Ind ian Jou rnal of Experimental Biology Vol. 40, Decembcr 2002, pp. 1344- 1352

Review Article

Serotonin/dopamine interaction-Focus on 5-HT2C receptor, a new target of psychotropic drugs

G Oi Giovanni "', V Oi Matteo;! & E Esposito;!

':'Dipart imento di Mcdicina Sperimcntale, Sczionc di Fisiologia Umana "G. Pagano", Un i vc rs it ~l di Palermo, C. so Tukbry,

129 1-90 134 Palcrmo, Italy

"Istituto di Ri cerche Farmacologichc Mario Ncgri , Consorzio Mario Negri Sud. 66030 Santa Maria, Imbaro (Chieti ), Italy

Scvcra l hypothcscs rcgarding phys iopathology of major psychi atric diseases cxist. Atten ti on has been focused on cc rc­bra l monoam incrgic systcms, thc dysfunct ion of which is thought to undcrli c various aspccts of thcir sy mptomatology. Thcrc arc rcports descri bing thc in vo lvcmcn t of serotoncrg ic and dopamincrgic systems in the mcchan ism of ac ti on of psy­chotropic drugs. T his art iclc rcv icws current kn owlcdgc on intcrac ti on betwccn 5-hydroxy tryptaminc (5- IIT), ac ting at 5-HT2c rcceptors in the ccntral dopami nc (DA) systems. Sincc 90s. a growing body of bchavioura l, ncurochcmical and elcc­trophys iological cvidencc from anima l studics have dcmonstratcd a clcar rolc for 5-HT:!c rcccptors in modulation of acti vity of dopamine ncuroncs. This evidence has led to the suggest ion that drugs acting on 5- HT2c receptors havc potcntial as novcl antipsychoti c and antidepressant agcnts and may also be used in the treatmcnt of othcr neuropsychi at ric disorcicrs SLich as Parki nson' s di seasc and psychoacti vc substancc abuse.

Serotonin (5-HT) containing neurons originating from mid-brain raphe nuclei innervate both substan ti a nigra (S ) and ventral tegmental area (VT A). Thus, neuro­anatomical studi es have shown a high density of 5-HT immunoreacti ve f ibers both in substantia ni gra pars compacta (S c), pars reti culata (SNr), and VTA 1.2.

Serotonergic termin als make synaptic contacts w ith both dopaminergic (DA) and non-DA neurons in S c, S I I' , and the VTAI.2. Interes tin gly, ventral mesen­cephalic tegmentum including SN contains the high­est brain concentrat ions of 5-HT, and both SNc and SNr rece ive a dense 5-HT input , wh ich is higher in SNr (9x 106 var icos ities/mm3

) than in SNc (6x 106

vari cos ities/mm3)", Moreover, v irtuall y all 5-HT vari­

cos ities form synaptic spec iali za ti on in SNr, whereas on ly 50% do so in SNc2

, In add ition, terminal areas of S IC and VT A , such as striatum or nucleus accum­bens, receive an input from serotonergic neurons originating in raphe nuclei3. Several 5-HT recepr"!' subtypes have been shown to be present in the basa l ganglia. Thus, a high density of 5-HTIIl receptors has been round in S , VTA , globus pallidus, and entope­duncu lar nucleus4

,5 . In contras t, leve ls of 5-HTIA bind­ing sites and mRNA encod ing 5- HTI A receptor are barely detec tab le in basa l gangli a5

, On the other hand,

':'Correspondcnl aU lhor : e-mail: giuciigiova @hotma i l.com Phonc: . ++39.09 1.65 1.20.70 Fax : ++39.09 J.(j52.07.0 I

high to moderate levels of 5-HT 2A and 5-HT2C recep­tor binding and corresponding mR A are present in several fo re-brain areas including oasal ganglia and the limbic system, Thus, high leveh of 5-HT2A and 5-HT2C binding sites are found in caudate nucleus, nu­cleus accumbens, olfac tory tubercle, and pyriform cortex4

. There is a good concordance between distri ­bu ti on of 5-HT2i\ and 5-HT2C binding sites and their relat i ve mRN A 6. However, relat i \'e distri bution of mRNA for 5-HT2A and 5-HT2C receptors is different. Thus, moderate levels of both 5-HT2A and 5-HT2C receptor mRNA have been detected in S , while VTA contai ns 5-HT2C but not 5-HT2;'\ receptor mRNA 6-8. There are reports concerni ng the ro le of different 5-HT receptor sUbtype in the control of brain DA transmi ssion. For example, there is ev idence that 5-HT IB receptors underlie 5-HT-induced inhi bition of GABAIl receptor mediated IPSPs in rat mid-brain DA neurons ill vitro'>, However, ill vivo electrophysiolog i­ca l experiments have shown that selec ti ve activati on of 5-HTIB receptors does not cau,;e any signi f icant change in the basa l acti vi ty of VTA DA -containing neurons, thus suggesting that 5-HTI B receptors do not playa relevant role in the control of meso limbic DA sys tem ill viva lo

. Moreover, systemic admini stration of potent and selecti ve 5-HTIA receptor agon ist, 8-hydroxy-2-(d i-n-propy lamino)tetralin (8-0H-DPA T), causes a pronounced exc i tatory effec t on firing and bursting acti vity of neurons w ithin a subpopulation of VTA DA-containing neurons lO

, M icroiontophoreti c

0 1 GIOVAN I er al.: 5-HT2c AND DOPAM I ERGIC FU CTION 1345

application of 8-0H-DPAT into VT A does not have any effect on basal firing rate of DA-containing neu­rons, and selecti ve lesions of serotonergic neurons by 5,7-dihydroxytryptamine (5,7- DHT) aboli sh the exci­tatory effects of systemic 8-0H-DPAT IO

. These data indicate that stimulati on of 5-HT I A receptors by 8-OH-DPAT does not inhibit DA-containing neurons by reducing a tonic inh ibitory activity exerted by sero­tonergic system lO

. A series of studi es have shown that 5-HT exerts a tonic and phasic inhibitory control main ly on mesolimbic and mesocortical DA system, by timulating 5-HT2C receptors. On the other hand , 5-HT2A receptors seem to have an opposite effect on these systems, and evidence is there that 5-HT2A re­ceptor agoni sts en hance 3,4-methy lenedioxymetha­mphetamine-induced DA release I I. In this paper, the most relevant findings regarding role of 5-HT2C re­ceptors in the con trol of ni gros tri atal and mesocorti­colimbic DA functions have been rev iewed.

Effects of drugs enhancing 5-RT synaptic levels OJ!

electrical acti vity of DA neurons in SNc alld VTA -Acute adm inistration of tluoxetine causes a dose-dependent inhibi tion of firing rate of VTA DA

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Fig. 1- Effec t of fluoxetine on the firin g rale of VTA dopa­Illinergic neurones- (A) representat ive rate histogram showing the typical inhi bitory effec t of intravenous flu oxetine (20, 20, 40, RO, 160,320, (i.:lO, 1280 ~g/k g, at arrows): (8 ) CUlllulat ive dose­response curve show ing mean percentage of change (± S.E.M.) in firing rate of VTA dopaminergic neurons after intravenous flu oxetine. r*p < .05; ** <.0 I compared to basa l firin g rate (one­way analys is of vari ance, followed by Tukey"s test). (Taken fro m Pri sco and Espos ito, 1995.)]

neurons, but it does not affect the act ivity of DA cell s in SNc l2 (Fig. I). A simil ar effect, though less pro­nou nced, has been observed with citalopram t2

. Fur­thermore, mesulergine, an unselective 5-HT2C receptor antagoni st ' 3, as well as destruction of 5-HT neurons by 5,7-DHT, prevents the tlouxetine-induced inhibi­tion of VT A DA cells 12. These results indicate that fiouxeti ne inhibits the mesolimbic DA pathway by enhancing the extracell ul ar level of 5-HT, wh ich would act through 5-HT2C receptors l2 . This study al so demonstrates that tluoxetine-induced inhib iti on of DA neurons in VT A is no longer observed after chronic treatment (2 1 days) wi th thi s drug (Fig. 2). Interest-

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Fig. 2- EITects of chronic treatment with in traper itoneal flu oxet­inc ( 10 mg/kg, for 2 1 days) on the response of VTA dopaminergic neurones to acute intravenous tluoxetine-(A) Representative rate hi stogram showing the typical inhibitory effect of acute intra­venous flu oxetine (20, 20, 40, 80, 160, 320 ~g/kg , at arrows) in a contro l rat ; (8 ) Typica l rate hi stogram showing preventi on by chronic int raperit oneal flu oxetine (20, 20, 40, 80, 160, 320, 6-W, 1280, 2560 ~g/kg, at arrows); (C) Cumulat ive dose- response curves showing mean percentage of change (± S.E.M.) in the fir­ing rate of VTA dopaminergic nelli-ones after acute intravenous fluoxetine in control rats (D) and in animal s treated chronica lly with fluoxetine (_ ). Complete tol erance developed after chronic flu oxetine admini strati on. r*p < .05 (F(6,84) = 6.27) , two-way anal ys is of variance, split-plot design, followed' by Tukey's test]. (Taken from Prisco and Esposito, 1995)]

1346 INDIAN J EXP BIOL. DECEMBER 2002

ingly, m-ch loropheny lpi pcrazine (mCPP), a mixed 5-HT1N2B/2c receptor agoni st5.J.j, inhi bits the f iring activ­iLy of VTA DA neurons in contro l animals but not in those ch ronically treated with r1ouxetine I 2

. The au­thors suggest that 5-HT2c receptors may be down­regulated after repeated r1uoxetine adm ini strati on. Cons istent with this hypothesis, ev idence is there that chronic trea tment wi th sert ral i ne and ci tal opram, two se lect i ve serotonin re-uptake inhi bitors (SS Rl s), in­duces tolerance to hypolocomotor effect of mCpp l5.

Thi s hyposensiti v ity o f 5-1--IT2C receptors may be a key step for ach ievement of an an tidepressant effect. Indeed, it is poss ible to argue that acute inhi bitory effect of f10u xet ine on meso limbic DA system would mask its cl ini ca l effi cacy in the early stage of treat­ment. Thi s mask ing effect may disappear when hypo­sens iti vity of 5-HT2c receptors occurs. A seri es of studies carried out in our laboratory have shown that acute admini stration of SSRls such as paroxetine, ser­traline, and f1uvoxamine causes a slight but signifi­cant decrease in basal firing rate of VTA DA neu­ronsl6. Therefore, it is conceivab le th at, similar to fluoxetine, these three SSR ls can reduce mesocorti­co limbic DA transmiss ion by acti va ting 5-HT2C re­ceptors.

£.frec/s of variolls 5- HT2C recep/or agollis/s alld all­lagollis/s all lIigros /ria/al and lIIesocor/ico/illlbic DA jil ile/ioll - Seri es of studies carried out in our labora­tory ha ve clearl y shown that 5-HT2C receptors playa prominent ro le in the control of mesocorti colimbic DA func ti on . Ini tia ll y, it has been found th at the f iring rate of DA neu rons in VTA is red uced by mCPP and trifluoromethylpheny lpiperazine (TFMPP), two mixed S-HT2A/21l/2C receptor agoni s t sl ~ , whereas these neu­rons are stimul ated by mesulcrginelo. Based on these find ings, it has been suggested th at 5-HT may exert an inhibitory act ion on DA neurons in VTA by acting through 5-HT2 receptors I II. However, these data do not allow to distingu ish the relati ve contribution of 5-HT2 receptor subtype in the con trol of central DA funct ion. Subsequent studi es clearly indicate a selec ti ve in­volvement of 5-HT2C receptors on the basis of ev i­dence that the inhibitory effec t of mixed 5HT2 recep­tor agoni sts !1 1CPP and 6-chloro-2-( I-piperaziny l)­piperazine (MK 2 12) on the activ ity of VTA DA­containing neurons and on accumbal DA release is completely preven ted by 6-ch loro-5 -meth y 1-1-1 2-(2-methylpyridi y l -3 -oxy)-pyrid-5-y I carbamoyll i ndo l i ne (SB 242084), a selec tive 5-HT2C receptor antagoni st ' 7.

M oreover, SB 242084 blocks the inhibitory act ion of (S)-2-( ch 101'0-5- rI ouro- i ndo- I-y I )- I-methy leth y lami ne 1: 1 C4 H4 0 4 (RO 60-0 175), a selecti ve 5-HT2C re­ceptor agon ist7 (Figs 3, 4). Another seri es of studies' ha ve shown th at 5-methy l-I-(3-py rid y Icarbamoy l)-1,2,3,5-tetrahydropyrrolor2,3-fJ indo le) (SB 206553),

I . 5 I-IT . IX • a se ectl ve - 2C12 1! receptor antaoon lst , Increases the basa l f i r i ng rate and the bursti ng acti vi ty of VT A DA neuronsl9 and enhances DA release in the rat nu-l I d f I 19-ry l C . c eus accumoens an pre ronta cortex -. onslstent

w ith these findings, indoline (S B 242084), the most powerful and selec ti ve 5-HT2C receptor antagoni st22

,

se lecti ve ly enhances the mesocorti colimbic DA fu nc­ti on (Figs 5, 6) , wh i le RO 60-0175 and MK 2 12, two 5-HT2C receptor agonists, reduce itn.2~ . M oreover, SB

242084 has been fou nd to poten ti ate the phency­clidine-induced increase in accumbal DA release25

On the one hand, it does not seem that 5-HT2C recep­tors exert a re levant role in the control of nigrostri atal DA system. Thus, there is ev idence that 5-HT2C receptor agonists such as mCPP, M K 2 12, and RO 60-0175 do not signi f icant ly affect the act ivity of SNc DA neurons, and in vivo D A release in stri atum I7

.23

.

On the other hand, mi xed 5-HT2B/2C antagonist SB 206553 causes on ly a slight increase in the basa l ac­ti v ity of DA neurons in SNc and stri atal DA release l,). Therefore, on the basis o f the above mentioned data, it is poss ible to conclude that serotonergic system exerts both ph asic and tonic control of mesocorti co limbic DA fUl1cti on by ac ting through 5-HT2C receptors. A recent study carri ed out in our laboratory has shown th at mCPP exc ites non-DA (presumab ly GABA­containing) neuro ns both in SNr and VTA by activat­ing 5- HT 2C receptors26. One interest ing f inding of that study is the ditTerenti al effect exerted by I11CPP on subpopulati ons of SN r neurons. Th ~l. , mCPP causes a marked excitat ion of so-ca ll ed P(O) SNr non-DA neu­rons, whereas i t does not affect P( +) neurons. These neurons are identi ri ed on the basis of presence 1 P( +)1 or the absence [P(O)] of an exc itatory response to a nox ious stimulus (footpinch)26. There is ev idence th at P(+) SNr neurons are GABA-conta ining interneurons those exert a direct inhibi tory in fluence on DA neu­rons in SN, whereas P(O) ce ll s represent GABA-ergic SNr projection neurons26. On the other hand, all nOI1 -DA neurons in the VTA are eq ually exc ited by mCPP. It is tempting to speculate that this differenti al re­spo l1 se to I11CPP may be the basis of the preferential inhibitory effect of 5-HT2C agonists on the l11esocorti­co limbic versus nigrostriatal D A function.

01 G IOVA N I el al.: 5-HT2c A 0 DOPA M INERGIC FUNCT ION 1347

Therapeutic potelltial of drugs actillg through 5-HT2c receptors- In view of the hypothesis that dis inhi bi­tion of the meso limbic DA system underli es the mechani sm of action of several antidepressant drugs27

, the disinhibitory effect of SB 206553 and SB 242084 on the mesoli mbic DA system may open new

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poss ibilities for the employment of 5-HT2c receptor antagoni sts as antidepressants. This hypothes is is con­sistent with the suggestion that 5-HT2c receptor blockers may exert antidepressant activit/ so In thi s respect, it is interesting to note that severa l antide­pressant drugs have been shown to bind with submi-

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ri g, 3-EfTecLs of various agonisLs on Lhe firing raLe VT A dopaminergic neurons. RepresenLaLi ve raLe hisLograms showing Lhe Lypical effw of inLravenous RO 60-0 175 (320 m k/kg) (A), (±)-DOI (640 ~g/k g) (D), and I3W 723C86 (640 ~lg/kg) (F). HisLograms showing mean peree nLage change (± SEM ) in Lhe firing raLe of DA neurons after inLravenous RO 60-0 175 (80- 320 ~g/kg) (C, left ) , (±)-DOI ( 160-640 ~g/kg) (E). and 8W 723C86 ( 160- 640 ~l g/kg) (G). * p <.05 cO lllpared Lo Lhe veh icle group (one-way analys is of vari ance, followed by Tukey's LesL) (C, lefL ) . RepresenLaLi ve raLe hisLogram showing LhaL inLravenous SB 242084 (200 ~ g/kg) prevenLs Lhe inhi biLory elTecLs of RO 60-0 175 (320 ~g/kg , i v) (8 ). The arrows indicaLe Lhe Lime of drug injecLi on, (C, righL) HisLograms showing LhaL preLrCalillenL WiLh

SB 242084 (200 ~g/kg, iv) aboli sh Lhe inhibiLory cfTeeLs of RO 60-0 175 (320 ~g/kg, i v) on Lhe firing raLe of DA neurons. [F( I,1 3) = 14.52: ** p < ,0 1 (Lwo-way anal ys is of vari ance, spliL-ploL design, followed by Tukey's LesL). (Taken fro lll Di M aLLeo el al. , 2000,) 1

1348 I DIAN J EX P BIOL, DECEMB ER 2002

RO 60=0175 SB 242084 + RO 60-175

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pig. 4-Time course of the effect of in traperitoneal :.Hj min istration of I mg/kg of RO 60-0 I 75 (A). I mg/kg of (±)- DOI (C), and I mg/kg of BW 723C86 (D) on ex trace llul ar DA levels in the rat nucleus accumbens. (D) cont ro l groups trea tcd with the vehicle. Drugs wcre ad ­min istered at the ti me indica ted by vertica l arrows. Each data point represe nts mean percentage ±SEM of the basl: line value calculated from three samples before drug injection. Each ex periment was carri ed out on five to six animal s per group. ** p < .0 1 vs cont ro l grou p (tlVo-way analysis or variance foll owed by Tukey"s test). (B) Time course of the effect of RO 60-0 175 (_) ( I mg/kg, ip) and pretreat men t of SB 242084 (1'» (2.5 mg/kg, ip) on extrace llu lar DA levels in the nucleus accumbens. RO 60-0 175 was adm inistered at the time indi­catcd by ve rtical arrow. SB 2.+2084 was given 10 min before RO 60-0 175. Each data point represents mean perccntage ± SEM of the baseli ne va lue calcul ated fro m th ree samples before RO 60-0 175 injec ti on. Each ex periment was carried out on rive to six animab pc:r grou p. I F( I, 10) = 10.252. ,. p < .05, ** P <.0 I RO 60-0 175 versus SB 2420R4 + RO 60-0 175 (tlVo-way anal ysis or vari ance, split-plot de­sign. fo ll owed by Tukey"s test). (Taken rrom Di Malleo et aI. , 2000)1

cromolar affinity to S-HT2C receptors in the pig brain and antagonize mCPP-induced penile erecti ons in rats, an effect mediated through sti mulati on o f central S-HT2C receptors2

'.! . Based on these f indings, Oi M at-{ '0 I . I . h' I teo el (/ .. l ave carn ec out ex penments s owing t l at

acute administration of amitripty line and mianserin , tWO antidepressants w ith high affini ty for S- HT2C rc-

ceptors, enhances OA release in the rat nucleus ac­cumbens probabl y by blocking these receptor sub­types. Interestingly , amitripty linc an d mi anserin have been tes ted in chronic, mild , stress-induced anhedonia model of depression and are found to be effecti vc in

. I 'f ] 1 1? A . I d . f ' reversll1 g tle stress elooects' .. - . nllaille onlc e 'Iecls of tri cyc li c anti depressants, mi anserin , and fluoxetine

0 1 GIOVA l eI 01. : 5-HT2c A 0 OOPA M INERGIC FUNCTION 1349

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rate istograms showing the lack of cfl'ect of in travenous SI3 242084 (640 ~lg/kg) in the SNc (B) and the typica l excitatory response in the VTA (0 ). I*P<.05, ** P<O.OI compared wi th the control group (one-way anal ysis of vari ance, followed by T ukey's tes t]. (Takcn from Oi Malteo et aI. , 1999.)

aboli sh by pretreatment with D2/DJ receptor antago­nists, thu s indicating an invo lvement of DA in the antidepressant effec t of vari ous drugs in thi s model:ll.JJ

. A lthough, DA has received little attention in biologica l research on depression, w ith respect to other monoamines such as 5-HT and noradrenaline, it is now well establi shed that di sturbances of mesolim­bic DA function are implied in the pathoph ysiology of d . 3435 H f . . I epresslOn ' . owever, uture experiments atme( at inves ti gating the effects of chronic administrati on of 5-HT2C receptor antagonists on mesolimbic DA func­tion will help to clari fy the role played by thi s recep­tor subtype in their putati ve antidcprcssant acti on. Preferential disinhibition of mesocorti colimbic DA function by 5-HT2C antagonists may be relevant for the poss ible use of these compounds in the treatment of negati ve symptoms of schi zophrenia, a clinica l condition in which a reduced function of mesocorti­co limbic DA system has been hypothes ized36

. M ore­over, it is noteworthy to mention recent data showing that atypical anti psychoti c drugs (c lozapine, scrti n-

dole, olanzapine, ziprasidone, ri speridone, zotep ine, ti ospirone, f1u perl apine, tenilapine), which producc litt le or no ex tra-pyramidal side effects while improv­ing negative symptoms of schizophrenia, exert sub­stantial in verse agonist acti vity at 5HT2C receptors37

.

Thus, 5-HT2C receptor inverse agonism may underli e the unique clini cal properti es of atypi ca l antipsychotic d 37 H . . . rugs' . owever, III VIVO experiments are necessary to confirm the relevance of thi s action of atypi ca l an­tipsychotics on 5-HT2C receptors. In addition, thc evi­dence of selecti ve reduction of mesocortico limbic DA functi on by 5-HT2C receptor agonists may bc ex­ploited for therapeuti ca l purposes. Thus, it has re­centl y been found that RO 60-0 175 reduces cocaine­reinforced behav iour by stimulating 5-HT2C recep­tors38

. M oreover, these authors have also shown that RO 60-0175 reduces ethanol- and nicotine- induced

I f d .. . d h . . 39 40 Th d se -a mll1 lstration an yperactl vtty·. ese ata are consistent with biochemical studies showing that 5-HT2C receptor agonists inhibit morphine-induced DA rel ease in the rat nucleus accumbens4 1

• Therefore, it is

1350 I DIAN J EX P BIOl, DECEMB ER 2002

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Time (min) Time (min)

Fig. (i - Timc coursc of the erfect of inlrapcrito nca l admin istration of 5 ( A ) and 10 mg/kg 5B 242084 (_) on ext raccllular DA and DOPAC Icvcls in the striatuIII (l eft col umn) and the nuclcus accLlmbcns (ri ght co lumn). (0 ) Co mol grou p trcatcd wi th vchi cle. 5B 2.+20X.+ was adm ini stered at the ti mc indicatcd by vc rti ca l arrows. Each data poin t represc nts mca n perec ntagc±5EM of thc baseline val ue calculated frolll thrcc salllpies bcforc 5 B 242084 i njcc ti on. Eac h cxpcri ment was carricd out on fi ve to six ani mal s pcr group . I" P < .05. ** P < 0.0 I co mparcd wit h thc control grou p (Two-way an alys is of variance, followed by Tukey ' s test). (Taken froIll Di Malteo 1'( ({ t .. 1<)99·)1

conceivable that 5-HT2C receptor agonists may be use­ful 1'01' the treatment of drug addiction. Another interest­ing app licati on of the data regarding func ti onal ro le of 5-HT2C receptors in basa l ganglia is the poss ible use of 5-HT2C receptor antagonists in the trea tment of Parkinson's disease. The neural mechani sms underly­ing the generat ion of parkinsonian sy mptoms are thought to in vo l ve reduced act i vation or pri mary mo­tor and premotor cortex and supplementary motor areas, secondary to over-acti va ti on of the output re­gions of basa l ganglia, ie, SNr and globus pal li dus intcrnus (Gpi )~2, large ly because of excess ive exc ita­lory dri ve from sub-thalamic nucleus (STN). Therapy

o f Parkinson's di sease consists main ly of amelioration or symptoms with class ical dopal11in omimetics~3 Th is treatment, however, is ch a raeteri zl~d by declining efTi­cacy and occurrence of di sab ling side-effects-l-l . Func­ti onal inhibition of GPi or STN, has prov ided an al­ternati ve to les ion, by deep brain st imulati on associ­ated with modest s id e-effec t s~5. As already men­ti oned, 5-HT2C receptors arc located in SNr and me­dia l segment o f pallidal complex in rat and human brainx

.-I6 . I n addi tion, 5-HT2c li ke receptor bind ing is increased in a rat model of parkinso ni sm~7 and in hu­man parkinsoni an patients-iR . Gi ven that 5- HT2C recep­tor ac ti va tion leads to excitat ion of SNr, it is tempting

01 GIOVANNI et al .: 5-HT2c AND DOPAMINERGIC FU CTION 1351

to speculate that excessive 5-HT2c receptor stimul a­tion may contribute to increased activity of output regions of basal ganglia and thus to symptoms of parkinsonism. In thi s respect, it is noteworthy that preliminary experiments carri ed out in our laboratory show that SB 242084 red uces basal firing rate of P(O) neurons in SNr. Thus, based on these findings, it would be very interest ing to test the effects of 5-HT 2C receptor antagon ists on basal activity of GABA-ergic neurons in SNr, and on in vivo GABA release in SNr and thalamus (which is a projection area of SNr) of normal and 6-0HDA-lesioned rats, which represent a suitable animal model of Parkinson's disease.

Acknowledgement We would li ke to thank Samantha Austen of the

department for her helpful assistance in the prepara­tion of the manuscript.

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