excitation and endocannabinoid-mediated disinhibition of PAG-RVM projection neurons.

In vivo electrophysiological assays in anesthetized rats have been used to compare the effects of the <em>5HT</em>1B/1D receptor agonist, naratriptan, on central trigeminal nociceptive processing from dural and cutaneous inputs with its effects on nociceptive processing in the spinal cord. Naratriptan inhibited responses of single trigeminal neurons, to noxious electrical and mechanical stimulation of the dura and face, dose dependently by a maximum of 67+/-3% and 70+/-18%, respectively, at 3 mg kg(-1) i.v. In contrast, naratriptan did not affect spinal dorsal horn neuronal responses to noxious mechanical stimulation of the hind-paw. These findings suggest that <em>5HT</em>1B/1D receptors have differential effects on nociceptive processing in the trigeminal versus spinal dorsal horns and provide a potential explanation for the lack of general analgesic effects of brain penetrant <em>5HT</em>(1B/1D) agonist antimigraine drugs.

alpha(1)-Adrenoceptors of the locus coeruleus (LC) have been implicated in behavioral activation in novel surroundings, but the endogenous agonist that activates these receptors has not been established. In addition to the canonical activation of alpha(1)-receptors by norepinephrine (NE), there is evidence that dopamine (DA) may also activate certain brain alpha(1)-receptors. This study examined the contribution of DA to exploratory activity in a novel cage by determining the effect of infusion of various dopaminergic and adrenergic drugs into the mouse LC. It was found that the D2/D3 agonist, quinpirole, which selectively blocks the release of CNS DA, produced a dose-dependent and virtually complete abolition of exploration and all movement in the novel cage test. The quinpirole-induced inactivity was significantly attenuated by coinfusion of DA but not by the D1 agonist, SKF38390. Furthermore, the DA attenuation of quinpirole inactivity was blocked by coinfusion of the alpha(1)-adrenergic receptor antagonist, terazosin, but not by the D1 receptor antagonist, SCH23390. LC infusions of either quinpirole or terazosin also produced profound inactivity in DA-beta-hydroxylase knockout (Dbh -/-) mice that lack NE, indicating that their behavioral effects were not due to an alteration of the release or action of LC NE. Measurement of endogenous DA, NE, and <em>5HT</em> and their metabolites in the LC during exposure to the novel cage indicated an increase in the turnover of DA and NE but not <em>5HT</em>. These results indicate that DA is a candidate as an endogenous agonist for behaviorally activating LC alpha(1)-receptors and may play a role in the activation of this nucleus by novel surroundings.

Several amino acids including aspartate, glutamate and glycine and the monoamine serotonin were retrieved from the extracellular space of the dorsal horn of the lumbar spinal cord in the alpha-chloralose anesthetized cat in vivo using a transverse microdialysis probe. Neurotransmitter concentrations were determined using high pressure liquid chromatography in combination with fluorescence (amino acid) or electrochemical (serotonin) detection. Intradermal injection of 3% capsaicin into the hindleg either ipsilateral or contralateral to the dialysis probe was used to evoke release. Extracellular concentrations of aspartate, glutamate and serotonin increased significantly following capsaicin injection into the ipsilateral limb. An almost equal increase in serotonin and a less pronounced, but still significant, increase in aspartate accompanied contralateral capsaicin injection. Glutamate concentrations increased in the dialysate during contralateral capsaicin injection in about half of the animals. These data are consistent with the hypothesis that Asp and Glu are both neurotransmitters released from nociceptive primary afferent fibers and/or interneurons activated by these fibers. In addition, Asp is presumed to be released from intrinsic spinal or descending systems following nociceptive stimulation. Bilateral release of <em>5HT</em> into the dorsal horn most likely results from non-topographic activation of descending endogenous analgesia pathways.

Repeated high dose (5.0 mg/kg) anabolic-androgenic steroid (AAS) exposure during adolescence stimulates offensive aggression in male Syrian hamsters. These studies examined whether AAS-induced aggression was regulated by the activity of serotonin (<em>5HT</em>) type-1B receptors and correlated with altered <em>5HT</em>1B expression. AAS-treated hamsters were tested for offensive aggression following the administration of the <em>5HT</em>1B agonist anpirtoline (0.125-0.5 mg/kg). Anpirtoline dose-dependently reduced select components of the AAS-induced aggressive response, with significant reductions observed at 0.25 mg/kg. Aggressive, AAS-treated hamsters showed significant decreases in the area covered by <em>5HT</em>1B-containing neuronal puncta and increases in the number of <em>5HT</em>1B-containing neuronal somata in select brain regions implicated in aggression control. Together, these data support a role for site-specific alterations in <em>5HT</em>1B signaling and expression in adolescent AAS-induced aggression.

Learned helplessness, a behavioral depression caused by exposure to inescapable stress, is considered to be an animal model of human depressive disorder. Like human depression, learned helplessness has been associated with a defect in serotonergic function, but the nature of this relationship is not entirely clear. We have used in vivo microdialysis brain perfusion to measure serotonin (5-hydroxytryptamine, <em>5HT</em>) in extracellular space of medial frontal cortex in conscious, freely moving rats. Basal <em>5HT</em> levels in rats perfused before exposure to tail-shock stress did not themselves correlate with subsequent learned helplessness behavior. However, <em>5HT</em> release after stress showed a significant increase with helpless behavior. These data support the hypothesis that a cortical serotonergic excess is causally related to the development of learned helplessness.

The purpose of this study was to investigate the role of serotonin (<em>5HT</em>) in patients with analgesic-induced headache (AIH). We estimated platelet <em>5HT</em> concentration in patients with AIH, migraine patients and non-headache controls, by using high performance liquid chromatography with electrochemical detection. Our results revealed a significant decrease (p < 0.001) in platelet <em>5HT</em> content in patients with AIH as compared to migraine patients and non-headache controls (221.8 +/- 30.7, 445.3 +/- 37.4 and 467.2 +/- 38.5 ng/10(9) platelets, respectively). In contrast, a difference of lesser statistical significance (p = 0.022) was observed in platelet <em>5HT</em> content after incubation with excess <em>5HT</em> (1940.0 +/- 195.1, 2610.0 +/- 173.1 and 2560 +/- 165.2 ng/10(9) platelets for patients with AIH, migraine patients and non-headache controls, respectively). These data suggest that analgesic-induced suppression of <em>5HT</em> uptake may interfere with the function of the pain modulatory system in the brainstem. Although the process by which analgesics interfere with this system is as yet unknown, it is possible that it may not be entirely due to defective <em>5HT</em> uptake mechanisms.

BACKGROUND

Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa plant that promotes antianxiety and anti-panic effects in animal models after acute systemic or intra-dorsal periaqueductal gray (DPAG) administration. However, the effects of CBD repeated administration, and the possible mechanisms involved, in animal models of anxiety- and panic-related responses remain poorly understood.

OBJECTIVE

The present study evaluates the role of the serotonergic neurotransmission within the DPAG in the modulation of escape responses of rats chronically treated with CBD.

METHODS

Male Wistar rats received acute or repeated (5 mg/Kg/daily/21 days) administration of CBD and were submitted to the elevated T-maze (ETM). We also investigated if CBD effects on the ETM depend on facilitation of 5-HT1A-mediated neurotransmission in the DPAG. To this latter aim, we verified if these effects would be prevented by intra-DPAG injection of the 5-HT1A receptor antagonist WAY100635 (0.37 nmol/0.2 μL). Also, we verified, by in vivo microdialysis, if CBD chronic treatment increases serotonin (5-HT) release and, by quantitative polymerase chain reaction, if there are changes in <em>5HT</em>-1A or <em>5HT</em>-2C mRNA expression in DPAG.

RESULTS

The results showed that repeated but not acute peripheral administration of CBD decreases escape responses in the ETM, suggesting a panicolytic effect. This treatment did not change <em>5HT</em>-1A or 5-HT-2C receptor mRNA expression nor modify serotonin extracellular concentrations in the DPAG. CBD effects were prevented by DPAG injection of the 5-HT1A receptor antagonist.

CONCLUSIONS

Together, these findings suggest that repeated treatment with CBD induces anti-panic effects by acting on 5-HT1A receptors in DPAG.

Serotonin (5-HT) plays an important role as a signalling molecule in the gastrointestinal (GI) tract. The regulation of GI sensitivity via 5-HT is mediated by specific 5-HT receptor subytypes on intrinsic and extrinsic afferents. This review discusses visceral afferent hypersensitivity in irritable bowel syndrome (IBS) and the importance of <em>5HT</em>(3), <em>5HT</em>(4), and <em>5HT</em>(2B) receptor-mediated mechanisms in the regulation of visceral sensitivity.

Eleven cases of primary pancreatic adenocarcinomas have been investigated histochemically, immunohistochemically and with electron-microscopy. Endocrine-paracrine (EP) cells were present in six of these tumours. In one case numerous <em>5HT</em>-enterochromaffin cells (EC) of the intestinal type and a few somatostatin immunoreactive D cells were found. Two cases contained insulin-immunoreactive cells and another case displayed glucagon-IR elements. In the remaining two cases argyrophilic cells were present. These findings demonstrate that polypeptide hormone or amine production is not restricted to islet cell tumours. It is suggested that both endocrine and exocrine components of the tumours studied might have derived from a common precursor.

Variations in <em>5HT</em>-related genes contribute to the alterations of serotonergic neurotransmission, which is implicated in the etiopathology of alcoholism. In this preliminary study we have tested polymorphisms of genes involved in <em>5HT</em> transport and turnover for their association with alcohol dependence. A case group of males with type 2 alcoholism (N=59) and a control group of healthy males (N=282), both of Croatian origin, were analyzed for the frequency distribution of polymorphisms in <em>5HT</em> transporter (<em>5HT</em>T-VNTR2, <em>5HT</em>T-LPR), monoamine oxidase A (MAOA-uVNTR) and B (MAOB-A/G) and tryptophan hydroxylase 1 (TPH1 A218C) and 2 (TPH2 G-703T) genes. An increase in the frequencies of 10-repeat allele (p = 0.010; OR = 1.73; 95% CI = 1.14-2.60) and 10/10 genotype (p = 0.006; OR = 2.57; 95% CI = 1.32-5.00) of the <em>5HT</em>T-VNTR2 polymorphism was found in alcoholic patients. No differences between case and control groups were observed for the other tested polymorphisms. Present results support earlier studies implicating the role of <em>5HT</em>T gene in alcoholism. The increase of sample size (in progress) is expected to enable search of more subtle differences, as well as re-evaluation of these preliminary findings.

This issue of Peptides was inspired by a gathering of CCK researchers at the first Neuronal Cholecsytokinin Gordon Conference. The papers in this issue reflect the diversity of CCK research and demonstrate how the field has matured. Reviews describe the regulation of CCK gene expression and CCK release, the nature of the hormone binding site of the CCK A receptor, interaction of CCK, dopamine and GABA, the role of CCK in thermoregulation, sexual behavior and satiety in rodents and humans. The research articles document features of cardiovascular regulation, reduced cocaine sensitization and decreased satiety in rats that lack the CCK A receptor. Pro CCK processing in neuroblastoma cells and the elevation of CCK levels in CSF in a model of chronic pain are detailed in other articles. Three articles using different behavioral paradigms in rat and sheep examine CCK in learning and memory. Two articles that examine CCK in different behaviors that have a dopaminergic component are included. Other articles describe the interaction between a <em>5HT</em>(3) antagonist and CCK-induced satiety and c-fos activation and document secretion of oxytocin and vasopressin in female patients and controls in response to CCK 4 administration. There is good reason to believe that the future is bright for research on CCK. With the organization of national and international meetings, CCK researchers have a forum for communication. Opportunities for cooperation and collaboration have never been better. The easy integration of academic basic and clinical science with industrial science bodes very well for the advancement of our understanding of the multiple roles that CCK plays in the brain and for the future development of CCK-based therapies.

The cocaine analogue 2-beta-carbomethoxy-3-beta-(4-iodophenyl)-tropane (beta-CIT) is a potent ligand for both dopamine- and serotonin uptake sites which in its 123I labeled form can be used for single photon emission computerized tomography (SPECT). It was demonstrated previously by SPECT-studies in non-human primates that 123I-beta-CIT binds to dopamine transporters in the striatum and to serotonin transporters in hypothalamus and midbrain. The aim of the present study was to compare 123I-beta-CIT binding in the brain stem of normal controls and a group of subjects under treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram. 123I-beta-CIT-SPECT was performed in 12 depressed patients under 20 mg (n = 5), 40 mg (n = 6) and 60 mg (n = 1) citalopram daily, in one untreated depressed patient and in 11 controls at regular time intervals up till 24 hours p.inj. A highly significant reduction of beta-CIT binding was found in an area including mesial thalamus, hypothalamus, midbrain and pons in patients under citalopram compared to controls (44.1 +/- 14.4 vs. 82.3 +/- 18.6cpm's/mCi x kg body weight; specific binding 4 hrs p.inj.; p = 0.0001). No differences were seen between the high and low dose group and no changes were found in the striatum. 123I-beta-CIT binding in the brain stem and striatum in one untreated depressed patient fell within the range of control values. To our knowledge this is the first report directly demonstrating the effect of a selective serotonin uptake inhibitor in the brain in humans in vivo. SPECT measurements of serotonin uptake sites in patients with depression and other psychiatric disorders might provide better insights into the pathophysiology of these disorders and into mechanisms of drug action.

This study investigates the effect of chronic treatment with Fluvoxamine, a potent and specific serotonin reuptake sites inhibitor (SSRI), on <em>5HT</em>(2) serotonin and D(2) dopamine receptors in the brain of drug naive unipolar depressed patients. Drug effect was evaluated in different cortical areas and in the basal ganglia by positron emission tomography (PET) and fluoro-ethyl-spiperone ([(18)F]FESP), an high affinity <em>5HT</em>(2) serotonin and D(2) dopamine receptors antagonist. Patients underwent a PET study at recruitment and after clinical response to Fluvoxamine treatment. Nine of the 15 patients recruited completed the study. Fluvoxamine treatment significantly improved clinical symptoms and modified [(18)F]FESP binding in the frontal and occipital cortex of all of the nine patients who completed the study; in these regions a mean 31% increase in the in vivo [(18)F]FESP binding was found (P < 0.01). On the contrary, no significant changes in the in vivo [(18)F]FESP binding were found in the basal ganglia where [(18)F]FESP binds mainly to D(2) dopamine receptors. Chronic treatment with Fluvoxamine significantly increases the in vivo binding of [(18)F]FESP in the frontal and occipital cortex of drug naive unipolar depressed patients. The increase of the in vivo binding of [(18)F]FESP may reflect a modification in <em>5HT</em>(2) binding capacity secondary to changes in cortical serotonin activity.

OBJECTIVE

Although serotonin and serotoninergic drugs are known to cause myxomatous-like valvulopathy, the role of serotonin in spontaneous myxomatous valve disease (MVD) remains unclear. Tryptophan hydroxylase 1 (TPH1) is the limiting enzyme for peripheral serotonin synthesis, and its expression in myxomatous valves could implicate an autocrine serotonin signaling mechanism. Studies in cultured cells demonstrate a close coupling between serotonin and transforming growth factor beta1 (TGFbeta1) signaling. The study aim was to investigate serotonin and TGFbeta1 signaling in spontaneous MVD.

METHODS

In canine normal and myxomatous mitral valves, target signaling proteins including TPH1, serotonin 2B receptor (<em>5HT</em>(2B)R), serotonin transmembrane transporter (SERT), total and phosphorylated extracellular signaling-regulated kinase (ERK) 1/2, latent TGFbeta1 and TGFbeta1 receptors I and II, were studied using immunohistochemistry and immunoblot analysis. In human myxomatous valves, TPH1 was determined using immunofluorescence and immunoblot analysis.

RESULTS

In canine mitral valves, both <em>5HT</em>(2B)R and TPH1 were increased in myxomatous valves, whereas SERT, a key protein in serotonin metabolism, was decreased in myxomatous valves. Phosphorylated, but not total, ERK 1/2 was increased in myxomatous valves, consistent with an enhanced active serotonin signaling. The expression of TGFbeta1 receptors I and II, and of latent TGFbeta1, was increased in myxomatous valves. Human myxomatous mitral valves expressed TPH1.

CONCLUSIONS

The expression of TPH1 by canine and human myxomatous valves demonstrates a capacity for local serotonin production. Key signaling protein expression patterns support active serotonin and TGFbeta1 signaling in canine myxomatous valves. These findings implicate an autocrine serotonin and TGFbeta1 mechanism in the pathogenesis of spontaneous MVD.

Several lines of evidence suggest that genetic factors constitute an important determinant of suicidal behavior. A significant association between the 5-HT(2A)-C allele and suicidality has recently been reported. The aim of this study was to investigate whether the proposed association between 5-HT(2A)-102T/C polymorphism and suicidality could be replicated in a larger and independent sample of Spanish patients with major depression. The 102T/C polymorphism of the 5-HT(2A) receptor gene was analyzed in 159 patients with major depression (DSM-IV criteria) and 164 unrelated and healthy controls using a case control design. All individuals were subjects of Spanish origin. Significant differences in allele (chi-square = 4.13, df = 1, P = 0.04) and genotype (chi-square = 6.19, df = 2, P = 0.04) distributions were found between non-suicide attempters and suicide attempters. Moreover, those patients carrying 5-HT(2A)-C allele had more than five times the risk for attempting suicide than noncarriers (OR = 5.50, 95% CI = 1.18-35.20, P = 0.01). Our results replicate the proposed association between <em>5HT</em>(2A)-C allele and suicidality in major depression. Moreover, no overall associations are detected when patients with major depression and controls are compared for 102T/C frequencies, suggesting that the increased risk for suicidality conferred by 5-HT(2A)-C allele is primarily associated with suicidal behavior and not with the diagnosis of major depression itself.

The vulnerability to mood disorders, impulsive-aggression, eating disorders, and suicidal behavior varies greatly with gender, and may reflect gender differences in central serotonergic function. We investigated the relationships of gender, mood, impulsivity, aggression and temperament to <em>5HT</em>(2A) receptor binding in 21 healthy subjects using [18F]altanserin and PET neuroimaging. Binding potentials in pre-defined regions-of-interest (ROI) were calculated using the Logan graphical method, corrected for partial volume effects, and compared by gender with age co-varied. SPM analysis was used for voxel level comparisons. Altanserin binding (BP(P)) was greater in male than female subjects in the following nine ROIs: hippocampus (HIP) and Lt. HIP, lateral orbital frontal cortex (LOF) and Lt. LOF, left medial frontal cortex (Lt. MFC), left medial temporal cortex (Lt. MTC), left occipital cortex (Lt. OCC), thalamus (THL) and Lt. THL. Differences in Lt. HIP and Lt. MTL remained significant after Bonferroni correction. Gender differences were noted in the co-variation of psychological traits with BP(P) values in specific ROIs. Among males alone, aggression was negatively correlated with BP(P) values in Lt. LOF and Lt. MFC, and Suspiciousness positively correlated in LOF, Lt. LOF and Lt. MFC. Among female subjects alone, Negativism was positively correlated with BP(P) values in HIP, and Verbal Hostility in Lt. HIP. Altanserin binding in Lt. MTC was positively correlated with Persistence, with no significant gender effect. Gender differences in <em>5HT</em>(2A) receptor function in specific ROIs may mediate expression of psychological characteristics such as aggression, suspiciousness and negativism. Future studies of <em>5HT</em>(2A) receptor function and its relationship to behavior should control for gender.

The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, <em>5HT</em> subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED(50) value.

Behavioral profiles composed of both locomotor activity and investigatory behavior were established for the <em>5HT</em>-1A agonists 8OHDPAT, buspirone, gepirone, and ipsapirone using rats tested in a Behavioral Pattern Monitor. Typically these compounds dose-relatedly decreased horizontal locomotion and investigatory activity during the first half of the 1-h test session. Time-course studies revealed that the time interval between injection and placement of the animal in the testing chamber made no difference in the temporal distribution of locomotor activity following most <em>5HT</em>-1A agonists. These results were compared and contrasted to the behavioral profiles previously established for hallucinogenic compounds such as LSD and DOM, the psychoactive properties of which have been suggested to be mediated by <em>5HT</em>-2 binding sites. Examination of ipsapirone and 8OHDPAT in a familiar environment paradigm revealed that both drugs decreased behavioral responding independently of the animals' familiarity with the test environment, in contrast to the behaviorally suppressive effects of hallucinogenic <em>5HT</em>-2 antagonists which disappear in a familiar environment. Additionally, d,l-propranolol was used as a <em>5HT</em>-1 antagonist and was found to block the behavioral effects of the <em>5HT</em>-1A agonists ipsapirone and buspirone without having significant effects by itself. Propranolol was also used to identify the contribution of the <em>5HT</em>-1 binding site to the behavioral effects of LSD. Even at relatively high doses, propranolol only partially antagonized the effects of LSD, supporting the hypothesis that the behavioral effects of LSD reflect the activation of both <em>5HT</em>-1 and <em>5HT</em>-2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)