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Serotonin1a Receptor Activation by Flesinoxan in Humans Body Temperature and Neuroendocrine Responses B

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Serotonin1a Receptor Activation by Flesinoxan in Humans Body Temperature and Neuroendocrine Responses B J:'r!'·~, .:i~>t~~~.t c< . I 1.\1 \ l·R Serotonin1A Receptor Activation by Flesinoxan in Humans Body Temperature and Neuroendocrine Responses B. Seletti, M.D., C. Benke/fat, M.D., P. Blier, M.D., Ph.D., L. Annable, B.Sc., Dip. Stat., F. Gilbert, M.D., and C. de Montigny, M.D., Ph.D. The effects of tlze selectir 1e 5-HT,A re(eptor agonist lwnnone response to flesinoxan was blocked by pindolol flesinoxan on neuroendouine funct/011, temperature, a11d but not by methysergide, whereas the prolactin response belzavior were assessed i11 male healt/1y volunteers usi11g a ,uas blocked by methysergide but not by pindolol. The double-blind, placebo-controlled crossouer design. ACTH and cortisol responses to flesinoxan were Flexinoxan (7 and 14 µg/kg), administered intravenously potentiated by methysergide. The flesinoxan-induced in 11 healthy voluntl'ers, elicited a dose-related deuease !1ypothermia was attenuated by both methysergide and in b,)dy temperature and increases i11 growth lzormone, pindolol, although the latter effects did not reach adrenocorticotropic hormone (ACTH), cortisol, a11d statistical significance. The present results suggest that prolactin plasma levels. In a second independent study, the growth hormone response and the hypothermic 12 healthy rnlunteers were pretreated sequentially, at response to the intravenous infusion of flesinoxan may one-week intervals, ,uith either the S-HT1" antago11ist serz,e as a ualid index of S-HT1A receptor function in pindolol (30 mg, PO), t/ie nonselectil·e S-HT1 c /1w11ans. [Neuropsychopharmacology 13:93-104, antagonist methysergide (4 mg, PO!, or placebo. prior to 1995/ being administered flesinoxa11 (1 mg, IV). The growtli KEY WORDS: Flesinoxan; Hypothermia; Growth probes such as buspirone (Meltzer and Maes 1994; hormone; Pindolol; Methysergide; 5-HT1A receptor Moeller et al. 1994), gepirone (Anderson et al. 1990), tandospirone (Miller et al. 1990), and ipsapirone (Lesch Over the past decade, the development of nontoxic, et al. 1989). Although buspirone has a high affinity for selective serotonin (5-HT) receptor agonists has made 5-HT 1A receptors, its complex pharmacological effects it possible to probe 5-HT receptor function in humans on dopaminergic neurotransmission make us question in vivo by means of pharmacological challenges. More its validity as an index of S-HT1A function, particularly specifically, studies exploring the role of brain S-HT1A with respect to measurements of buspirone-induced receptor function in major affective and anxiety dis­ prolactin release (Meltzer et al. 1983). Moreover, many orders have now been made possible using receptor of these agents share a common metabolite, 1-(2-pyri­ midinyl) piperazine (1-PP), which displays a2-adreno­ From the Neurobiological Psychiatry Unit, Department of Psy­ receptor antagonist properties (Gobbi et al. 1990; Blier chiatry, McGill University, Montreal. Canada H3A lA 1. and the et al. 1991 ), which may constitute a confounding factor Department of Endocrinology, Maisonneuvc-Rosemont Hospital, Montreal, Canada HlT 2M4. in the interpretation of these studies. Address correspondence to C. Benkelfat, M.D., l\eurobiological Flesinoxan is a newly developed substituted ben­ Psychiatry Unit, Department of Psychiatrv, McGill University, 1033 zamide with high affinity and selectivity for the 5-HT1A Pine Ave. West, Montreal, Canada H3A lAI. Received August 31, 1994; revised Januarv 10, 1995; accepted Janu­ receptor subtype (2 nM); (Olivier et al. 1991). In autora­ ary 27, 1995 . diographic studies, flesinoxan showed a regional dis- .'Jl:UROl'~Y(HOPlfAR\1,\LOltlCI ;c1ci, \~\I ,';, \.1.) . ..:' © 19<i5 American Cullegc of '\Jcuwps\, huph.ir111.i, lliug\ Publi,hed bv ElsL'\'il'r Scienn• In, 0893-133X/95/$9.50 h55 t..vl'nu,• of tfll' Anwnc.i, '''" \ ,,r, '\:'r 1111111 1 SSDI 0893-133X(95)00025-9 94 B. Seletti l'l al. t\;~LROPSYCHOPHARMACOLOGY 1995-VOL 13, NO. 2 tribution cumparable t,1 that ot 8-hvdroxy-2-(di-n-pfll­ 29 years (SD = 4.8; range = 21 to 37 years; weight = pylamino)tetralin (8-01-1-DPAT; Schipper et al. 1991) 73.2 ± 10.5 kg; and height = 1.76 ± 0.15 m) each re­ It decreased body temperature and reduced aggressivitv ceived two intravenous infusions of flesinoxan (7 µg/kg scores in animal models (Schipper et al. 1991). Flesi­ and 14 µg/kg) and one of saline, over a period of 10 noxan displays high putency at both somatodendritic minutes, on three separate occasions, a minimum of and postsynaptic 5-HT I.\ receptors 1Hadrava et al. 1 week apart, between August and November 1992. 1995). For instance, in microiontophoretic studies, it was Neuroendocrine, physiological, and psychological mea­ found 17 times more potent than gepirone in suppress­ sures were collected over a 2-hour period during each ing the firing rate of dorsal hippocampus pvramid,,1 session. neurons (de Montignv et al. 1991), These characteris­ tics, together with the fact that. contrary to the azap1- Antagonist Study. In a randomized, double-blind, 3 x rones, it does not generate I-PP, make it a potentiallv 3 Latin-square design, 12 men (age = 28.3 ± 4.7 years; valuable probe for assessing =;-HT 1\ rL'Ceptor function range= 20 to 40 years; weight 71.3 ± 5.6 kg; height = in humans. 1.78 ± 0.15 m) received orally, on three separate occa­ The present studv determrnl'd tht· effects of flesinli­ sions each, a placebo, 30 mg of racemic pindolol, or xan on body temperature, and neuruendocrine and bl'­ 4 mg of methysergide, 90 minutes prior to the infusion havioral measures in vnung male healthv volunteer-. of l mg flesinoxan over 10 minutes. Each subject was The selectivity uf these respunst·s for the 5-HT svstem. tested on three separate occasions, a minimum of 1 and more specifJCally for the ''i-HT \ receptor, was fur 1 week apart, between November 1992 and February ther investigated in volunteers pretredted with the mixed 1993. Five subjects participated in both the dose-re­ 5-HT1 ::i antagonist nwthvsl'l)~ilk. tlw 5-HT1 \ antagt•• sponse and the antagonist studies. Neuroendocrine, nist pindolnl, and pl,Kebu phvsiulogical, and psychological measures were col­ lected over a 3.5-hour period during each session. MATERIALS AND METHODS Subjects Twenty-eight healthv niluntl'er-. were recruited through Procedure local nev,·spaper advertisements. All potential research Subjects arrived at the Clinical Investigation Unit of the subjects underwent physical and psychiatric examina­ Royal Victoria Hospital in Montreal at 8:30 A.M., hav­ tions (using the Structured Climcal Interview for DSM­ ing fasted since midnight. They wore normal indoor IE-R, nonpatient version. '::ipit1er et al. 1992). had an attire and, after being weighed, reclined on a bed in electrocardiogram and routine laboratorv tests, includ­ a comfortable position with the head elevated. They ing serum sequential multiple analysis by computer were not allowed to eat, sleep, or watch television un­ complete bluod count. thvroid !unction tests, HIV test til the procedure was completed. Two indwelling ve­ u ~ine analysis. and a urine tuxil·ulug\'-screen for drugs nuus catheters were inserted into the antecubital vein of abuse. Unlv ph\'SJC all\' heal th v su biects \\ ithou t .i and kept opened with a slow infusion of 5% dextrose personal histtin of psHhidtric illness Pr a family h1--­ in a normal saline solution. After insertion of the intra­ tory of mood disprdn-. ur ciln,hPlism in first-degree rela­ venous catheters, baseline blood samples were obtained tives were in\'ited tu partiCipate Subjects scoring 2 m folluwmg a 45-min rest period and again, 15 minutes mnre on at least three svmptom-, ( m the Hopkins Svmp· later. to determine baseline hormone concentrations. tom Checklist (HSCI -90l and mun· than 3 on the B,'rk Immediately following the collection of the last base­ lnventur\· flH Dq1r1c'-s1on 11. en· c'\dudt·d. All subjt•ct.; line sample, around 10:00 A.M., subjects received an were mediLatlun free· tor .i minimum ot 2 weeks priur rntravenous infusion of either flesinoxan or saline de­ to testing, smuked iv-,-, than H' Cigarettes per dav, <1nd l!\·ered over a 10-minute period. Additional blood sam­ ingested nu more th,w the l'(jUI\ alent of five beer-, pe1· ples were collected at 15, 30, 45, 60, and 120 minutes ,,.-eek and three cup.., Pt ( L'ftt·t' ~w1· dav. fh1s studv \\ d.., attl'r the start of the infusion. ln the antagonist study, approved by thl' Re-.t•,m h Uh1c-, Board nf t\w Dep,irt the first blood sample was obtained 45 minutes after rwnt ut Pc-\ ch1,1tn , it \ k( ,ill L nivers;t\ . \,\ ntten in insertion of the intravenous catheters. Then, subjects f..irmed consent\\ ,b obt.rnwd trum all ·,ubject-, lwkn· hen· administered orally either a placebo, pindolol, or enrullment 111 tlw ,tu,h methysergide 90 minutes prior to the flesinoxan infu­ sHin Blood samples were collected at -15 minutes, im­ Experimental Design rnediatelv prior to the flesinoxan infusion, and at 15, Dose-Respo11se!,f11d11, l11 ,, 1c1nd,,m1,1ed, ,iuuble-hl111d ;u, 45, hO, and 120 minutes following the flexinoxan in­ :, x 3 Latin-squ,Ht' de-,1.~n 11 nwn 1,itli a nwan c1g,· ,1t tus1un NEUROPSYCHOl'HARMACOLOL) ['!Cle; \ lll.. I,, I\:()_ 2 Flesinoxan and Serotonin1A Receptors 95 Neuroendocrine, Behavioral, and tiunal-Deficit. The somatic symptom checklist is a Physiological Measurements compendium of the most frequent somatic complaints cummonly encountered during treatment with seroto­ Neuroendocrine Measurements. Blood samples for nergic agents, in particular flesinoxan (flesinoxan in­ measuring hormone plasma levels were collected in ice­ wstigator brochure, Solvay-Duphar, Weesp, Holland); cold plastic tubes containing 10 µI/ml of 0.5 M Na2 it consists of 29 physical symptoms rated by subjects EDT A. They were centrifuged (20 minutes at 2,500 x on a five-point scale (none, slight, moderate, much, se­ at 4cq within one hour of sampling.
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