TiPS- October 1991 [VoJ. 121

Receptors for neuropeptide Y: subtypes and multiple

second messengers Martin C. Michel

Neuropeptide Y (NW) can elicit numerous physJoJogica1 responses by acti- vating specific pre- and postsynaptic receptors. Different orders of potency for agonists in valious model systems suggesf that there are multiple sub- types of NPY receptors, described here 4y Martin Michel, but their phar- macological dcpnition remains tmktiue, awaiting deuelopment of specific antagonists and receptor cbming studies. The coupling of NPY receptors to various signal transduction mechanisms is also reviewed, including inhibitiun of ad&yJyJ cyclase and stimwlafion or inhibition of increases in intracellular CaZ+, but a link between indJviduaJ NJ?’ receptor subwes and specific signal transduction pathways has no! been established.

Neuropeptide Y (NPYI is a 36 amino acid peptide which was fimtisolakdin1982fromporcine bmin.Itbelongstothe’~family of stMurally related peptides (named after one member, pan- cmatic polyp+ide) with which it shares a common secondary struc- ture known as the PP fold. Within this family, peptide W (PYY), which is found mainly in the gut, is most closely related to NPY (sharing 66% sequence identity). C-ten&al fragments of NPY and Pw have been isolated, such as NPY- NPYIJo or PYY- which may be degradation prod- ucts; nwarlheless some of them may be biologically important since - in contrast to the hoio- peptides - they act selectively on Y&e NPY receptors (see below).

NPY is found in many central and peripheral neurons (mostly co-local&d with catecholamines) and is the most abundant peptide in the mammalian brain. Ex- ogenous NPY can elicit numerous physiological effects. Since NPY is also evo~tionarily well conserved it is assumed to be an important neuro&ansmitter. Accordingly, it has been implicated in the patho- physiology of various disease states, ix&ding hypertension, congestive heart faihne and various psychiatric disorders.

SpeCifUtyOfNPYttfccb NPY is believed to exert ik

physiological effects by acting on

M. C. hiicbd h a mwchcr in Ike M&in- hrbr KMb Nepb ic, UtAw#iM&.

7 bfbifhum Essm, Hufrbia traw 55. D-4300 Esm 1, FRG.

specific receptm, since these ef- feck are usually not blocked by known antagonists at other trans- mitter receptors; induding a- or $~~~$fic$

inability of other related peptides (with the exception of PYY) to mimic ik effects; moreover, distinct structure-activity re- lation&i logues J

exist for peptide ana- NW. Binding sites for

tritiated or iodinated NPY exhibit structure-activity relationships similar to many physidogical assays with e. such NPY- binding sites have been solubil- ized and

P urified by several

laboratories -11. NPY-induced sec- ond messenger responses can be measured in Xmopus oocytes fol- lowing injection of lune mRNA*“, but cloning of the gene for a NPY receptor has not been accom- plished.

SubtypesofNPYmceptom Struchu+acMty relationships

for NPY analogues in various model systems indicate that mul- ti $

e NPY -toor subtypes exist. is was first proposed by Wahle-

stedt and colleges’, who com- pared the relative potency of NPY, PYY and ik C-terminal fragment PYY- in guinea-pig iliac vein, rabbit femoral artery and vein, and rat vas deferens. Whereas NW and PYY had similar PO_ ten&s in all systems, ~&EL-Z was only slightly less NPY in vas deferens ETen t ineffec- Hve in the vascular preparations. Wahlestedt et al.‘) pmposed the existence of two subtypes of NPY

receptors, termed YI (having a low affinity for C-terminal fragments of NPY) and Y2 (having a high affinity for C-terminal fragments of NPY). These initial obser- vations were confirmed by other investigators using NPY,- and other C-terminal fragments of NPY such as NPY,, (Ref. 14). However, such data could not prove the existence of NPY recep- tor subtypes because neither a different order of potency for agonists nor different affinities were demiontrated.

Such pruof has meanwhile been obtained in three ways. Sheikh et ~1.‘~ have demonstrated in bind- ing studies that the affinity of NPY- (but not NPY itself) diirs markedly among model systems. Fuhlendorff et ~1.‘~ have utilized novel analogues of NPY ([Leu3’,*]NPY, [P#]NPY) in combination with NPY- in binding studies to demonstrate a diffeEntorderofaffinity:NPYb [L+eu3’,P&INPY >> NPY- in SK-N-MC cells (putative YI sub- type)andNPYbNPY->> [Leu3’,Pn?‘]NPY in SM-KAN and CHP-234 cells (putative Y2 subtype). A reversed order of potency and efficacy in various physiological test systems was demonstrated using NPYlbsd and [DT~]NPY (Ref. 3). PYY is ap- pmximately equipotent with NPY in all of thi abwc modal systems.

C-terminal fragments of NW, such as NW- or NPY,- which discriminate NPY recentor subtypes in vitlv, call have efkk in viva that are dislinct from those elicited by NPY (Refs 17-19). It remains to be clarified whether these distinct and often opposing effect8 in viva of the C-terminal fragmenk are due to activation of specific NW receptor subtypes or to antagonism of endogenous NPY (Refs 3,17,19).

It is now widely accepted that NPY acts via at least two subtypes of receptor. It is questionable, however, whether C-terminal fragments of NPY are sufficient to define such’ subtypes. Although the potency:affinity ratio of Npy: c-terminal fragment is very low (610) in some model systems and quite high in others @loo), many systems exhibit in&mediate ratios (Table I). These data might be explained by the co+xisMce of two receptor subtypes me- diating the same response; in this

~199l.ElWk5d8W Fubhh,, Ud (UK) Ol65 - 610/9l/602.~

TiPS - October 2991 Dbl. 121

161 4

17

386 2.7. 14 6.1 20 13

6

20

>300

515

ii 10

174

ratCNSbindingsites pighippcampw~ngsitas rat CNS binding sites

rathypothelemwbinding sites

rabbilaoctabbMgSit63

pisalwta~sites

!sksMsNeel)bhdingsitm SMS-MSN cdl binding sites

SMS-KAN cdl bindirtg Silas

CHP-234 cell binLiii sitas

SK-N-MC cell binding sites

Pcl2mnbkKlh9sim HELceNbiNRgsllm

15

2

Marld.J-C.et~(l9m)fM -98,- Swdl.s. P.etrl.(ls9)FEBsld&24&299-214 ChaI&FLS.Letd.(1999)Bxhm7.~Res. cwnuz 151.1213-1219 Oanlm,W.rt~.(l999)ht.J.Rwld8PtddnRes.

MRw,S-l.~~(1999)typrJmkrt22*203-212 Stmikh,S.P.atd~(lf&B)Am.J.Pf@ok2S7,p97tcFge4 Lunlbag, J. M. eta/. (1999) Ew. 3. ITmmad 145,2l-29 ht~dbd,A.D.rld(l999)~Plpt25,~13~ Sfmik&S.P.etJ.(1999)m?!suta45,299-214 Fuhbndcd. J.etaI. (1939)Ruc MAcad. Sd. IJS487, 192-199 Fuhbdotff, J. et cd. (1990) Proc Nallkad. Sd. USA 87, 192-199 Fulhndodf, J. etel. (1990) hc. NIII1 Acad. Sd. USA 97, 192-199

case the concentratio*response curve for the C-terminal hag ments shdd be conskierabfy shal- lower than that for NPY, but such differences in slope have not been reported. Another possibility is that additional subtypes of NPY mceptor exist with intermediate afffnity for C-terminal fragments, but the above data are insufficient to prove or reject this idea.

Other data provide flnner sup- port for the existence of mom than two subtypes of NPY receptor. As mentioned above, PYY mimics the effects of NPY in most model systems (fnchading those used for the definition of Yr- and Yr-like =ep@s)# its potency being simflar to or slightly greater than that of NPY. fn some tissues, however, PYY either does not mimic the effects of NPY or has the oppoafte action. Such model systems inchrde inhibition of cat-

echolamine release from bovine chromafffn cellsr”, reduction of rat gastric mucosal blood flowa* and increases fn plasma atrial natri- uretic factor (Ref. 22). PYY-insen- sitive NPY-binding sites have been detected in bovine chrom- afffn cells, rat intestine and myo- cardiumrs30~. PYY-insensitive NPY receptors may aIso exist in rat brain (Fig. 1). Taken together, these functfonal and binding data argue for the existence of a third subtype of NW receptor charac- terized by the order of potency NPY >> PYY; following previous suggestions3S we have tenta- tively called this subtype Ys-like (Table II).

Label& studies with sub- sequent solubilfzation of the NPY-binding site also support the idea of more than two subtypes of NPY reaptor. The apparent mol- ecular masses of solubilized NPY

Iweptor8 from well-defined models for Y1-like receptora (MC- IXC human nm cell line) and Y2-like ruxptom (rat hippocamy) are 70 and 50 kDa,

ficity with regard to the affinity of c-terminal fragments, PYY and PP; their apparent mokcuku masses range from 38 to 1OOkDa (Refs 7,8,10,11)

Some of the physfological ef- fects of NPY can be blocked by histaminean&@ats~.Whether this is due to the histamine &ease from mast cells caused by high concentrations of NW=, or by direct actfon of NFV on histamfne receptors, ir not known; however, the only competitive nonpaptfde antagonist at NPY torsalso

“R acts as an antagonist at fatamine H, receptors (see Box). FinaUy, low

TiPS - October 2991 IVd. 121 391

micromolar concentrations of NPY may also have non-receptor me- diated effects due to the amphi- philic a-helical region of NPY.

What conchmions can be drawn from these data regarding the classification of NPY receptor sub- types?Thea ist studies suggest that at least tRon ree subtypes of NPY receptor exist. However, studies using only agonists are inad- equate because the efficacy of the agonists is frequently unknown and may vary among model sys- tems and receptor subtypes. For example, NPYiw is a full agonist in various Y&ke systems, a partial agonist in Yi-like systems and a pure antagonist in a puta- tive Y&e systemJSS. Attempts to develop NPY receptor antagonists have not yet led to compounds that are suitable for the definition of NPY receptor subtypes (see Box). Also, attempts to define NPY receptor subtypes have mainly relied on one chemical class of compound, i.e. C-terminal frag ments and analogues of NPY.

It is clear that multiple subtypes of NPY receptor exist but current pharmacological tools do not allow their unquivocal defi- nition. In this situation, research- ers would be well advised to study at least four compounds when in- vestigating the receptor subtype mediating a given NW response: NW, PYY, a C-terminal fragment. and one of the available [Pro%]- substituted anames of NPY. Designations such as ‘Yi-like’ are preferable in thiz situation of un- certainty.

Mechanisms of NPY receptor function

In addition to the direct ac- tivation of specific post-synaptic receptors, NW elicits its diverse effects via three indirect mechan- ism?. First, NPY can act pre- synaptically to inhibit its own release and that of catecholamines and 5-HT. Secondly, NPY can potentiate the vasoconstrictor action of other neurotranamitters and hormones such as noradren-

aline, angiotensin 11 and histi I- mine. This occurs frequently in vascular beds where NPY itself lacks vasoconstrictor effects. Whether the potentiating action of NPY is dependent on endo- thehum is still a matter of contro- versy. The molecular basis of the potentiating effect is unclear and may be related to an enhancement of the stimulation of a phospho- lipase C by other hormones (see below).

Thirdly, NPY can induce hista- mine release from mast ceW and thus act via activation of histamine receptors. The first two indirect effects are mediated via spedfic NPY receptors; it is not known whether the histamine- liberating effect of high NPY con- centrations is mediated by recep tour or caused by amphiphilic properties of NPY.

s IingofNPYrecapWs %? ree lines of evidence suggest

thatNPY rec7m

rsbekmgtothe superfamily 0 C protein-coupled

392 TiPS - October 2991 [Vool. 121

Yrlike NW >> WY adenytytcyclsaaInhWti

receptors. First, almost all effects of NW are sensitive to pertUSSiS toxin, which ADP-ribosylate% and thereby inactivates, some G proteins including the three forms of Gi and G, The only exceptions are the inhibition of transmitter release in mouse atria and rat brainaD; inhibition of tram- mitter release in other Systems, however, is sensitive to pertussis toxinSS. !kondly, binding of the agonist NPY is sensitive to GTP and to pertussis toxir?. Finally, in neurons that have been pretreated with pertussis toxin, reconsti- tution with recombinant a sub- unit protein of G, restores the pres ptic inhibitory effect of NPJuS Together, these data demonstrate that the NW signal is transduced via G proteins that are mostly (if not exclusive!y) sen- sitive to perhuvtis toxin and are a form of G, or G,.

Pertussis toxin-sensitive inhi- bition of adenylyl cyclase by NPY receptors ha~ been demon&rated in every tissue studied and in several cell lines, including model systems with pharma&gical ChamcteriStics of Y&hes, Y&ce’z and YS-Ithe= NPY receptors. Thus, it can be astmmed that inhibition ofadenylylcydaseisauniven3al sim mechanism of NPY r&to< The G protein involved in this response may be a form of Gt because inhibition of CAMP generation can be observed in the HEL cell line=, which la&s G,. However, these data do not ex- clude the possibility that inhi- bition of adenylyl cyclase in other systems may be mediated via G,.

In many cell types, activation of

!ZZkZ!$?o.?& may occur via at le;lst four distinct mechanismsz activation of Ca2+ influx through L-type channels and fnhibftion of Ca2+ infhrx through N-type channels, and mobikation of Ca2+ from intra- celhrbr stores secondary to ac- tivation of a phospholipase C or

independent of inositol phos- phates.

Evidence that L-type Ca” channels are activated by NPY is indirect and comes mainly from functional studies on vascular smooth muscle. Such studies demonstrate that NPY-stimulated direct and indirect (i.e. poten- tiation of noradrenaline response) vasoconstriction in vitro and in aioo is sensitive to dihydm

ockJJ% dine-type Ca2+ entry bl There is, as yet, no electrophySio- logical evidence for the activation of L-type Ca2+ channels v NPY.

Inhibition of N-type Ca + chan- nels by NPY has been studied electrophysiologically in various neuronal pmpaMotw induding rat dorsal root gangii&*, rat vagal atkent neuronsSO and cul- tured rat myenkric neurons~. These studies have also demon- strated that inhibition is mediated via G, (Ref. 31) and is not ac- companied by inhibition of L- or T-type Ca2 w. Inhi- bition of N-type Ca2+ channels in neuronA preparations is of inter- est berause it is believed that this may be the mechanism of pre- ~2’ inhibition of transmitter

Mobkaation of Ca2+ from intracellular stores was first demonstrated in HEL cell@ and has now been found in various other cell types=? since mobilization of Caz+ from fntra- cellular stores by many receptors occurs secondary to the gener- ation of IPS, it has been debated whether or not Ca2+ mobilization by NPY mceptom depends on the activation of a phosphoiipaae C. Generation of 1% at early time points (before or during the C3’ rise) has been convincingly dem- onstrated in two studics3bsp. Other investigators, however, were unabie to denu .rstre~ in- ositol phosphate generation by NPY at early time points, even though other hormones (which were equallv effective at raisinn

intracellular Ca”) significantly stimulated inositol phosphate gellerationS=s~?

Thus, NPY receptors can couple to mobilization of Ca2+ from intracell~ stores via inositol phosphata-dependent and -inde- pendent pathways. Although the inositol p-t pathway of Ci++ ntob&atim is still obscure, it is dear that it dws

butinSteaduaasrthqa&q@ sensftive#.However,NPY recepummayalaoatimuLatein- ositol phosphate genamtion in- d -inatMltaC8lltjrpcrNPY p=% enknutathc~on induced by other harmoncr”“. Since some bfurma of phoa- phoiipaae C am Ca2+4atdtive it ispoaaiblethattitiapo&ntWon of inoaitol pho@t&a gltneration is a result of NPY-&t&cad in- a-eases in intrxdl&r caz+. such apmcessmi#taIsokthebasIs of endotMiuln-~t po- tentiation of vasocon&ctIon by NPY.

The potential couplbrg of NPY receptom to addithd t&pUng mechanisma haa not been studied Systcnstlrrlly. It haa been

tNPYc&nstimuMe syntbiainrat

that IVPY-mediated mcreases in canine ammary n- sistance axe aensitim to cydo- oxygenase inhibitI&. Mhough the8edataindic&ethepotential coupling of Npy recaptcmt to a PEP?

n/!z! AZ, .&is hes not

ed.InbcuscGeN- leus *us, NPY stilnulatc3 K+ fluxes via a pertussis toxin- sendtive G protein’?

recap&X sttbtypea. Inhibition of adenylyl cydme has been shown inmodeIsystemofaraIlknown mceptor subtypes (m above). Inositol phosphate-independent

TiPS - October 1991 /Vol. 12) 383

Ike devebpment of potent and sped& antagonists at NPYreaptomisimprhntforcmrmlrensons:un- quivaal phamwbgicat deft&ion d NPY mceptor

asswmentdtheph~ologi~and

thak8pWiCpOhlthlOf~drtllpIn1990fi~ of in- intmduced am+Wnd8 which, id

themMe8, may act as useful leads for such

TL and S&r@ showed that NPY- (in contm8t to the Mpqtide) doer not inhibit ad@- ylcychinratheutmtmbmna(8PYr-~tive Y*ltke8yatQm)butnthashtftsthe-- cumfarNPYtothertghtwith&.-9m;the1<1!due inthecaqoFhdingbinding6huiklJwrsl4onu.

dditi0nS of the compound) reduced the maximal contmctionofthisbbudves&lbyNPy.Thtsautqon. ismwasduetoamdu&undthemaximatresponmu, NPYwitheutattf3aGomofitsp~values.Intimttat cmcentmttonsPP56didnotdhut&hmmra&om elicitedbyenduthetin1hilWmne,~.norad-

rabbitfemdarbrid.lntherkcnrcd~~, it is not known whether Pm ilnbg&B NPY- lI&dbbdrrtaLlCLlSltnctionvirWl(-~h~- tiunwitbNPYraeptomavban&tiononpo!st- recqdorevmbqmificforthearted- indtKedbYNPY.

1 e, A. md Sheriff, S. (1990) J. B&I. Chm. 26!!, 14724-14727

2 ~ktw~ M. c. tt rl. (1990) kn. J. phylid. 2~9, em-m9

3 lC.(l9#@An11.NY.4&3c&611,1-6

B~am.s.S.,MIpa.D.W.,U,K.ndT~. En. J. Rwwmf. US, 1X3-114

5 Bdvlara L, AdBmnon, M. and Jamen, I. (1990) &mu- p@k 17,9%2M

6Adwssm,M.u1d-, L (1991) NNmpcpila 19,

7 iii%, M. C. and hUubky, H. J. (195’0) Ann. MAcud. Sci. 611, B&S94

Ca” mobilization has been demonstrated in hvo well-defined Y&e cell lines, HEL and SK-N- MC celi#ju7, but the data are currently insuffident to exchtde this signailing mechanism for other receptor subtypes. Unfortu- nately, all other reports on NW receptor signailing have failed to charackrize the receptor sub- type involved. Since most (but not all) presynaptic NPY receptors

appear to be Y&ke, this subtype may couple to inhibition of N- type Ca + channels (sea above) but such indirect associations are hazardous since most functional NW responses, in&ding vaso- constriction and pre-sy~ptic in- hibition af transmitter release, appear not to be specific for a given receptor subtype. Thus, at present it is not possible to aasoei- ate certain NPY receptor subtypes

with distinct signalling mechan- isms or vice versa.

cl 0 Cl

Much has been learned about NpYreceptors,theirsubtypesand signalling mechanisms since the discoveryofthepepttdejustnine years ago, but many qwations re- maintobeanswered,inpartku- lar those concerning the physio-

TiPS - October 1991 /Vol. 121 394

logical role of

and pathophysiological NPY and the number of

NPY receptor subtypes. The development of specific high- affinity antagonists, preferably nonpeptides, is required to ad- dress these questions rigorously.

Acknowledgement Work in the author’s laboratory

is supported by the Deutsche Forschungsgerneinschaft (Mi 294/ 2-l).

Note added in proof The cloning of a NPY receptor

cDNA will be reported at the November meeting of the American Society for Neuro- science by J. R. Rimland et al. (pers. commun.;. The cDNA en- codes a 353 amino acid protein with a membrane topology similar to that of other G protein-coupled heptahehtial receptors.

Refermces 1 Rioux. F., Bachelard, H., Martel, J-C.

and St-Ptenv, 5. (1986) Pcptidcs 7.27-31 2 W&kstedt. C.. Yanaihrra. N. and

Hakansun, R. (19136) Rcgul. Pcpt. 13. 3u7-318

3 Mihel, M. C. c1 al. (1990) Am. 1. Phyriol. 259, E131-El39

4 Walktr, M. W. and Miller, R. J. (1988) Mol. Phanmuol. 34,~792

5 Martel, J-C. Cl al. (1990) Mol. PCaro1ac0l. .J. 494-%x

6 I+th. F.. Rascher. W. and Michel. M. C. (1’)91) Nwnyn-S;hmicd. Arch. P&ua. ccl. 344,1-7

7 Inui, A. rl al. (1989) Endocrinology l24, 402-409

8 Gimpl, C., Gerslberger, R., Mauss, U., Klutz, K-N. and Lang, R. E. (1990) J. Biol. CJ~ern. 265,18142-l&147

9 She&h. 5. P. and Williams, J. A. (1990) I. Biol. Chcm. 265,8X4-8310

IO N@~yen, T. D., Heintz, G. G., Kaiser, L. M., Stlley, C. A. and Taylor, 1. L. (19901 J. Biol. C!;rm. 265, Ml-

11 Nata. K.. Yo~ekura. H.. Yamamuto, H. and 0kamota, H. (1990) Biockcot. Bio- phys. Rcs. Comman. 17l, 330-335

12 Wahkstedt, C. ci al. (1990) Ann. NY Acud. Sri. 611,7-26

13 Wahkstedt, C., Edvinsmm, L., Ekblad, E. and )Irkursun, R (1%7) in Neuronal Messetfgefs in Vascular Function (Nobin, A., Chvmw. C. and Ameklo-Nobin, 8.. eds). pp. 231-242, Elsevkr

14 Chang. R. S. L., Lotti, V. 1. and Chen. T-B. (19881 Biochem. BioPhyr. Rcs. Commun. 151.1213-1219

15 Shefkh, S. P., Hakanson. R. and Schwartz, T. W. (1989) FEES Len. 245, 203-214

16 Fuhlendorff, J. cl rl. (1990) Plor. Nut/ Acad. Sri. USA 67.182-186

17 Heilig, M., Wahkstedt, C. and Wideri&, E. (1988) Eur. J. Phnrmarol. 157.~213

18 kotr. N. A. et al. (1990) Am. J. Physiol. 259, H1’CHlixl

19 At@ve. J. A., Fuxe. K., Agnatl, L. F. and van Euler. G. (1990) Ncumsri. LP)L

118.5-8 20 Higuchi, H., Costa, E. and Yang, H-Y.

T. (1988) I. Phnrmacol. Erp. Thu. 244. 4681174

?I Tepperman, B. L. and Whittle, 8. J. R. (1991) Br. /. Phanacol. 102.9%IM)

22 Baranowska, B., Gutkowska, J., Lemire, A., Cantin. M. and Genest, J. (19871 Biochem Eiophys. Rcs. Commm. 145. 680-685

23 Malasubramaniam, A., Sheriff, 5.. Rigl, I). F. and Fischer. J. E. (1990) Peptides 11, S-G-550

24 Martin, J. R.. Beinfeld. M. C. and Westfatl, T. C. (IsaS) Am. 1. Physiol. 254, H879-H888

25 Grundemar, L., Wahlestedt, C., Shen, C. H., Zukowska-Cmjec, 2. and Hakansan. R. (1990) Eur. 1. Phanacol. 179, 8.%8?

26 B&subramaniam, A. and Sheriff. S. 11990) 1. Biol. Chcm. 265,14724-14727

27 Edvinssun, L.. Hakansun, R., Wahlestedt, C. and Uddman, R. (1987) Trends Pbonoacol. Sri. 8,231-W

28 Foucart. S. and Maiewski. H. (1989) Nawryn-Schmicd. Arch. Phatmacol. 340, 658-665

29 Cdmers, W. F. and Pittman. Q. J. (1989) Brain t?es. 498,99-104

30 Wiley, J. W.. Cm% R. A., Lu. Y. and Macdonald, R. L. (1990) 1. Ncurophysiol. 63,1499&x7

31 Ewald, D. A., Stemweis, P. C. and

h$rrR.j.(lg; Proc. Naff Acad. Sci.

32 Motu&, H. 1. and Mkhcl, M. C. [1988) Am. 1. Physiol. US, EBBo-EBB5

33 Lundberg J. M. et al. (1985) Rcgul. Pcpt. 13,41-52

34 Lundberg, J. M. 4 al. (1988) Eur. J. Pharwmcol. 145,21-29

35 Pemey, ‘I: M. and Miller, R. J. (1989) 1. Biol. Chcm. 264,7X7-732?

36 Himing, L. D., Fox, A. P. and Milkr, R. J. (1490) Brain Res. 532,120-X30

37 Aaktrlund, L., Gether, U., Fuhkndortf, J., Schwartz, t. W. and %strup, 0. (1990) FEBS Mt. 260,73-78

3.3 Mihara, S-L, Shigeri, Y. and Fuiimutu, M. (1989) FEBS Lctt. 259,79&!

39 Daniels, A. J,, Lazamwski, E. R., Matthews. I. E an4 Latina. E. G. (1989) Biochcm. Biophys. ‘&s. commun. 165.1138-1144

40 Lobaugh. L. A. and Black&ear, P. I. (1990) Am. J. Physioi. 258, C923-C922

41 Hq@ad, J. & Fmdhalm. R. I!. (19K’J Nwosci. &It. %2,211-216

42 Lobrugh, L A. and Hack&ear, P. J. (1990) J. %I. them. 265,1&3%16399

43 &Din, hf. M. M. and hi&k, K. 0. I’%&. Pharmacol. Exp. ?-hcrrct. 246,

44 Martin, S. E. and Patkraat, R E. (1989) Am. J. Pkysial. 257, H!F27-H594

45 Ilk, P. and Regent&i, 1. T. 119w) Nutwc 344,62-63

-

Sex, drugs and violence - the dopamine connection The Mesolimbic Dopamine System: From Motivation to Action

edited by P. Wilftler and I, Scheef- Kriiger, Iohn Wiley 6 Sons, 1991. fXO.UO (xvii + 656 pages) ISBN 0 471 92886 0

The ascending dopamine pro- jection has been impQcated in many functions in animals and humans, including sensorimotor integration, posture, movement initiation and certain attributes of cognition, as well as in the mo- tivational properties of nat- urally occurring stimuli, drugs of abuse, and rewarding electrical brain stimulation. Whereas the nigrostria$l component of this pathway is critical to normal movement and sensorimotor integration (witness the symp toms of Parkinson’s disease), the

mesolimbic component seems to be especially important in modulating the impact of emotions and motivation on actions. Correspondingly, dis- turbances of this pathway may contribute to specific symptoms of depression, mania and schizo- phrenia.

While the framework for dis- tinguishing between these two branches of the dopamine pro- jection has been in place for more than 15 years, a recent upsurge in experimentation concerning the mesolimbic system has motivated this volume. Condsting of an introduction plus 23 chaptw, the book is divided into four sections, which are centered around the mesolimbic pathway’s structure and function, behavioral pharma- cology, dysfunctions (in animal models and dinical dieorders) and operating principles.

Clearly, this volume was written and edited principaUy for sciuitiSt8 involved in this area of nseaxh. The chapters, mostly by more than one author, are writhm by many of the leading scientists