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Ketanserin binding characteristics to 5-HT2A receptor: Evidence for two binding subsites
534
Abstracts
IlIOL PSYCUlATR Y I 996:39:Soo-666
release in the medial prefrontul cortex (mPFC) than in the nucleus accurnbcns (NAC). The effect of AP 011 5-HT release would also clarify the differences irt actions between typical nnd atypical AP. We examined the effects of 3CUte systemic admlnlstrailon of four AP, APZ (10 mg!kg), CLOZ (20 rng/kg),haloperidol(HAL, I mglks) and S(-)-sulpiride (SUL, 25 mglkg), on the releaseof DA anl.l5-HT ln 1"'.11 mPFC and NAC. using III ,'1m mlcrodialysis, Both APZand Cl.OZ produced a greaterreleaseof DA inthe mPFC(maximum increaseof basal levelsduring 180min after drug injection: 358% and 226%) than in the NAC (130% anti 133%). APZ and CLOZ also increased 5·HT release in the NAC (140% and 14)%). while APZ. bUI not CLOZ. increased5·HT release in the mPFC (209%). HAL signilic3ntly enhanced DA release in the NAC (16-1%), but not in the mPFe, whereas 5-HT release was increased in both the mPFC (143%) and the NAC (172%). SUL lncreased DA releaseup to 160% in both regions, but had no effecton S-HTrelease in either regions. Thus the results indicate the greater ability of HAL 10 release S-HTcompared to DA in the mPFC whileAPZ, CLOZ and SUL have theopposite. Possible mechanismts) are discussed. Supported in pan by NARSAD.
us.
KETANSERIN BINDING CHARACTERISTICS TO 5.HT 2A RECEPTOR: EVIDENCE FOR TWO BINDING SUBSITES
more impulsive following tryptophan depletion (T-), a procedure believed to lower brain serotonin (SHT) activity. Presently. we are investigating the effects of T- on impulse control in aggressive, disruptive male adolescents who have been followed since age six in It larger prospective study on the psychosocial factors contributing to disruptive behavior. Their behavior wasassessedvla teacherand parentratingsover a slx-year period fromages 6 to 12. Subjects were males (mean age = 17 years) with histories of aggrcsslveranxlous behavior (Ag-An; n"'6). anxious behavior alone (An; n=6) or no such history (C; n""3). Behavioral disinhibition(impulsivity) was assessed by performance on II go/no-go task in which individuals learn to respond to active stimuli associated with reward, and withhold response to passive stimuli assoelated with punishmentor Joss of potentlal reward. There wereno group differences 011 errors of omission (failure to respond to active stimuli). ahhough there was a trend for the Ag-An boys, comparedto group C. [0 commit more passive avoidanceerrors (failures to withhold responses to passive stimuli). However, unlike what was seen in MFH men, there were no significant main or interaction effects of T- in our adolescents. We await the inclusion of more panlclpants who exhibit aggressive behavior without high anxlety. Correlntlnns between cognitive tests measuring prefrontal functioning and go/no-go performance will be presented.
. I") ") .., GNM . . . Gurguis '-, K. Shewmake", & A.I. RushIDepartment of Veterans Affairs Medical Center, Dallas, TX 75216: ~University of Texas Southwestern Medical School. Dallas. TX 72235
• Binding studieshave idcntlfled a site with n lowani nit)' forserotonin thai hu...recently beenclasslfied as the5-TH 2A subtype.5·HT~A receptors arc distributed in the neocortex (particularly laminae III and V in humans), some puns of the limbic system and the basal ganglia. They have also been ldentlfled on peripheral tlssues (platc-Ict membranes and the vasculature). S-HT::!A receptors have been implicated in a variety of behavioral lind neuroendocrine functions, hence their potential role in the neurobiology of psychlmric disorders. We have compared different binding mcthodologies thm were used to examine SJlT~A receptors in psychietric literature, Besides other methodological differences. studies using 3H-Ketanscrin haveemployed It wide concentration runge from 10 pM to 32 nM with widely varied am nilyand maximum binding capacity, We will be presenting data fromour laboratory to suggestthat kctanserin, though art antagonist. ldentlfics two sites. The second site may have no functional slgnificance. We will also present data On characteristics of ..gonists' dlsplacernem curves of Kelanserin binding at dlfferent ketanserin concentrations, Implications of these I1nding.~ for research into the role of 5HTJA receptors In psychiatric disorders will be discussed
119. TRYPTOPHAN DEPLETION AND BEHAVIORAL DISINHIBITION IN MALE ADOLESCENTS WITH AGGRESSIVE. DISRUPTIVE BEHAVIOR
D.G. LeMarquand, C. Benkclfat. R.E. Tremblay, R.O. Pihl, S.N, Young, & R.M. Palrnour Dept. of Psychiatry. McGill University, 1033 Ave. des Pins Ouest. Monlrc!al, Quebec, H3A IA I Recently, wc reported that, compared to controls, young men with II multlgenerutlonal family history (MFH) of paternal alcoholism were
120. NEW INDICES OF SEROTONIN FUNCTION AND THEIR RELATIONSHIP TO
IMPULSIVITY C. Reistl. 2 , L. Albers'r', K BeIl L 2 , D. Treml, ., I 'l D. Helrueste", & S.W. Tang .IVA Medical Center, 5901 E. 7th St.. Long Beach. CA 90822; JUniversily of California Irvine Department of Psychiatry and Human Behavior A large body of literature nowexists Indicating disturbances of serotonin
function in many psychiatric disorders. In the current research program we have studied new techniques for measuring 5HT function to determine their usefulness in lnvestigaling the behavioral dimension of Impulsivity. To study 5HT: receptor slgnal transduction, a flouromctrlc assay for measuring 5HT stirnulated huraccllular Ca++ moblllzatlon in platelets WIlS established and first tested in withdrawn alcoholics who were found to have Cnl-'<' responses no different from controls (Reist. 1995), The second project focused on developing paroxetlne as a neuroendocrine challenge agent. This compound has vel}' high aflinlty for the SUT transporter and insignificant binding for post synaptic receptors of uny class. In 0 study of 10 normals, paroxetine (40 mg) elicited an increase in cortisol that was maximal at 3 hours post dose (Reist, in press). AUC increased significantly after paroxetlne compared to placebo (t .2,77. df= 10, P '= 0.02). No effects on prolactln or growth hormone were observed, Ma:dmum platclct Ca"'+ response to 5tlT was also measuredamIexhibited II direct correlation withchange in cortisol AUC (r = 0.74. P "" 0.03) supporting a relationship bctweea central anti peripheral measuresof 5 HT function. An i nverse correlation of the Bnrrau Impulsivity Scale WaS found with Acortisol AUC(r '" -0.7. P ... 0.04) but not maximum Ca++ response. Finally. the efFect!> of paroxctlne on cerebralblood llow has beenstudied in normah.. n... aaother potential indexof 5HT function. Paroxcune resultedin decreases in CBP averaged across &11 regions, Regional cap was lncreased in the right medial temporal cortex and decreased in the left lnlerlor temporal cortex and thalamus.
=
Abstracts
IlIOL PSYCUlATR Y I 996:39:Soo-666
release in the medial prefrontul cortex (mPFC) than in the nucleus accurnbcns (NAC). The effect of AP 011 5-HT release would also clarify the differences irt actions between typical nnd atypical AP. We examined the effects of 3CUte systemic admlnlstrailon of four AP, APZ (10 mg!kg), CLOZ (20 rng/kg),haloperidol(HAL, I mglks) and S(-)-sulpiride (SUL, 25 mglkg), on the releaseof DA anl.l5-HT ln 1"'.11 mPFC and NAC. using III ,'1m mlcrodialysis, Both APZand Cl.OZ produced a greaterreleaseof DA inthe mPFC(maximum increaseof basal levelsduring 180min after drug injection: 358% and 226%) than in the NAC (130% anti 133%). APZ and CLOZ also increased 5·HT release in the NAC (140% and 14)%). while APZ. bUI not CLOZ. increased5·HT release in the mPFC (209%). HAL signilic3ntly enhanced DA release in the NAC (16-1%), but not in the mPFe, whereas 5-HT release was increased in both the mPFC (143%) and the NAC (172%). SUL lncreased DA releaseup to 160% in both regions, but had no effecton S-HTrelease in either regions. Thus the results indicate the greater ability of HAL 10 release S-HTcompared to DA in the mPFC whileAPZ, CLOZ and SUL have theopposite. Possible mechanismts) are discussed. Supported in pan by NARSAD.
us.
KETANSERIN BINDING CHARACTERISTICS TO 5.HT 2A RECEPTOR: EVIDENCE FOR TWO BINDING SUBSITES
more impulsive following tryptophan depletion (T-), a procedure believed to lower brain serotonin (SHT) activity. Presently. we are investigating the effects of T- on impulse control in aggressive, disruptive male adolescents who have been followed since age six in It larger prospective study on the psychosocial factors contributing to disruptive behavior. Their behavior wasassessedvla teacherand parentratingsover a slx-year period fromages 6 to 12. Subjects were males (mean age = 17 years) with histories of aggrcsslveranxlous behavior (Ag-An; n"'6). anxious behavior alone (An; n=6) or no such history (C; n""3). Behavioral disinhibition(impulsivity) was assessed by performance on II go/no-go task in which individuals learn to respond to active stimuli associated with reward, and withhold response to passive stimuli assoelated with punishmentor Joss of potentlal reward. There wereno group differences 011 errors of omission (failure to respond to active stimuli). ahhough there was a trend for the Ag-An boys, comparedto group C. [0 commit more passive avoidanceerrors (failures to withhold responses to passive stimuli). However, unlike what was seen in MFH men, there were no significant main or interaction effects of T- in our adolescents. We await the inclusion of more panlclpants who exhibit aggressive behavior without high anxlety. Correlntlnns between cognitive tests measuring prefrontal functioning and go/no-go performance will be presented.
. I") ") .., GNM . . . Gurguis '-, K. Shewmake", & A.I. RushIDepartment of Veterans Affairs Medical Center, Dallas, TX 75216: ~University of Texas Southwestern Medical School. Dallas. TX 72235
• Binding studieshave idcntlfled a site with n lowani nit)' forserotonin thai hu...recently beenclasslfied as the5-TH 2A subtype.5·HT~A receptors arc distributed in the neocortex (particularly laminae III and V in humans), some puns of the limbic system and the basal ganglia. They have also been ldentlfled on peripheral tlssues (platc-Ict membranes and the vasculature). S-HT::!A receptors have been implicated in a variety of behavioral lind neuroendocrine functions, hence their potential role in the neurobiology of psychlmric disorders. We have compared different binding mcthodologies thm were used to examine SJlT~A receptors in psychietric literature, Besides other methodological differences. studies using 3H-Ketanscrin haveemployed It wide concentration runge from 10 pM to 32 nM with widely varied am nilyand maximum binding capacity, We will be presenting data fromour laboratory to suggestthat kctanserin, though art antagonist. ldentlfics two sites. The second site may have no functional slgnificance. We will also present data On characteristics of ..gonists' dlsplacernem curves of Kelanserin binding at dlfferent ketanserin concentrations, Implications of these I1nding.~ for research into the role of 5HTJA receptors In psychiatric disorders will be discussed
119. TRYPTOPHAN DEPLETION AND BEHAVIORAL DISINHIBITION IN MALE ADOLESCENTS WITH AGGRESSIVE. DISRUPTIVE BEHAVIOR
D.G. LeMarquand, C. Benkclfat. R.E. Tremblay, R.O. Pihl, S.N, Young, & R.M. Palrnour Dept. of Psychiatry. McGill University, 1033 Ave. des Pins Ouest. Monlrc!al, Quebec, H3A IA I Recently, wc reported that, compared to controls, young men with II multlgenerutlonal family history (MFH) of paternal alcoholism were
120. NEW INDICES OF SEROTONIN FUNCTION AND THEIR RELATIONSHIP TO
IMPULSIVITY C. Reistl. 2 , L. Albers'r', K BeIl L 2 , D. Treml, ., I 'l D. Helrueste", & S.W. Tang .IVA Medical Center, 5901 E. 7th St.. Long Beach. CA 90822; JUniversily of California Irvine Department of Psychiatry and Human Behavior A large body of literature nowexists Indicating disturbances of serotonin
function in many psychiatric disorders. In the current research program we have studied new techniques for measuring 5HT function to determine their usefulness in lnvestigaling the behavioral dimension of Impulsivity. To study 5HT: receptor slgnal transduction, a flouromctrlc assay for measuring 5HT stirnulated huraccllular Ca++ moblllzatlon in platelets WIlS established and first tested in withdrawn alcoholics who were found to have Cnl-'<' responses no different from controls (Reist. 1995), The second project focused on developing paroxetlne as a neuroendocrine challenge agent. This compound has vel}' high aflinlty for the SUT transporter and insignificant binding for post synaptic receptors of uny class. In 0 study of 10 normals, paroxetine (40 mg) elicited an increase in cortisol that was maximal at 3 hours post dose (Reist, in press). AUC increased significantly after paroxetlne compared to placebo (t .2,77. df= 10, P '= 0.02). No effects on prolactln or growth hormone were observed, Ma:dmum platclct Ca"'+ response to 5tlT was also measuredamIexhibited II direct correlation withchange in cortisol AUC (r = 0.74. P "" 0.03) supporting a relationship bctweea central anti peripheral measuresof 5 HT function. An i nverse correlation of the Bnrrau Impulsivity Scale WaS found with Acortisol AUC(r '" -0.7. P ... 0.04) but not maximum Ca++ response. Finally. the efFect!> of paroxctlne on cerebralblood llow has beenstudied in normah.. n... aaother potential indexof 5HT function. Paroxcune resultedin decreases in CBP averaged across &11 regions, Regional cap was lncreased in the right medial temporal cortex and decreased in the left lnlerlor temporal cortex and thalamus.
=