S-7-4 Platelet markers in aggression

179

S-7 Aggression and impulse control." bastc and clintcal aspects Considering aggress~vlty i ~" a stncter sense samples of patients with or genie mental disorders (mental retardation, post-traumatic b~ain d~sorders) with aggressive behavior have been studied In t h o s e there ~s httle sates factory response to neurolept~c drugs used for the control of symptoms Clinical trials have been carned out with a new group of drugs, the serenlc of which the first representative ~s eltop,azme, a partial agon~st of the 8H ~la and 5HTlb agonists Although some of this research ~s not conclusive ,t may lead to the development of more usefu' treatments A problem ot research ,n this group of patients is the need for more reliable and precise evaluation t o o l s Alasttheraoeutls metbod ;or the more severe cases ~s the use of psychiatric surgery

Platelet markers in aggression B Mulle Oerlinghausen, R Uebe hack Department of Psych/err}4, Frelc Universitdt Berlin; Department of Psychratoz, C,~ante, H~Jmboldt Unfvers/tat, Berlin The earliest and most conwncing evidence o| a relatlonsnlp oetween su~31 dal or aggressive behavior and decreased centra 5-PTJunctlon stems from investigations on the 5-HIAA concent'atien m hJmar CSF Such studies were performed in sub}ects with depression and scbizophrema (Van Praag 1986), or sociopathic persenahty(B~own et al 1979 !982, Coccaro et al 1989; L i n n o i l a e t a t 1983) o r ~ n h e a l t h y v o u n 1 : e e ' s ( R o y e t a l 1988) Inorder to minimize the need of this kind of invaswe studies various markers of serotonerglc neurotransmisslon in platelets were studied more recently. M o d a et al (1989} assessed 5-HT uptake by p:ate~ets of suicidal and aggress ve adolescent psychiatric patients Thei~fnd~ngs - - poss~b y due to the smail number of subiects - - were inconsistent, only in SChlZOpr;renlcs a nega tire correlation between violent su cides and 5-HT uptake was observed I' contrast Brown et al (1989) reported on a 18% lower 5-HT uptake 15HF concentration in the assay 10 7i M ,n 15 patients witheoisodicaggresslo' as compared to matched non-aggresswe controls Scores on the Baratl Impuisivity Scale, not however on the Anger Expression Scale by Spei bergen were significantly correlated with 8-HT uptake. Vmax values are n<, given: Kin, however, was signihcantly ~lgher n seven of e~ght aggresswe subjects (Considable scatter of the data was caused by seasonai varlatloni H-3-imipramine b,ndipg to plateiet membranes was also found to be lower in severely aggressive subjects, with Bmax be ng even more reduced tha'in suicide attempters {Marazziti et al 1993) K~ was ur'changed which ,s hard to be reconcded with results ef Meyer L ncenberg ;nd Rap {1993) who found a negative correlation betweer t~'e Kd of ~mipram ne brad,rig arK~ blood serotonine levels Another nteres:,ng olatelet marker is MAOactivnv which was found tc be lowered m rne~:aly d~sorcered vloleqt offenders (Belfrageet al 1992) Recently 5-HT 2 receptor blncing o~ o~ateLets ras ;ound increased ~r terest. Biegon et al (19901 observec ele',ated 5-H~ 2 receptor binding or platelets of suicidal men Their findings ha'~e been q,.est oned. howe,~er because the method using ketanse~n as radtoaot ve I gand cou d not De reproduced in other laboratories oecaJse of a too qlg h unspecific blnelrlg (Steckler et al 1993) The group cf B~egor has very recently repo'ted o'~ a Lowering of 5-HT 2 receptor binding n medication free!,Jvel]le delinquents (51umensohn et al 1998). According to :he authors [hese resu ts vVOuld mn support a "neurobiological overlao' o~ cepress.en, suicide and aggressK)r Mc B r i d e e t a l ( 1 9 9 4 1 m a v e r y c a r e f u : a r ~ a l y s i s o ; t h e ~ e l a t i o n s h i p o f v a n c ~ . aspects of depression of su~c~dal/aggress,ve Der]avlcdr on one side and 5-HT 2 receptor bind ng on tqe other foJrld a slgn~fr::art positive correlat~er between 8max and the potentlal letba ity of the oarasulcKJe, and a so bt tween the receptor mediated platelet aggregation a i d the lifetime h stor~ :a aggression (r - 0 3 0 } No strong ass.ac,ation cou,d be demonstrated be tween other receptor parameters and aggress~orq 'Tqpuia!vlfy, Or bo~derli.,e personality disorder as a second diagnosis In view of the former findings by Mann et al (~992) that {~-HT2 recel; tor density correlates positively with prolactrl resperlse to ferfluraml'e one may speculate about the outcome of neuroendoorme challenge exoer iments ir aggression In f a c t some ewoence has Oeen accumu atec tna: the prolactin response to fenfluram ne ,s blunted in soclopathlc sublects or a g g r e s s w e p a t i e n t s w i t h p e r s o n a l i W d s o r d e r ( C o c c a r o e t a l 1992; O K e a " e et al. 1992)Tryptophan depletion increases aggressweness ~n healthy ma,e subjects with preexisting aggresswe tra~ts (Cleare and Bond 19961 Taken together with postmortem bra~n stooges in suicide v:ctims the d~!a would suggest that subjects with a qls~ory of aggressive behav,our inL!;n: be characterized oy a reduction irl presynaotlc and a possibly ccmpensat: !~ increase m postsynaptlc 6-HT function Our own research :s focussing on a ~ynolst cai analysis Ot varlouS 1~(-r(

toninergic parameters In platelets of acutely depressed patients before and a*ter treatment The aim isa biochemical, characterization of individualpa ~ents and subgroups of affective disorders The core set of assessments ,qcludes 5-HT concentration in platelets, 5-HT uptake, 5-HT 2 receptor bindmg MAP A/B activity and also tryptophan and other neutral amino acids m Dlasma Self-directed and other directed aggressivity is measured by the ~AF (Hampel and Selg 1975); 77 ~tems are grouped into five factors (F1 : spontaneous aggressiveness; F2 reactive aggressiveness; F3 = excitability; 14 self-directed aggressiveness/depression; F5 = inhibition). arehm nary findings will be reported from this ongoing collaborative study. n comparison to healthy volunteers the patient data reveal a considerably greater variability Thus, e g the mean 5-HT piatelet concentration in six teen severely depressed patients (HDRS 33.2 :I: 4.2) is 671 :]_ 419 ng/109 olatelets as compared to 601 i 165 ng/109 platelets in mildly depressed subjects (HDRS 16.0 :L 24). Ir those patients with entremely high serotonin concentration (1071:1: 249, Le. < mean ± ls of control values) a high effP clency o # the 5-HT transport - Vmax/K m (4.67 4- 0.67, N - 11 ) as compared 1o those w~th low serotonin concentration (307 :I: 102; 3.26 -E 1.00, N = 19i'was observed. The Km values for 5-HT uptake are significantly higher in tqe group with low 5 HT pratelet concentration, anxiety (item 10 of HDRS) selevated n patlents with very !ow as well as in those with very high B-HT concentration A trend towards h,gher 5-HT concentration and also activated 5-HT uptake was found m e~ght patients w~th FAF 4 >50 (T values) compared to tmrteen pahents with FAF 4 >50 A similiar weak trend exists with regard to :A s 7 (sum of spontaneous and reactive aggressweness) AIsotrYbtophan concentrahon tended to be higher in the more aggressive subjects. ~ne failure to demonstrate a consistent specific relationship between 6-HT platelet parameters and aggressiveness is probably caused by the contamination of various neurobiological factors inherent in the pathogenes!s of depression, ar'xlety, and suicidal or aggressive behavion Also in 33 euthymlc patients with affective d sorder on Iongterm lithium treatment no s~gnificandy correlation between FAF factors such as "'exc,tability" or "readiness to aggression" and 5-HT concentration in platelets could be demonstrated. Platelet studies in depressed patients can probaolv not contnbute in a meaningful way to the issue of "serotonin and aggresslon" W/eintend. however, to repeat some of these investigations in patients wl'~b general anxiety

References Be frage H LIdberg L and Oreland L (1992): Platelet monoamLneoxidase activity in mentally dpsorderec violent offenders Acta Dsychiat, scan@ 85:2218 221 Blegon A Grinspoon A. Blumenfeld B. Bleich A Apter A, Mester R (1990): Increased seroton~n 5 qT2 "eceptor binding on blood platelets o1 suicidal men Psychopharmacology 100 165 167 BIumensohn R Rarzoni G, Wetzman A, Lsraeb M, Greuner N, Apter A, Tyano S Biegon ~, (1995) Redbct,on in serotonm 5HT 2 receptor binding on platelets of delinquent adolescents Psvchol~harmacology 118:354~356 Brown GL, Good~v~n FK, Ballengger JC, Goyer PE Maior ~F (1979): Aggression in humans correiates wltb serebrospinal ftu~d amine metabohtes Psychiatry Res I: 131-139 Brown GL. Ebert MH, Goyer PE Jimerson PC, Kleqn W J, Bunney W E Jr. and Goodwin FK 11982', Aggression suicide, and serotonm Relationships to CSF metabolites American Journal of Psychiatry 139:741-746 Brown [ZS Kent TA Bryart SG. Gevedon R Campbell J, Felthous A, Barratt E, Rose R {1989} Blood slateIet uptake of serotonrn ,n episo@c aggression Psychiatry Res 27: 515 :£1eare AJ. Bond AJ {1995): The effect o1 tryptophan depletion and enhancement on sublectlve and :ehavioural aggression tn normal male subjects Psychopharmacology 1"8 72 81 .Soccaro EE Sieve' : ~, Klar H Maurer G, Cochrane K, Cooper TB, Mobs RC and Davis KL ~19891 Serotor erglc studies in affeetwe and personaldv disorder patients: Correlates vwtb sulc,~ai and ~mpulsive aggressive behavior Arch Gen Psychiatry46:587 599 ::occarc EF, Kavobssi RJ and Lesser JC (1992): Self-directed and other-directed human aggression the role O1the central serotonergic system international Chnical Psycmopharmacology 6 : 7 0 4 3 bampe R Belg "q i'975~ FAn, Fragebogen zur Erfassung yon Aggressiwtatstaktoren Vertag ful Psvchoiogie Dr C J Hogrefe, GOttimgen Toronto, Zgrich Linrolla M. Virkupnen M Scheinin M. Nuutila A. Rimon R Goodwin FK (1983): Low cerebrospmal fluid 5-hydroxy-indolacet,cacid differentiates impulsive from non-impulsive aggresswe bebaviour Lde Sci 33:2609-2614 McBdde PA Brown RR DebMeo M, KeitpJ, Mieczkowskl T and Mann JJ (1994) The relationship of platelet 5-HT2 receptor indices to me}or depressive disorder, personality traits and suicidal behavior Biol Psychiatry35 295 308 M~na JJ. McBride PA Brown RR Linnoila M. Leon KC. DeMeo M, Mieczkowsky T, Myers ~E Stanley M "992}: Relationship between central and penpheral serotonin indexes ,n depressed and suictdal psychiatric mpatients Arch Gen Psychiat49:442~46 M ~razziti D Rotondo A. :'testa S, Pancioliguadagnucci ML, Palego L and Conti I. (1993) Role o1 serotomn m human aggressive behav,our Aggressive Behaviour 19:347-353 :toy A Ao~ncffB Linnotla M (1988) Acting out hostilily in normal volunteers: negative

S-,~ Modulatton of receptor and gene expression by psychopharmacological agents

] 80

correlation with levels el 5-HIAA ~ncereDrosp~nal fluid PsychiatryRes 24 187 lC~4 Meyer-Lindenberg A and Rag ML (1993i Interrelationship between blood seroton~n evels and affinity of platelet ~mipramine bindmg sites ~n healthy subjects Pharmacopsy chiat26 15 19 Modal I, Apter A, Meltzer M, TyanoS. Waievski A, Jerushalmy Z 11989): Serotonlr- uptake ey pLatelets of suicidal and aggressive adolescent psychiatric mpatleqts Neuropsychobiology 21 : 9 13 O'Keane V. Moloney E, O'Neill H. Smith C and Dinah TG (1992): Blunted prolacnn re sponse to d-fenfluramlne in soc~opathy Bqt J Psychiatry 160:643-646 Stockier ]~ Ruggeberg-Schmldt K and Muller-Oerlinghausen B (1993) Human platelet 5-HT, receptor b~nding s~tes re-evaluated: a cnticism of current techniques J Neural Transm 92 11 24 Van Praag HM (1986): {Auto) Aggression and CSF 5-HIAA ~ndepression and sch zopbre nia Psychopharmocoi Bull 22 669 673 7

Psychiatric effects of the anabolic steroids: IS - 7 - 5 ~ aggression and impulse dyscontrol D L Katz 1,2 HG. Pope Jr. 1 1 Harvard Medical School, Department ot Psychlatry, McLean Hospital, Biological Psych/atry Laboratory, 115 Md/ Street, Belmont, MA 02178, USA, Z Arno/d 0 Porter, 555 12th Street, NPI/, Washmgton, DC 20004- t202, USA Over the past several years, increasing attention has been paid to tne psychiatric effects of anabo ic steroid {steroid) use Evidence from resent studies suggests that individuals who use tnese drugs may exper,ence aggression, irritability, obsesswe tlqoughts and manic-li~
References Pope, H G , ~r and Katz, D L i1988) Affectwe and ~s~'chotbcsymptoms associated wnh anabolic steroid use Am J Psychlalry 145 498~190 Katz, D L and Pope, H G , Jr (1390) At'abe ic androgenic steroid induced mental status changes, in National IPstltute on Dr~g Abuse Research %1onographAnabohc Steroid Abuse 102 215 Pope, HG , Jr and Katz, D L 11994)Psychiatric anc~medico effects of aPabohc steroids a controlled study of 160 athletes Arcs Psychiatry51. 375 382 Pope, H G , u~ and Katz D L (~990) Horqlclde and near born ctde by anab~hc ~tero :~ asers J Chn Psychiatry 5~ 28 31 Choi, PY L, Parrott, A C , and Ccwan, D (1990) H~gh-dose ana~olic steroids ~n slrer~gtb athletes: effects upon hostility one aggression Human Psychopqarq~acoi rj a49 356 Dalby, J ~ 11992)Bqel anabolic stere d use and sustained behavlora~reactlor, At-" ,I >s'¥ chiatry 149, 27" 272

S-8 Modulation of receptor and gene expression by psychopharmacological

agents I S-8-1 i Multiple ATP receptors in the nervous system: new and widely-distributed drug targets Molecular Neuroblo/ogy Unit, Royal Free Hospital 5crToc; e~ Medicine, London NPl/3 2PE UK E A. Barnard

Specific receptors for extracellu ar ATP that recc~3mze the triphcaphat ~ n_. cleotide but not adenosine were f r s t proaosed m "972 by G Burnstock Tqe original pharmaco oglcai evidence for this -as slrce heel] greatv ex tended ;n the autonomic and enteric nervous s y s t e m s Tqls concept was further strengthened by direct ev donee for A] P release at responsive ~,tes

either ir" a paracnne mode, for example, in the vascular and immune sys terns, or from peripheral and central nerve terminals {where it can be found stored as a co-transmitter with ACh or catecholamines). These receptors are the P2 purinoceptors, and are entirely distinct pharmacologically from the adenosine receptors (the P1 purinoceptors). The P2 purinoceptor category was further divided pharmacologically into two major classes, P2X and P2Y receptors. The P2X receptors are members of the transmitter-gated ion channel receptors, The P2Y receptor family are linked to second messenger s y s t e m s Both t h e P 2 x and the P2Y receptors have become directly accessible for study within the last two years, due to the r DNA cloning. Tania Webb in our laboratory cloned a cDNA encoding a P2 p~rinoceptor from chick brain {Webb et al., 1993) and Lustig et a]. {1993) s~milarly for another of mouse glioma origin. The latter had (in oocyte expression) the agomst potency order ATP UTP > ATP~,S >> 2-methythio ATP and was designated as a P2U receptor (i.e. recognizing uridine as well as adenine nucleotides), a sub-class of the P2Y receptors. The former gave in oocyte expression the potency order 2-methylthio ATP > ATP - ATP/~S > ADR hence of the P2Y class as previously defined from tissue pharmacology and was cesignated as P2Y1. These proteins are both 7-transmembranedomam receptors of the maior G-protein-coupled receptor superfamily. A rat homologue of the chicken P2Y1 receptor has since been obtained by us by DNA c~oning{sharing 86% amino acid identity) The adenosine and P2 receptors are entirely distinct structures. Several other P2 purinoceptors, homologous to P2Y1, have now been cloned, these being in the brain or peripheral tissues (Barnard et al. 1994 and unpublished results). All mobilise Ca 2+ from intracellular stores and most are linked to phosoholipase C, It is of interest here that in the brain (both avian and mammalian) the P2Y1 receptor ~s extremely abundant. Thus, in Northern blots the P2Y1 mRNA has the h~ghest level in the brain and ~s absent in heart, liver, stomach, lung and kidney (Webb et al, 1993). In specific ligand binding the P2Y1 protein is present~n rater chick brain membranes at ~ 3 0 pmol/mg membrane protein, the highest content reported for any brain receptor. The P2Y1 receptor is expressed m neurones, astrocytes and also abundantly in the brain capillary endothelial cells of the blood-brain barrier, as cultured by Vigne et al. (1994) In addition, fast excitatory transmission at a variety of loci is mediated by ATP via the P2X receptors, also recently the subject of cDNA cloning {Brake et al, 1994; Valera et ai, 1994), these being ATP-gated ion channels. Among mteresbng effects of ATP in the nervous system reported in the recent Iterature are (for P2X receptors)convulsant activity in the preoiriform cortex and also excitation of some central sensory pathways, and (for P2Y or P2U receptors) stimulation of NO synthase, replacement of opioids in analgesia, control of cortical noradrenaline release, differentiation of gila, adhesion of neurones, responses to brain trauma (where cellular ATP is massively ~beratedi and (as noted above) a regulation of the blood-brain barrier. By in situ mRNA hybridization, P2 receptors are expressed widely in the brain It is sow clear that very many P2 punnergic central pathways exist; these are as yet unmapped but drug targeting to these receptors represents a new opportunity for selective activities

References 6arnard, E A Burnstock, G E Webb, T E {1994l Trends Pharm Sci. 15, 67-70 Brake A ~ Wagenbach, M J 6 Julius, D (1994) Nature 371, {6497} 519-23 [ dstig, K D Shiau, AK , Brake, A J 8 Julius. D (1993) Prec. Natl Acad. Sci USA 90, 5113 5117 Valera S Hussy, N Evans. RJ Adami. N North. RA Surprenant, A. 8 Buell. G (1994) Nature 371. 516-519. Vigne P Feolde, E Breittmayer.J R ~ FreJin, C (1994) Br J Pharmacol. 112,775 780 Webb TE Simon, J Krishek, B J Bateson, AN Smart, 1-G King, B.E Burnstock, G 8 Barnard, E A {lg93) FEBS Lett 324, 219 225

Regulation of gene expression in adult brain JJ Vanderhaegnen, S.N Schiffmann, P Mailleux, F. Zhang, L. Van Bree.

B,,a~n Research Unit and Laboratory of Neuropathotogy and Neuropeptide Research, UniversitO /uT~re de Bruxe/les, Campus Erasme, CP601, 808 route de Lennik, 1070 Bruxe/les Modulation of neuronal expression of immediate early genes, neurotransm=tters and related enzymes, biologically active neuropeptides and receptors by other neuromessengers has been reported in several brain regions Such regulation of brain neuronal expression has been first reported in the basal ganglia, where expression of proenkephalin and protachykinin genes ,were shown to be regulated partly by dopam~ne. Changes in immediate early genes, neuromessengers and receptors, glial fibril!ary acidic protein expression will be reported in the homolateral cerebral cortex foliowing minimal cortical infarct. The role of glutamate