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Biomedical subjects

H Hall

Publications and source records attributed to H Hall.

At least 37 records · Page 2Linked to original sources
PubMed2000

Second primary ovarian cancer among women with cancer.

PURPOSE: Some studies suggest women with certain types of cancers are at increased risk for ovarian cancer. This study assessed the risk of second primary ovarian cancer among U.S. women who have cancer by anatomic site, age, race, and time since diagnosis of the first primary cancer.METHODS: We analyzed data from SEER cancer registries for women diagnosed with invasive cancer between 1973 and 1996. Person-years were accumulated from 2 months after initial cancer diagnosis to date of ovarian cancer diagnosis, death, loss to follow-up, or end of follow-up, December 31, 1996. The expected number of cases was obtained by multiplying 5-year age and calendar year interval specific ovarian cancer rates by the accumulated person-years at risk. We calculated the risk (observed [O]/expected numbers [E]) of second primary ovarian cancer by cancer site and age (<50 years, >/=50 years), race (all, white, black), and time since first cancer (0-4, 5-9, 10-14, 15-24 years). Statistical tests and 95% confidence intervals (CI) were based on the assumption of a Poisson distribution.RESULTS: A significant increased risk of ovarian cancer was found for women aged <50 years at time of diagnosis with melanoma (O/E = 3.5, 95% CI = 2.1-5.5) and cancer of the breast (O/E = 6.0, 95% CI = 4.9-7.2), cervix (O/E = 4.2, 95% CI = 2.6-6.3), corpus uteri (O/E = 11.91, 95% CI = 7.3-18.4), colon (O/E = 17.9, 95% CI = 11.1-27.3), and ovary (O/E = 4.9, 95% CI = 2.7-8.2); no increased risk was found for women aged >/=50 years. Ovarian cancer risk remained elevated following all of these first primary cancers 5-9 years after diagnosis; for women with breast and colon cancer, risk remained elevated 15-24 years after diagnosis. A significant increased risk was found for all of these cancers among white women <50 years at diagnosis; risk was increased among black women <50 years with cancer of the breast, cervix, and colon.CONCLUSIONS: We found an ovarian cancer risk higher than expected for women with certain types of cancer; however, the risk was limited to women <50 years of age.

Journal Article↗
PubMed2000

Dopamine-transporter density in nucleus accumbens of type-1 alcoholics.

We have shown that alcoholic patients have a lower number of dopamine transporters in the nucleus accumbens, which mediates the rewarding effects of addictive drugs. Thus, certain dopaminergic agents may be beneficial in the treatment of alcohol withdrawal and in the long-term treatment of alcoholism with selective use.

Alcoholism↗
PubMed2000

Prognostic factors for time receiving workers' compensation benefits in a cohort of patients with low back pain.

STUDY DESIGN: Prospective inception cohort study. OBJECTIVE: To develop a prognostic model that predicts time receiving workers' compensation benefits for low back pain claimants. SUMMARY OF BACKGROUND DATA: As the cost and difficulty of managing low back pain escalate, any predictor of outcome is advantageous. METHODS: To obtain the outcome and predictor variables, patient data from two separate databases were linked: a clinical database and an administrative (Ontario workers' compensation) database. Claimants injured between January 1 and December 31, 1994, were included and observed for 1 year from the date of accident. The outcome variable was cumulative number of calendar days receiving benefits. RESULTS: Multivariable Cox proportional hazards regression (forward stepwise) showed eight significant predictors; five were associated with increased time receiving benefits compared with their reference groups: 1) working in the construction industry, 2) older age, 3) lag time from injury to treatment, 4) pain referred into the leg, and 5) three or more positive Waddell nonorganic signs. Three predictors were associated with reduced time receiving benefits: 1) higher values of questionnaire score, 2) intermittent pain, and 3) a previous episode of back pain. A predictive score was calculated to categorize claimants as at high or low risk for chronicity. When an arbitrary cutoff point was set at the 75th percentile of predictive score, negative predictive value was 94%. CONCLUSION: This research identified eight factors for time receiving workers' compensation benefits among claimants with low back pain. This model discriminates between high- and low-risk claimants. Few low-risk claimants continued to receive benefits for more than 3 months.

Adult↗
PubMed2000

Mapping of serotonin 5-HT(4) receptor mRNA and ligand binding sites in the post-mortem human brain.

The anatomical localization of 5-HT(4) receptor mRNA and 5-HT(4) receptor protein was examined in sections of post-mortem human brain by in situ hybridization histochemistry and radioligand receptor autoradiography. In the in situ hybridization study, the highest levels of 5-HT(4) receptor mRNA were found in caudate nucleus, putamen, nucleus accumbens, and in the hippocampal formation. No 5-HT(4) receptor mRNA was detected in globus pallidus and substantia nigra. For receptor autoradiography, two new and highly selective radioligands were compared: [(3)H]prucalopride, which preferentially labels the G-protein coupled fraction of receptors, and [(3)H]R116712, which labels the entire receptor population at subnanomolar concentrations. [(3)H]Prucalopride and [(3)H]R116712 binding was performed on human brain hemisphere sections. The highest densities for both radioligands were found in the basal ganglia (caudate nucleus, putamen, nucleus accumbens, globus pallidus, substantia nigra). Moderate to low densities were detected in the hippocampal formation and in the cortical mantle. Mismatches between 5-HT(4) receptor mRNA and binding sites in the globus pallidus and the substantia nigra suggested that the binding sites may be localized on axonal projections originating from the striatum. To compare densities of binding sites, concentration binding curves with [(3)H]prucalopride, [(3)H]R116712 and [(3)H]GR113808 were performed on membranes from homogenates of several human brain regions. Comparison of B(max)-values obtained with [(3)H]prucalopride and [(3)H]R116712 indicated that the G-protein coupled fraction of 5-HT(4) receptors in the substantia nigra was exceptionally high (54%) in comparison with percentages (16-27%) found in the frontal cortex, the striatum and the hippocampus. Such a high percentage (40%) of [(3)H]prucalopride vs. [(3)H]R116712 binding was also observed in the substantia nigra in the receptor autoradiography experiments. The [(3)H]prucalopride binding was GppNHp-sensitive, whereas [(3)H]R116712 and [(3)H]GR113808 was not. These data indicate that in the substantia nigra 5-HT(4) receptors are more strongly coupled to their signal transduction pathway than in other brain regions.

Aged↗
PubMed2000

CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells.

CD4+CD25+ T cells have been shown to inhibit experimentally induced organ-specific autoimmune disease and depletion of these regulatory T cells from normal mice results in development of such conditions. Furthermore, CD4+CD25+ T cells suppress the IL-2 production and thereby the proliferation of polyclonally activated CD4+CD25- T cells in vitro. The suppression in vitro is independent of secreted factors but requires interactions between CD4+CD25- and CD4+CD25+ T cells and antigen-presenting cells (APC). We have now further investigated the function of CD4+CD25+ T cells in vitro and have focused on their interactions with APC. We found that CD4+CD25+ T cells down-regulated the expression of the co-stimulatory molecules CD80 and CD86 on dendritic cells. The steady-state level of CD80 mRNA was also decreased, while the steady-state level of CD86 mRNA was not, suggesting that distinct mechanisms regulate the expression of these molecules. The down-regulation occurred even in the presence of stimuli that would normally increase the expression of CD80 and CD86 molecules. Thus, down-regulation of co-stimulatory molecules may be an additional effector function of these regulatory T cells.

Animals↗
PubMed2000

Z-IQNP: a potential radioligand for SPECT imaging of muscarinic acetylcholine receptors in Alzheimer's disease.

RATIONALE: The density of the M2 subtype of muscarinic acetylcholine receptors (mAChR) has been shown to be reduced in the brain of patients with Alzheimer's disease (AD). It is therefore of interest to develop a brain imaging method for diagnostic purposes. Z-(R,R)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo1-propen-3-yl)-alpha-phenylacetat e (Z-IQNP) is a muscarinic antagonist with high affinity for the M2 subtype. OBJECTIVE: The pharmacological characteristics and topographic distribution of radiolabelled Z-IQNP as a radioligand for the M2 mAChR subtype were examined in vitro and in vivo. METHODS: Z-IQNP was labelled with 1251 and 123I. Autoradiography was performed on whole-hemisphere cryosections from human post mortem brains. SPECT was performed in a cynomolgus monkey. RESULTS: Autoradiography showed binding of [125I]Z-IQNP in all brain regions, which was inhibited by the non-selective muscarinic antagonist scopolamine. The addition of BIBN 99, a compound with high affinity for the M2 subtype, inhibited [125I]Z-IQNP binding particularly in the cerebellum, which has a high density of the M2 subtype. SPECT demonstrated high uptake of [123I]Z-IQNP in all brain regions. The binding was markedly reduced in all brain regions after pretreatment with the non-selective muscarinic antagonist dexetimide and also the M1 antagonist biperiden. Dexetimide markedly inhibited [123I]Z-IQNP binding in the cerebellum, which is consistent with a high density of M2-receptors in this region. The sigma receptor binding compound DuP 734 had no effect on Z-IQNP binding either in vitro or in vivo. CONCLUSIONS: This study indicates that radiolabelled Z-IQNP has high specificity for mAChR with higher affinity for the M2 than the M1 subtype and negligible affinity for sigma recognition sites both in vitro and in vivo. [123I]Z-IQNP should be useful for future SPECT studies in AD for examination of the density of M2 receptors particularly in the cerebellum.

Alzheimer Disease↗
PubMed2000

GTP differentially affects antagonist radioligand binding to adenosine A(1) and A(2A) receptors in human brain.

The effect of guanosine triphosphate (GTP) on the interaction of antagonists with human adenosine A(1) and A(2A) receptors was studied using whole-hemisphere sections from human brain and membranes from Chinese hamster ovary (CHO) cells expressing human A(1) and A(2A) receptors. Adenosine A(1) receptors, studied using [3H]1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX) as radioligand, showed the expected regional distribution in human brain. Addition of 500 microM GTP significantly increased (23-55%) [3H]DPCPX binding in all regions measured. In CHO cells transfected with human adenosine A(1) receptor cDNA, the number of receptors, B(max), increased from 401 (359-442) to 667 (592-743) fmol/mg protein upon addition of GTP. [3H]5-Amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo-[4,3-e]-1,2, 4-triazolo-[1,5-c]-pyrimidine ([3H]SCH 58261), a selective adenosine A(2A) receptor ligand, showed saturable binding to membranes from CHO cells transfected with adenosine A(2A) receptor cDNA and was localized to striatum and globus pallidus in human brain sections. Addition of GTP did not significantly change [3H]SCH 58261 binding to brain sections or CHO cell membranes. These results indicate that human A(1) and A(2A) receptors are not substantially different from those of the rat as regards regulation by GTP and interactions with endogenous adenosine in binding experiments. However, the relative abundance of the receptors differs between species, and this may be related to the differences observed in the potency of the endogenous agonist.

Animals↗
PubMed2000

Trimerization of cell adhesion molecule L1 mimics clustered L1 expression on the cell surface: influence on L1-ligand interactions and on promotion of neurite outgrowth.

Several studies indicate that cell adhesion molecules have to be clustered on the cell surface to engage in adhesive functions. We investigated adhesive functions of clustered versus monomeric L1 extracellular parts in vitro to distinguish how clustering affects ligand binding and promotion of neurite outgrowth. Trimeric L1 was recombinantly expressed and covalently assembled by the cartilage matrix protein's coiled-coil domain. Trimeric L1 has an apparent molecular mass of approximately 380 kDa in the nonreduced form and approximately 130 kDa in the reduced form. Rotary shadowing electron micrographs of trimeric L1 revealed a rod-like shape terminating in three globular domains. Monomeric L1 assumes a horseshoe shape of domains Ig I-IV followed by a rod-like structure consisting of Ig V and VI and fibronectin type III 1-5. Circular dichroism measurements showed that the secondary structure consists of beta-sheets. Trimeric L1 binds to itself, to monomeric L1, to laminin-1, and to alpha5beta1 integrin in a concentration-dependent manner. In contrast, binding of monomeric L1 could only be saturated with itself but not with laminin-1 and with alpha5beta1 integrin. Promotion of neurite outgrowth from PC12 cells cultured on adsorbed trimeric L1 was increased by 100%, whereas on monomeric L1 the increase was only 50% over the control value. Promotion of neurite outgrowth from PC12 cells was specifically inhibited in a concentration-dependent manner by a polyclonal antibody against L1. These findings show that clustering of only three extracellular domains increases considerably L1's binding affinity to different ligands and enhances neurite outgrowth, suggesting that adhesive functions of L1 on the cell surface depend on cluster formation.

Animals↗
PubMed1999

Elevation of the epidermal growth factor receptor and dependent signaling in human papillomavirus-infected laryngeal papillomas.

Laryngeal papillomas are benign tumors caused by human papillomaviruses types 6 and 11. This study addressed alterations in levels of signal transduction from the epidermal growth factor receptor (EGFR) in papillomas and cultured papilloma cells compared to normal tissue and cells. Mitogen-activated protein kinase (MAPK) was activated to a greater extent, phosphotyrosine was more abundant, and EGFR was overexpressed in laryngeal papillomas compared to normal laryngeal epithelium by Western blot analysis. The EGFR was 3 times more abundant in cultured papilloma cells than in normal laryngeal cells by Scatchard analysis and Western blot, without gene amplification or an increase in steady-state levels of mRNA. Following stimulation with EGF, a significant portion of the EGFR was recycled to the surface in papilloma cells, whereas in normal cells, it was not. Tyrosine kinase activity and activation of MAPK was more responsive to epidermal growth factor stimulation in papilloma cells than in uninfected primary laryngeal cells. PD153035, a specific inhibitor of the EGFR, and an EGFR-specific antibody that blocks ligand binding completely abrogated basal MAPK activation by endogenous ligands in laryngeal papilloma cells. These results demonstrated that infection of laryngeal epithelium by low-risk human papillomaviruses elevates the EGFR by posttranslational mechanisms, increasing its responsiveness to ligand-mediated activation. They also showed that MAPK activation in laryngeal papillomas depends upon ligand-mediated EGFR stimulation.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1999

Characterization of the surface proteins of influenza A (H5N1) viruses isolated from humans in 1997-1998.

Influenza A (H5N1) viruses infected humans in Hong Kong between May and December, 1997. Sixteen viruses, including 6 from fatal cases, were isolated during this outbreak. Molecular analysis of the surface proteins genes encoding the hemagglutinin (HA) and neuraminidase (NA) of these H5N1 isolates, of a subtype not previously known to infect humans, are presented. The 16 human H5 HA sequences contain multiple basic amino acids adjacent to the cleavage site, a motif associated with highly pathogenic avian influenza A viruses. The phylogenetic relationship among both avian and human H5 hemagglutinins indicates that the human isolates are related directly to isolates that circulated among chickens in the live poultry markets in Hong Kong prior to and during the outbreak in humans. HA sequences from the human isolates and a recent chicken isolate represent a separate clade, within which there are two subgroups that are distinguishable antigenically and by the presence of a potential glycosylation site. Likewise the N1 neuraminidases of the human H5 isolates represent a clade that is evolutionarily distinct from previously characterized N1 neuraminidases. The recent human H5N1 virus NA genes are avian-like, indicating direct introduction from an avian source rather than evolution of a human N1 NA. All of the 16 human NA genes encode a shortened stalk due to a 19-amino acid deletion, also found in the recent avian H5N1 isolates from Hong Kong. Two unique amino acids were identified in the N1 NAs of the recent human isolates; however, it is not known if these residues influence host range. Neither the HA nor the NA genes of the human H5N1 virus isolates show evidence of adaptive changes during the outbreak. Although analyses of the surface protein genes of the H5N1 viruses from this outbreak did not provide immediate answers regarding the molecular basis for virulence, the analyses provided clues to potentially important areas of the genes worth further investigation.

Adolescent↗
PubMed1999

Intertester reliability of a low back pain classification system.

STUDY DESIGN: This prospective study of intertester reliability examined pairs of therapists' ability to agree independently on a patient's low back pain diagnosis. OBJECTIVE: To determine the intertester reliability of a low back pain classification system among experienced and novice clinicians. BACKGROUND: Many of the disparate categorization schemes for patients with low back pain are purely nominal, assigning designations based on the presumptive source of the problem without providing any practical guide for rehabilitation. A useful classification scheme reliably groups patients into treatment-directing categories. METHODS: The study included 204 patients with low back pain referred to 10 clinics across Canada. Paired physiotherapists performed separate physical examinations on each patient. Both examiners then completed a simple ballot choosing one of five pain patterns. RESULTS: Agreement on patient classification by independent examiners was 78.9% (kappa = 0.61). CONCLUSION: This clinically relevant and clearly defined pain pattern system uses key elements of the history and examination to classify patients with low back pain. The pattern provides a framework for initiating active rehabilitation strategy. Using this approach, clinicians agreed on the categorization of 78.9% of mechanical low back pain cases.

Adolescent↗
PubMed1999

Differences between bacterial species shown by simultaneous assessment of neutrophil phagocytosis and generation of reactive oxygen intermediates in trauma patients.

HYPOTHESIS: Previous studies on alterations in phagocytosis and bacterial killing after trauma have yielded conflicting results. We hypothesize that these changes are variable, depending on the species of bacteria used to assay these variables. DESIGN: Blood samples from patients were assayed by means of flow cytometry for phagocytosis and reactive oxygen intermediate generation. Several common clinical pathogens were used: Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus. Results were compared with those from controls. SETTING: Regional level I trauma center. PATIENTS: Ten consecutive patients were studied with E. coli and K. pneumoniae. Five of these were also studied with S. aureus. Patients were 18 years of age or older, with an Injury Severity Score of 16 or more. Patients who were taking corticosteroids before hospital admission or who were administered corticosteroids before blood was drawn were not studied. Isolated head injuries or limb fractures were also excluded. Controls consisted of healthy volunteers. MAIN OUTCOME MEASURES: The ingestion of bacteria by neutrophils and the generation of reactive oxygen intermediates. RESULTS: After trauma, phagocytosis of E. coli was enhanced, whereas ingestion of K. pneumoniae was depressed. Ingestion of S aureus remained unchanged. The generation of reactive oxygen intermediates was depressed after incubation with E. coli and unchanged with K. pneumoniae, but enhanced with S. aureus. CONCLUSIONS: Neutrophil response to trauma is dependent on which bacterial species the cell is attempting to kill. This may, in part, explain why only a limited number of bacterial species cause a significant proportion of early infections after trauma.

Adolescent↗
PubMed1999

Visualization of the dopamine transporter in the human brain postmortem with the new selective ligand [125I]PE2I.

Using a new, 125I-labeled, selective high affinity dopamine transporter ligand, N-(3-iodoprop-2E-enyl)-2beta-carbomethoxy-3beta-(4'-methy lph enyl)nort ropane (PE2I), the distribution of the dopamine transporter was characterized in the normal postmortem human brain using whole hemisphere autoradiography. PE2I was radioiodinated to high specific radioactivity (2200 Ci/mmol, 81 GBq/micromol). PE2I binds to the dopamine transporter with high potency and, in contrast to beta-CIT, it has very low affinities for the serotonin and noradrenaline transporters. The autoradiograms showed very intense binding in basal ganglia (putamen, nucleus caudatus, nucleus accumbens) and lower binding in substantia nigra. Very low or no binding was found in other brain structures, including the neocortex or cerebellum. The labeling of human dopamine transporters with [125I]PE2I was inhibited by the dopamine transporter inhibitors GBR 12909 and beta-CIT, but not by citalopram (serotonin transporter inhibitor) or maprotiline (noradrenaline transporter inhibitor). Possibly due to the relatively high lipophilicity of the compound (theoretical log p = 4.68), it accumulated slightly in white matter. Thus, in vitro autoradiography using [125I]PE2I provided detailed qualitative and quantitative evidence that the dopamine transporter is almost exclusively localized in the basal ganglia of the human brain. Moreover, the autoradiograms indicate that [11C]PE2I and [123I]PE2I should be suitable for the in vivo visualization of the human dopamine transporter with PET or SPECT, respectively.

Adult↗
PubMed1999

Surgery: indications and options.

The challenge is to better define the present role of spine surgery and more completely understand its realistic benefits and consequences. In spite of modern sophistication, spine surgery can still accomplish only the same two broad objectives, decompression and fusion, that have been possible for more than a century. Never vague or tentative, surgery has its place in the narrow spectrum of cases with clearly established, well circumscribed, structural pathology unresponsive to nonsurgical treatment and producing significant persistent disability. Identifying valid indications and options within the plethora of choices requires knowledge of what is available, what can actually be accomplished, and what limitations apply.

Decompression, Surgical↗
PubMed1999

Radiosynthesis and autoradiographic evaluation of [11C]NAD-299, a radioligand for visualization of the 5-HT1A receptor.

The selective 5-HT1A receptor antagonist NAD-299 ([R]-3-N,N-dicyclobutylamino-8-fluoro-3,4- dihydro-2H-1-benzopyran-5-carboxamide) was labeled with the positron-emitting radionuclide carbon-11. The radioligand was synthesized from NAD-195 ([R]-3-N,N-dicyclobutylamino-8-fluoro-5-trifluoromethylsulfonyl oxy-3,4- dihydro-2H-1-benzopyran) in two radiochemical steps. A palladium-catalyzed reaction of NAD-195 and [11C]cyanide was followed by hydrolysis of the carbon-11-labeled nitrile intermediate with basic hydrogen peroxide. The total radiochemical yield, based on [11C]CO2 and corrected for decay, was 20-40%. The specific radioactivity was 24 GBq/mumol (900 Ci/mmol) at end of synthesis, with a radiochemical purity better than 99% and a total synthesis time of 40-45 min. Autoradiographic examination of [11C]NAD-299 binding in human brain postmortem demonstrated high binding in hippocampus, raphe nuclei, and neocortex. The binding in the hippocampus was higher than in the neocortex. Within the hippocampus, the densest binding was observed in the CA1 region. [11C]NAD-299 binding was inhibited by addition of the 5-HT1A receptor ligands WAY-100635, pindolol, (+/-)-8-OH-DPAT, 5-HT, and buspirone, leaving a low background of nonspecific binding. The results indicate that [11C]NAD-299 binds specifically to 5-HT1A receptors in the human brain in vitro and is a potential radioligand for positron emission tomography (PET) examination of 5-HT1A receptors in vivo.

Autoradiography↗
PubMed1999

Carbon-11 epidepride: a suitable radioligand for PET investigation of striatal and extrastriatal dopamine D2 receptors.

Epidepride [(S)-(-)-N-([1-ethyl-2-pyrrolidinyl]methyl)-5-iodo-2,3-dimethoxybenza mide] binds with a picomolar affinity (Ki = 24 pM) to the dopamine D2 receptor. Iodine-123-labeled epidepride has been used previously to study striatal and extrastriatal dopamine D2 receptors with single photon emission computed tomography (SPECT). Our aim was to label epidepride with carbon-11 for comparative quantitative studies between positron emission tomography (PET) and SPECT. Epidepride was synthesized from its bromo-analogue FLB 457 via the corresponding trimethyl-tin derivative. In an alternative synthetic pathway, the corresponding substituted benzoic acid was reacted with the optically pure aminomethylpyrrolidine-derivative. Demethylation of epidepride gave the desmethyl-derivative, which was reacted with [11C]methyl triflate. Total radiochemical yield was 40-50% within a total synthesis time of 30 min. The specific radioactivity at the end of synthesis was 37-111 GBq/micromol (1,000-3,000 Ci/mmol). Human postmortem whole-hemisphere autoradiography demonstrated dense binding in the caudate putamen, and also in extrastriatal areas such as the thalamus and the neocortex. The binding was inhibited by unlabeled raclopride. PET studies in a cynomolgus monkey demonstrated high uptake in the striatum and in several extrastriatal regions. At 90 min after injection, uptake in the striatum, thalamus and neocortex was about 11, 4, and 2 times higher than in the cerebellum, respectively. Pretreatment experiment with unlabeled raclopride (1 mg/kg) inhibited 50-70% of [11C]epidepride binding. The fraction of unchanged [11C]epidepride in monkey plasma determined by a gradient high performance liquid chromatography (HPLC) method was about 30% of the total radioactivity at 30 min after injection of [11C]epidepride. The availability of [11C]epidepride allows the PET-verification of the data obtained from quantitation studies with SPECT.

Autoradiography↗
PubMed1999

Autoradiographic studies of 5-HT1A-receptor-stimulated [35S]GTPgammaS-binding responses in the human and monkey brain.

G-protein activation mediated by serotonin 5-HT1A receptors in human and monkey brain was investigated by using quantitative autoradiography of agonist-stimulated [35S]GTPgammaS binding to whole-hemisphere brain sections. [35S]GTPgammaS binding was stimulated by the mixed 5-HT1A/1B/1D agonist L 694247 (10 microm) in human brain regions enriched in 5-HT1A binding sites [e.g. hippocampus (132-137%), superficial layers of the neocortex (37-61%), and cingulate and entorhinal cortex (34 and 32%, respectively)]. L 694247 caused virtually no stimulation in regions with 5-HT1B/1D receptors, such as substantia nigra, caudate nucleus and putamen. Similar results were obtained with monkey brain sections. The L 694247-mediated [35S]GTPgammaS-binding responses in human and monkey brain sections were antagonized by the selective, silent 5-HT1A antagonist WAY 100635 (10 microm). The 5-HT1B inverse agonist SB 224289 (10 microm) did not affect the [35S]GTPgammaS-binding response of L 694247. The distribution pattern of the [35S]GTPgammaS-binding response and the antagonist profile suggest the L 694247-induced response in human and monkey brain is mediated by 5-HT1A receptors. A weak stimulation of [35S]GTPgammaS binding was also observed in human hippocampus with either 10 microm 8-OH-DPAT (25 +/- 4%) or naratriptan (42 +/- 2%) compared with that obtained with L 694247. In conclusion, G-protein activation by 5-HT1A receptors can be measured in human and monkey brain sections. L 694247 appears to possess higher efficacy at 5-HT1A receptors compared with 8-OH-DPAT and naratriptan.

8-Hydroxy-2-(di-n-propylamino)tetralin↗