Role of 5-HT1A receptors in the antinociceptive action of 8-hydroxy-2-(di-n- propylamino)tetralin in the rat

The role of 5-HT1A receptors in the antinociceptive action of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was investigated by using the shock titration test in rats. A subcutaneous injection of 300 micrograms/kg 8-OH-DPAT significantly raised the threshold for flinching, jumping and vocalization whereas 100 micrograms/kg only inhibited the flinch response. l-Propranolol and (+)-[N-tert-butyl-3-4-(2-methoxyphenyl)piperazin-1-yl-2-phenyl propanamide dihydrochloride], (+)-WAY100135, two antagonists at 5-HT1A receptors at 10 mg/kg s.c. antagonized the effect of 300 micrograms/kg 8-OH-DPAT on all measures. The effect of 300 micrograms/kg 8-OH-DPAT on the three measures was unmodified in rats which had received 150 micrograms 5,7-dihydroxytryptamine intracerebroventricularly 10 days before testing. The results suggest that 8-OH-DPAT inhibits nociceptive responses by stimulating postsynaptic 5-HT1A receptors.     

8-OH-DPAT-induced spontaneous tail-flicks in the rat are facilitated by the selective serotonin (5-HT)2C agonist, RO 60-0175: blockade of its actions by the novel 5-HT2C receptor antagonist SB 206,553

The 5-HT1A receptor agonist, 8-OH-DPAT ((+/-)-8-dihydroxy-2-(di-n-propylamino) tetralin), (0.63 mg/kg, s.c.) elicited spontaneous tail-flicks (STFs) in rats. This response was potentiated by the selective 5-HT2C receptor agonist, RO 60-0175 ((S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine) fumarate) (0.16 mg/kg, s.c.), the action of which was abolished by the novel 5-HT2C antagonist, SB 206,553 (5 methyl-1-(3-pyridil-carbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3 -f]indole) (0.16 mg/kg, s.c.). These data show that 5-HT1A receptor-mediated STFs in rats are facilitated by activation of 5-HT2C receptors supporting the existence of functional interactions between these sites.     

2-(1-Naphthyloxy)ethylamines with enhanced affinity for human 5-HT1D beta (h5-HT1B) serotonin receptors

Although the beta-adrenergic antagonist propranolol (1) binds at rodent 5-HT1B serotonin receptors, it displays low affinity (Ki > 10,000 nM) for its species homologue 5-HT1D beta (i.e., h5-HT1B) receptors. The structure of propranolol was systematically modified in an attempt to enhance its affinity for the latter population of receptors. Removal of the alkyl hydroxyl group, shortening of the O-alkyl chain from three to two methylene groups, and variation of the terminal amine substituent resulted in compounds, such as N-monomethyl-2-(1-naphthyloxy)-ethylamine (11; Ki = 26 nM), that display significantly higher h5-HT1B affinity than propranolol. Compound 11 was shown to bind equally well at human 5-HT1D alpha (h5-HT1D) receptors (Ki = 34 nM) and was further demonstrated to possess h5-HT1B agonist character in an adenylate cyclase assay. It would appear that such (aryloxy)alkylamines may represent a novel class of 5-HT1D receptor agonists.     

Cardiovascular effects produced by R-(+)-8-hydroxy-2-(di-n-propylamino) tetralin in the preoptic area of conscious rats

The effect of ancrod-induced defibrinogenation on thrombosis and bleeding time was determined in anesthetized rats. Functional plasma fibrinogen levels were reduced 42, 71, 94 and 93% by ancrod doses of 5, 10, 20 and 30 U/kg, respectively, while a 2.5 U/kg dose was without significant effect. Ancrod inhibited vena cava thrombosis induced by partial stasis of blood flow combined with mild vascular injury. Thrombus weight was decreased 85 and 93% by the 10 and 20 U/kg doses, but was unaffected at lower doses. In contrast, ancrod doses of up to 30 U/kg did not significantly decrease carotid artery thrombi formed in response to oxidative transmural vessel injury. Ancrod caused a dose-dependent increase in bleeding time measured by puncturing small mesenteric arteries with a hypodermic needle. The bleeding time increase was approximately 38% in response to the 2.5 and 5 U/kg doses, and 182% in response to the 10 U/kg dose. These studies demonstrate that ancrod-induced reductions in plasma fibrinogen more effectively inhibit venous compared to arterial thrombosis, although these activities require doses that also increase bleeding time in small arteries.     

Discriminative stimulus effects of 8-hydroxy-2-(di-n-propylamino)tetralin in pigeons and rats: species similarities and differences

S. E. Snodgrass (1985, 1992) examined interpersonal sensitivity within status-discrepant interactions. Using the correlation between how a participant thought another felt with how that person reported actually feeling, S. E. Snodgrass's measure of interpersonal sensitivity included both the expressivity of one person and the perceptivity of another person. The studies reported here were conducted to clarify the relative contributions of expressivity and perceptivity to this measure. Results indicated that interpersonal sensitivity was associated more with high expressivity on behalf of the sender than with the perceiver's perceptivity. Implications are discussed for research and theory on interpersonal sensitivity, and gender and leadership roles.     

Differential effects of serotonin (5-HT) lesions and synthesis blockade on neuropeptide-Y immunoreactivity and 5-HT1A, 5-HT1B/1D and 5-HT2A/2C receptor binding sites in the rat cerebral cortex

The present study was aimed at comparing the effects of serotonin (5-HT) synthesis blockade using chronic administration of p-chlorophenylalanine (PCPA) and 5,7-dihydroxytryptamine injections of variable volume (3 vs. 6 microl) on the density of NPY immunoreactive (Ir) neurons and binding of [3H]8-OH-DPAT, S-CM-G[125I]TNH2 and [125I]DOI to 5-HT1A, 5-HT1B/1D, and 5-HT2A/2C receptors in rat cortical regions. Three weeks after large but partial (89% depletion in 5-HT tissue concentration) lesions of 5-HT neurons no changes in neither NPY immunoreactivity nor 5-HT receptor binding were detected. The complete 5,7-DHT lesions produced increases in the number of NPY-Ir neurons in the upper regions of the cingular (134%), frontal (140%) and parietal cortex (48%) and corresponding decreases in 5-HT2A/2C binding (16-26%). No changes in 5-HT1A and 5-HT1B/1D binding were observed after lesions of this kind. After PCPA treatment, decreases in NPY-Ir neurons density (22-40%) and increases in 5-HT1A and 5-HT1B/1D receptor binding sites (20-50%) were distributed in both upper and deeper cortical regions. The lack of effect of the partial lesion suggests that spared 5-HT neurons may exert compensatory mechanisms up to a large extent. The changes in NPY immunoreactivity and 5-HT2A/2C binding detected in the upper regions of the cortex after complete 5-HT lesions probably result from local cellular rearrangements, whereas blocking 5-HT synthesis has more widespread influence on NPY neurons and on 5-HT1A and 5-HT1B/1D receptor subtypes. Moreover, decreases in DOPAC concentrations detected only after complete lesions suggest that the involvement of catecholaminergic transmission may also differentiate 5,7-DHT and PCPA treatments. Altogether, these data suggest that different receptor subtypes might be involved in 5-HT-NPY relationships.     

Facilitation of female rat lordosis behavior by hypothalamic infusion of 5-HT(2A/2C) receptor agonists

Ovariectomized rats were hormonally primed with 0.5 microg estradiol benzoate and 500 microg progesterone to produce two groups of rats differing in their lordosis behavior. Females with a lordosis to mount (L/M) ratio < 0.5 were used to test the hypothesis that 5-HT(2A/2C) receptor agonists could facilitate lordosis behavior. Females with L/M ratios > or = 0.5 were used to evaluate the potential suppressive effect of 5-HT(2A/2C) receptor compounds. Lordosis behavior was examined following bilateral infusion of drugs into the ventromedial nucleus of the hypothalamus (VMN). Drugs examined were the 5-HT(2A/2C) receptor agonist, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI), the 5-HT(2A/2C) receptor antagonist, 3-[2-[4-(4-fluorobenzoyl)-1-piperdinyl]ethyl]-2,4(1H,3H)-quinazoli nedione tartrate (ketanserin tartrate), and the non-selective 5-HT receptor agents, 2-(1-piperazinyl)quinoline dimaleate (quipazine) and N-(3-trifluoromethylphenyl)piperazine HCl (TFMPP). Drugs with agonist action at 5-HT(2A/2C) receptors increased lordosis behavior in rats with low sexual receptivity. The 5-HT(2A/2C) receptor antagonist, ketanserin, inhibited lordosis behavior in sexually receptive rats. DOI attenuated the lordosis-inhibiting effect of ketanserin, but ketanserin was less effective in preventing DOI from increasing lordosis behavior. These results strengthen prior inferences that activation of 5-HT(2A/2C) receptors can facilitate lordosis behavior and that the VMN is one site at which such facilitation can occur.     

Differential effects of neonatal handling on anxiety, corticosterone response to stress, and hippocampal glucocorticoid and serotonin (5-HT)2A receptors in Lewis rats

The health-related quality of life (HRQoL) literature presents a confused picture of what 'equivalence' in the cross-cultural use of HRQoL questionnaires means and how it can be assessed. Much of this confusion can be attributed to the 'absolutist' approach to the cross-cultural adaptation of HRQoL questionnaires. The purpose of this paper is to provide a model of equivalence from a universalist perspective and to link this to the translation and adaptation of HRQoL questionnaires. The model evolved from reviews of the HRQoL and other literatures, interviews and discussions with researchers working in HRQoL and related areas and practical experience in the adaptation and development of HRQoL instruments. The model incorporates six key types of equivalence. For each type of equivalence the paper provides a definition, proposes various strategies for examining whether and how types of equivalence can be achieved, illustrates the relationships between them and suggests the order in which they should be tested. The principal conclusions are: (1) that a universalist approach to the cross-cultural adaptation of HRQoL instruments requires that six types of equivalence be taken into account; (2) that these are sufficient to describe and explain the nature of the cross-cultural adaptation process; (3) that this approach requires careful qualitative research in target cultures, particularly in the assessment of conceptual equivalence; and (4) that this qualitative work will provide information which will be fundamental in deciding whether to adapt an existing instrument and which instrument to adapt. It should also result in a more sensitive adaptation of existing instruments and provide valuable information for interpreting the results obtained using HRQoL instruments in the target culture.     

Differential distribution of [3H]sumatriptan binding sites (5-HT1B, 5-HT1D and 5-HT1F receptors) in human brain: focus on brainstem and spinal cord

We report on the autoradiographic distribution of 5-HT1B, 5-HT1D and 5-HT1F receptor subtypes in human brain, focusing on the brainstem and cervical spinal cord. We have used [3H]sumatriptan as a radioligand in the presence of suitable concentrations of 5-CT (5-carboxamidotryptamine) to define 5-HT1F receptors, and ketanserin, to discriminate between 5-HT1B and 5-HT1D receptors. In the brainstem the highest concentrations of [3H]sumatriptan binding sites were seen in substantia nigra. The spinal trigeminal nucleus, substantia gelatinosa of the spinal cord, nucleus of the tractus solitarius and periaqueductal grey, also showed significant levels of [3H]sumatriptan binding sites. In the brainstem and spinal cord the total population of 5-CT-insensitive receptors, corresponding to 5-HT1F receptors, ranged from 9.8% in the periaqueductal grey to 53.4% in the substantia gelatinosa. This population represented 67.0% of binding in layer V of the frontal cortex. The decrease in [3H]sumatriptan binding in the presence of 200 nM ketanserin, indicative of the presence of 5-HT1D receptors, was very limited throughout the human brain, only reaching 20% of total specific binding over the periaqueductal grey. The proportion of [3H]sumatriptan binding sites displaced by 5-CT and insensitive to ketanserin, corresponding to 5-HT1B receptors, was, in general, the most abundant, ranging from 43.8% in substantia gelatinosa to 69.9% in the periaqueductal grey. Significant levels of 5-HT1B and 5-HT1D receptors found in migraine control pain areas suggest their involvement in antinociceptive mechanisms.     

高选择性试剂5-(2-羟基-3,5-二甲基苯偶氮)罗丹宁与钯Ⅱ的显色反应研究及其应用

阐明了新合成的高选择性试剂5-(2-羟基-3,5-二甲基苯偶氮)罗丹宁(HDPAR)与钯反应的研究与应用,建立了测定钯的新方法。在盐酸介质中,乳化剂OP存在下,HDPAR与钯 形成稳定的红色络合物,在25mL溶液中,钯在0～20μg范围内符合比尔定律,表观摩尔吸收系数ε=8.31×104,该试剂选择性好,无需加入掩蔽剂或其他分离手段,即可直接用于钯碳催化剂中钯 的测定,结果满意。     

Preparation of 8-[3-(4-fluorobenzoyl)-propyl]-1-(4-[123I] iodobenzoyl)-1,3,8-triazaspiro[4,5]decan-4-one: a novel selective serotonin 5-HT2 receptor agent

OBJECTIVE: to evaluate the effectiveness of a reduced-frequency prenatal visit schedule by comparing perinatal outcomes, anxiety and maternal satisfaction with prenatal care. METHODS: pregnancy outcomes of infant and maternal morbidity and mortality, anxiety and satisfaction for 81 women receiving prenatal care at a free-standing birthing center according to either an alternative prenatal care visit schedule (APCVS) (n = 43) or the traditional prenatal care visit schedule (TPCVS) (n = 38) were examined in this prospective randomized study. Upon entry into prenatal care, all women were of low obstetrical risk status. RESULTS: major findings revealed no significant differences in selected perinatal outcomes between the two study groups. Women in the APCVS group reported significantly higher levels of satisfaction than women in the TPCVS group on both the satisfaction with provider subscale (F = 5.74, P = .02) and the satisfaction with the prenatal care system subscale (F = 2.01, P = .04). There were no statistically significant differences found in anxiety scores between women in the two study groups. CONCLUSIONS: low-risk women who followed the reduced-frequency visit schedule experienced no difference in perinatal outcomes or anxiety. Women in the reduced-frequency (APCVS) group reported an increased level of satisfaction with both provider and the prenatal care system.     

Induction of burst firing in ventral tegmental area dopaminergic neurons by activation of serotonin (5-HT)1A receptors: WAY 100,635-reversible actions of the highly selective ligands, flesinoxan and S 15535

OBJECTIVE: To determine changes in the nutritional status of Guatemalan refugee children under six years of age, who lived in Mexico between 1982 and 1996, under various nutrition-related programs implemented during that period. MATERIAL AND METHODS: A comparative analysis of 4 cross-sectional anthropometric studies performed in Chiapas (1982, 1989), Quintana Roo (1989) and Campeche and Quintana Roo in 1996. Malnutrition prevalence by weight/age and height/age indicators was calculated. Odds ratio and 95% confidence intervals were estimated. The implemented programs to improve nutritional status and health conditions are described. RESULTS: In 1982, high rates of malnutrition and mortality prevailed among refugee children. In 1989 some had been transferred to Campeche and Quintana Roo and others stayed in Chiapas. Their situation had improved and remained so until 1996. CONCLUSIONS: The implemented programs were successful to control the emergency and prevent new crises. However they only managed to maintain similar conditions for the refugees as those which prevail among the Mexican indians.     

Synthesis and in vitro characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers: a novel selective alpha 1A receptor agonist

The existence of multiple subtypes of the alpha 1 adrenergic receptor has been demonstrated both pharmacologically and by molecular biological cloning techniques. The development of subtype selective antagonists has been the focus of much research within the pharmaceutical industry, and clinical evidence now exists that alpha-1A selective antagonists will have utility in the treatment of benign prostatic hyperplasia. However, highly subtype selective agonists are not known. Herein we report the synthesis and pharmacological characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers, a highly potent full agonist with excellent selectivity for the alpha 1A receptor subtype.     

Sustained desensitization of hypothalamic 5-Hydroxytryptamine1A receptors after discontinuation of fluoxetine: inhibited neuroendocrine responses to 8-hydroxy-2-(Dipropylamino)Tetralin in the absence of changes in Gi/o/z proteins

Long-term exposure to fluoxetine produces a desensitization of hypothalamic postsynaptic 5-hydroxytryptamine (5-HT)1A receptors, indicated by a substantial inhibition of the 5-HT1A receptor-mediated stimulation of oxytocin and adrenocorticotropic hormone (ACTH) secretion. The present study investigated the time course and mechanism of this desensitization after discontinuation of fluoxetine administration. Male rats were injected with saline or fluoxetine (10 mg/kg/day, i.p.) for 14 days and were challenged with a 5-HT1A agonist, [8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) 50 microg/kg, s.c.] 2, 4, 7, 14, 28, or 60 days post-treatment. In control animals, 8-OH-DPAT significantly increased (approximately 15-fold) plasma levels of oxytocin and ACTH. At 2 days post-treatment, oxytocin and ACTH responses to 8-OH-DPAT were reduced by 74% and 68%, respectively. During further withdrawal from fluoxetine, there was a gradual increase in the oxytocin response toward control levels. However, even 60 days after discontinuation of fluoxetine, the oxytocin response was still significantly reduced by 26% compared with controls. In contrast, the suppressed ACTH response to 8-OH-DPAT (a less-sensitive indicator of desensitization) gradually returned to control levels by day 14 of withdrawal from fluoxetine. Interestingly, the sustained reductions in the hormone responses occurred in the absence of reductions in Gz or Gi protein levels in the hypothalamus. Furthermore, this desensitization was sustained in the absence of detectable levels of fluoxetine and norfluoxetine in plasma and brain tissue. These findings suggest that the sustained desensitization of hypothalamic 5-HT1A receptor systems, observed during fluoxetine withdrawal, may be due to altered interactions among the protein components of the 5-HT1A receptor system, rather than their absolute levels.     

5-[I-125/123]lodo-3(2(S)-azetidinylmethoxy)pyridine, a radioiodinated analog of A-85380 for in vivo studies of central nicotinic acetylcholine receptors

The in vivo biodistribution profile of the novel nicotinic acetylcholine receptor (nAChR) radioligand 5-[I-125/123]Iodo-3(2(S)-azetidinylmethoxy)pyridine, [I-125/123]-5-IA, in mouse brain was examined. This radiotracer displayed good brain penetration (3.1% of the injected dose (ID) in whole brain at 15 min post-radioligand injection). Radioligand distribution was consistent with the density of high affinity nAChRs with highest uptake observed in the nAChR-rich thalamus (14.9 %ID/g at 60 min), moderate uptake in cortex (8.5 %ID/g at 60 min), and lowest uptake in the cerebellum (2.4 %ID/g at 60 min). Pretreatment with several different nAChR agonists (A-85380, (-)-nicotine, cytisine) significantly inhibited [I-125]-5-IA binding in all brain regions studied (P < 0.01) demonstrating the high specificity of the radioligand for nAChRs. Blocking doses of the muscarinic antagonist scopolamine and the non-competitive nAChR channel blocker mecamylamine had no significant effect on radioactive uptake supporting the in vitro selectivity of [I-125]-5-IA for the nAChR component of the cholinergic system. [I-125]-5-IA binding sites were shown to be saturable with unlabeled 5-IA. With a relatively low acute toxicity (LD50 > 3 mg/kg via intravenous injection in mice) and high in vivo specificity and selectivity, 5-IA labeled with the imaging radionuclide I-123 may prove useful for single photon emission computed tomography (SPECT) studies of nAChRs in human subjects.