PSYCHOPHARMACOLOGY 1993-VOL. NO.4 tiItJIo 8, 357

Anxiolytic-Like Action of N europeptide Y: Mediation by Yl Receptors in Amygdala, and Dissociation from Food Intake Effects IIIrkus Heilig, M.D., Ph.D, Sarah McLeod, Michelle Brat, Ph.D., Steven C. Heinrichs, Ph.D., frrtlerique Menzaghi, Ph.D., George F. Koob, Ph.D., and Karen T. Britton, M.D., Ph.D.

bidtnce from animal and human studies suggests that punished responding test. In contrast, microinjection of eropeptide Y (NPY) may be a potent endogenous NPY into the central nucleus of the amygdala did not .mytie. The anatomic structures mediating this action increase food intake in free-feeding animals, did not affect �fhtpeptide remain unknown. Furthermore, in addition unpunished lever pressing for food, but did reproduce the �iIsanxiolytic-like effects, intracerebroventricular anticonflictlanxiolytic-like effect with high potency. The ""istration of NPY induces food intake through selective NPY-YI agonist, p[Leu31,Pro34]NPY was IIJpothalamic mechanisms, making the anxiolytic-like approximately equipotent with native NPY in the conflict • of the peptide more difficult to interpret. The paradigm, and markedly more potent than the Y2 JI1JIOSiof this study was to examine the anatomic agonist, NPY13-36. Intrastriatal injections had no effect on _rate for the effects of NPY on anxiety, and to conflict behavior. Thus, activation of YI receptors in the _ferizethe NPY receptors mediating these effects. central nucleus of the amygdala produces effects similar lItrIctrebroventricular injection of NPY produced to established anxiolytics without affecting food intake, irrmsedfood intake in free-feeding animals, and dose­ suggesting that YI-receptors in the amygdala may be a Itpmdent anticonflictlanxiolytic-like effects in an substrate for anxiolytic actions of NPY. IIIbIished animal model of anxiety, the Geller-Seifter [Neuropsychopharmacology 8:357-363, 1993]

lEY WORDS: Neuropeptide Y; Receptors; Amygdala; anxiolytic-like action are prominent (for review see Hei­ Strrss; Anxiety; Depression lig and Widerlov 1990). The latter action of the peptide is particularly interesting in conjunction with reports NeuropeptideY (N PY) (Tatemoto et al. 1982) is one of that NPY may be involved in the pathophysiology of 6e most abundant peptide transmitters in the mam­ depressive and/or anxiety symptoms inhumans (Wider­ Mianbrain. In addition to numerous effectson endo­ lov et al. 1988; Heilig and Widerlov 1990; Widdowson aineandauton omic function, it produces striking be­ et al. 1992) . •ral effects after central administration. Among The anxiolytic-like actionof NPY has been observed 6ese, stimulation of food intake, and an anticonfiict/ indiff erent animal models of anxiety, but has only been reported after intracerebroventricular (ICV) adminis­ Fanthe Departmentof Neuropharmacology, The ScrippsResearch -.nte. (MH, MB, SH, FM, GFK), La Jolla, California; and the tration of the peptide (Heilig et al. 1989). Therefore, the Dlplrtment of Psychiatry, San Diego Veterans' Administration anatomic structures mediating this action of NPY re­ IIIIbICenter, and University of Californiaat San Diego (SM, KTB), .. Jolla. California. main unknown. Furthermore, ICV administration of Addresscorrespondence to: Markus Heilig, M.D., Ph.D., Depart­ NPY is sufftcient to increase food intake (Clark et al. ... of Psychiatry and Neurochemistry, University of G6teborg, 1984). Therefore, an increased appetitive drive could IIIndals Sjukhus, S-431 80 M6lndal, Sweden. constitute a confounding factor when apparent anxio­ I«eived July 7. 1992; revised November 24, 1992; accepted Damber 1. 1992. lytic-like effectsof NPY are observed after ICV adminis-

'\993American College of Neuropsychopharmacology Mlishedby Elsevier Science Publishing Co., Inc. • Avenue of the Americas, New York, NY 10010 0893-133X/93/$6.00 NEUROPSYCHOPHARMACOLOGY 1993-VOL. 358 M. Heilig et al. 8, NO.4

tration, in particular in tests that rely on measures of cured to the skull using stainless-steel screws and acrylic consummatory behaviors. cement, and were closed with obturators when not It has been established that hypothalamic structures used. At least 10 days of recovery were allowed after mediate the effectsof NPY on food intake (Stanley and surgery. For ICV experiments, 23-gauge guide cannulas Leibovitz 1985; Levine and Morley 1984). Conversely, aimed 1 mm dorsal to a planned injection site inthe the amygdaloid complex and in particular the central lateral cerebral ventricle were used (flnal coordinates: nucleus of the amygdala are known to be important for 0.6 mm posterior and 2.0 mm lateral to bregma, 4.2 mm emotionality, and the central nucleus receives a dense ventral to skull surface; tooth bar at +5.0 mm); pep­

NPY -ergic innervation (Chronwall et al. 1985; Zardetto­ tide or vehicle was injected over 1 minute through a Smith and Gray 1990). The present study was under­ 3D-gauge injector connected to a Hamilton syringe in taken to examine the question of whether orexigenic a volume of 51..tl. Conflict testing was started 60 minutes and anxiolytic-like effectsof NPY can be anatomically following injection. For amygdala injections, bilater� dissociated, and to test the hypothesis that anxiolytic­ 26-gauge guides aimed 3.0 mm dorsal to the finalinjec· like effectsof NPY are produced in the amygdaloid com­ tion site were used (2.3 mm posterior and 4.2 mm late� plex. An established animal model of anxiety, the to bregma, 8.1 ventral to skull surface; tooth bar at -3.3 Geller-Seifter punished responding test (Pollard and rnrn), and injections were given over 3 minutes through Howard 1979) was used to assess anticonflict/anxiolytic­ a 33-gauge injector in a volume of 0.5 Ill. Conflicttest· like effects.Food intake as well as conflict behavior were ing was performed 15 minutes after injection of drug. studied both after ICV injection of NPY and after For intrastriatal injections, the same procedure was used microinjections into the central amygdaloid nucleus. as for the amygdala experiments, but the flnal coor·

Since a heterogeneity of centralNPY receptors has been dinates were 1.0 mm anterior and 3.0 mm lateralto demonstrated (Wahlestedt et al. 1990; Aicher et al. bregma, 5.0 mm ventral to skull surface; tooth bar at 1991), selective ligands for NPY-Y1 and Y2 receptors - 3.3 rnrn. For the site injections, injectors were inserted were used to characterize the receptors involved in and left in place for 3 minutes 2 days prior to the fust producing anxiolytic-like effects of NPY. actual injection to minimize nonspeciflc injection ar­ tifacts upon subsequent injections. For ICV injections, correct placement was ensured by gravity injection of MATERIALS AND METHODS Sill saline prior to experiments. For site injections, coor· dinates were histologically verifled. Subjects Male albino Wistar rats, weighing between 200 and 275 g at the start of the experiment were used. Animals Conflict Test were housed three per cage, in a light- and temperature­ Training and testing of animals was performed in controlled environment. For operant training and test­ sound-attenuated operant chambers (Coulbourninstru­ ing, rats were food deprived to 85% of their free-feeding ments, Inc., Lehigh Valley, PA). Chambers were weight, and then maintained on 15 g food per day in equipped with stainless-steel bar floorsthrough which addition to that earned during testing. The following electric shock could be delivered. Animals were frrst groups of animals were used: ICV injections of NPY/ trained to lever-press for 45 mg of Noyes food pellets conflict testing (n = 32, also used for the tail-flick test; on a continuous reinforcement schedule. They were these data have been published as a part of another subsequently switched to a random-interval 30-second study [Heilig et a1. 1992]); amygdala injections of NPY reinforcement schedule, and flnally trained on I and analogs/conflict testing (n = 30; these animals were multiple-schedule conflict test with incremental shock used in three separate experimental trials; they were (Pollard and Howard 1979). The conflict test consisted allowed at least 7 treatment-free days after each of these, of three components: a pure reward (unpunished) com­ and were rerandomized for each trial); striatum injec­ ponent, a time-out component, and a conflict (pun­ tions of NPY/conflict testing (n = 15); ICV injections ished) component. Responses made during the reward of NPY/food intake (n = 16); and amygdala injections component were reinforced on a random-interval� of NPY/food intake (n = 16). All experimental proce­ second schedule in a darkened chamber. The chamber dures were approved by the animal ethics committee was illuminated with a house light during the time-out at the San Diego VA Medical Center. component, and responses were not reinforced. The third component (conflict) was signaled by three flash­ ing lights above the lever (l/sec) and responses were Surgical Procedure and Injections both rewarded with food and punished with footshocks Under halothane anesthesia, animals were stereotacti­ on a continuous reinforcement schedule. Footshoa cally implanted with guide cannulas, which were se- consisted of a scrambled biphasic square-wave pro- NwaOPSYCHOPHARMACOLOGY VOL. NO.4 1993- 8, Anxiolytic-Like Action of Neuropeptide Y 359

dIKedby a SGS-003 stimulator (BRS/L VE Division of RESULTS TedricalServices Inc., Laurel, MD). During the conflict Effects of Intracerebroventricular NPY CIIIlponent, shock was incremental in 0.15-mA steps IDamaximum of 3.3 rnA with delivery of every rein­ ConflictBehavior. In the conflict experiment, average beer. baseline responding on the unpunished component A testing session consisted of a 5-minute reward was 213.4 ± 11.2 lever presses per session, and on the period, a 2-minute time-out, and a 2-minute conflict punished component 19.3 ± O.Blever presses per ses­ period presented in succession, with this sequence sion (mean ± SEM). Neuropeptide Y (0.2 to 5.0 nmol) ipeatedtwice. Testing sessionswere repeated on suc­ increased punished responding in a dose-dependent

assive days, at the same time of day. For each animal, manner (F[26,3] = 9.0, P < .001). At the highest dose, t.elineresponding during both unpunished and pun­ punished responding was doubled (p < .001 vs. con­ ihedco mponents of the test was determined over two trols). A smaller increase in unpunished responding "threesessions preceding the session during which was also seen (F[26,3] = 4.2, P < .015), but was at most druge ffects were studied. For each subject, respond­ about 30%, and had already reached a plateau at 1.0 �during the actual testing session (number of lever nmol (Fig. 1). pmses) was expressed as a percentage of this individ­ Very similar results were observed in a replication ui'sbaseli ne. of this experiment in a separate group of rats. The doses of 0.2, 1.0 and 5.0 nmol ofNPY (Lc.v.) produced a dose dependent increase in punished responding reaching fGocl take Experiments In a maximum of 161 % of control, with no significant ef­

bseparate experiments, food intake was also measured fect on unpunished responding. in animals that had not undergone training for the Food Intake. NPY (2.0 nmol) produced a robust in­ aIlIfIicttest. Free-feeding rats were placed one per cage, crease in food intake over 2 hours (F[42,2,2,l] = 20.1, tJIdhab ituated over 3 days to the introduction of a Ninless-steel bowl containing a preweighed amount mNoyes precision pellets identical to those used in the Cllllfticttest. On the experimental day, sawdust was re­ lOVed,the bowl was introduced, and remaining food liICludingspill) was weighed after 30 minutes, 1 hour, � lid hours.2 z 200 [;rJ::3 � Tai1-Flick Test � Atai1-flicktest was performed immediately following o 150 dlesessionduring which effectsof ICVNPY on conflict flehavior had been studied. In this test, rats were held, melthe tail was dipped 3.5 cm in 55°C water. The illencyf or the tail to flick was measured (Jansen, 1963). 100

Mtical Analysis

IotMlntake. The consumed amount of food at 30, 60, -' UOminutes was subjected to a two-way analysis 0.0 0.2 1.0 5.0 0.0 0.2 1.0 5.0 afvariancew ith respect to treatment, time, and the in­ NPY (nmol i.e.v.) iaction between these two.

CltfIietTest. The percent change of unpunished and Figure 1. Dose-dependent increase of punished respond­ panished responding versus pretrial baseline were ing by NPY(0.2 to 5.0 nmol ICV) in the Geller-Seifter conflict test. Unpunished responding was only marginally affected. npmtely subjected to one-way analysis of variance Responding, that is, the number of lever presses during the lilhrespectto treatment. Multiple comparisons versus 2-minute punished, or the 5-minute unpunished test com­ atrols were performed using Dunnett's test. ponent, respectively, is expressed as the percentage of a base­ line value obtained over two to three sessions preceding the session in which injections were made. Values are means of Cllemicals six to eight animals SEM. For statistical analysis, see the 3 ± FwdneNPY, p[Leu 1,Pro34]NPY and NPY 13-36 were all Results. (., unpunished; "',punished .) Reprinted with per­ alltained from Bachem California (Torrance, CAl. mission from Heilig et aI. 1992. NEUROPSYCHOPHARMACOLOGY 1993-VOL. 360 M. Heilig et al. 8, NO.1

5 5 r------,------.------,-----,

4 4

.--.. � -!:9 � ::.:: 3 ::.::� 3 e::: e::: :z -:z

0c::l 2 0c::l 2 0 0 "" ""

1

�__ __� ______� ______-L ____ � o o 30 60 120 30 60 120 TIME (min) TIME (min)

Figure 2. Increased food intake after ICV injection of NPY Figure 3. Lack of effect on food intake of NPY (100 pmoJ) (2.0 nmol) in free-feeding animals. Cumulative food intake injected into the centralamygdaloid nucleus. Cumulative food during 2 hours is shown (mean ± SEM, n = 8). For statistical intake during 2 hours is shown (mean ± SEM, n = 8). Test­ analysis, see the Results. (e, vehicle; T, NPY.) ing conditions were identical to those in Figure 2. (., vehi­ cle; ..., NPY.)

p< .001). There was no signihcant interaction between ConflictBehavior AfterMicroinjections of the Selectiw treatment and time (Fig. 2). NPY-Yl Receptor Agonist p[Leu31,Pr034JNPY. Aver· age baseline responding on the unpunished component Pain Threshold. In the tail-flick experiment that fol­ was 307.3 32.5, and on the punished component 22.5 lowed administration of NPY to determine possible ± ± 1.6 lever presses per session (mean ± SEM). TheYI effects on pain threshold, no difference in latency to agonist produced an increase of punished responding tail flick was seen, indicating that the increase in pun­ of a magnitude similar to that seen with native NPY ished responding was not due to the analgesic effects at both 50 and 100 pmollside (F[21,2] = 6.7, P = .m; ofNPY (2.5 ± 0.7, 1.7 ± 0.2, and 1.7 ± 0.1 second; mean for overall treatment effect; both groups differedfrom SEM for NaCl, and 0.2, 1.0, and 5.0 nmol NPY, ± vehicle-injected controls at p < .01 on Dunnett's test). respectively; (F[26,3] = .77, P < .52, not signifIcant). Also here, both doses were equally efficacious,indicat· ing an ED50below 50 pmollside. Unpunished respond­ Effects of NPY and Its Analogs in the ing was not affected (Fig. 5). Central Nucleus of the Amygdala ConflictBehavior AfterMicroinjection of the Selectiw Food Intake. Free-feeding animals injected withNPY NPY-Y2 Agonist NPY13-36. Average baseline respond· (100 pmollside) in the central amygdaloid nucleus did ing on the unpunished component was 319.6 ± 43.6, not differfrom vehicle-treated controls (F[ 42,2,2,1] = and on the punished component 25.75 ± 1.Blever 1.1, P = .32, not signifIcant; Fig. 3). presses per session (mean ± SEM). The Y2 agonist was markedly less potent than NPY in producing a release ConflictBehavior AfterNPY Microinjection. Average of punished responding, requiring a dose of 200

baseline responding on the unpunished component pmollside for a signifIcanteffect (F[23,2] = 4.0, P = .033

was 359.6 ± 34.6 lever presses per session, and on the for the overall treatment effect; the 100 pmollside group punished component 24.8 ± 0.8 lever presses per ses­ not signifIcantlydifferent from controls, the 200 pmoV sion (mean ± SEM). NPY markedly increased punished side different at p = .037 on Dunnett's test). Theun­ responding both at the 50 and the 100 pmollside dose punished component was not affected (Fig. 6).

(F[25,2] = 7.7, P = .002 for overall treatment effect; both groups differed from controls at p < .01 on Dunnett's Effects of Intrastriatal Microinjection of NPY test). Both doses were equally efficacious,indicating an

EDso below 50 pmollside. Unpunished responding Average baseline responding was 492.9 ± 30.7 on the was not affected (Fig. 4). unpunished, and 17.9 ± 1.5 on the punished compo- NwaOPSYCHOPHARMACOLOGY 1993-VOL. NO.4 8, Anxiolytic-Like Action of Neuropeptide Y 361

175 .------,---,---,,---,--,---r--,----, 150 .--,,---,---.---,---,---,---,--,

i w- I , 150 z 125 Czl:l ; fJJ -< a � 10. to.. 0 0 ! 125 � 100 (.!) c z z a is z z f a: I 100 � 75 I �

a 50 100 o 50 100 o 50 100 o 50 100

PY (pmol/side) plLeu31 ,Pro34 INPY (pmol/slde).

f9at4. Markedly increased punished (right panel), and Figure 5. Increased punished, and unaffected unpunished lIIIffected unpunished (left panel) responding in the responding after injection of the selective NPY- Yl agonist, CIDer-Seitter conflict test after injection of NPY (50 to 100 p[Leu31,Pro34]NPY (50 to 100 pmol/side) into the central nu­ pdlside)in to the central nucleus of the amygdala. Respond­ cleus of the amygdala. Responding is expressed as described qisexpressed as described in legend to Figure 1. Values in legend to Figure 1. Values are means of 8 to 10 animals, "meansof 8 to 10 animals, and error bars represent SEM. and error bars represent SEM. For statistical analysis, see farslatisticaianalysis, see Results. (e, unpunished; �, pun­ Results. (e, unpunished; �, punished.) �.)

food intake mechanisms. It could, however, still be ar­ IIIIlofthe conflicttest (lever presses per session; mean gued that an increased appetitive drive can present a tSEM). NPY(100 pmol/side) injected into the nucleus confound in any anxiety model, for example, by Glldatus affected neither unpunished (116.8 16.7% ± stimulating exploration. Recently, an increase of pun­ 103.1 1 .5% of baseline) nor punished (135.2 a ± 4 ± ished milkdrinking was reported in mice after ICV ad­ M.O%vs. 128.5 15.2% of baseline) responding, show­ ± ministration of NPY (Flood and Morley 1991). Rather ISthe site specifIcity of the effects produced by mi­ than anxiolytic, this effectwas interpreted as indicative aoinjectionsi nto the central nucleus of the amygdala. of "an increased motivation to eat." Thus, other means of separating the orexigenic and anxiolytic-like actions of NPYwould be important. Establishing different ana­ DISCUSSION tomic substrates for the two effects, and demonstrat­ lathepresent study, ICV administration of NPY pro­ ing the anxiolytic-like action in the absence of increased daced both a robust increase in food intake, and a food intake would support the hypothesis that these riease of punished responding in the Geller-Seitter two functional effects are independent of each other. Cllllfticttest. The latter effect is similar to that seen with A key brain structure involved in emotionality is

Jll*XYPicaianxiolytics, and is therefore termed "anxio- the amygdaloid complex. In particular, the amygdaloid 1Jtic·like." Thus, ICV administration of NPY repro­ complex has been hypothesized to integrate autonomic dacedpreviously reported orexigenic and anxiolytic­ responses associated with emotion (Smith and DeVito "effects of the peptide (Clark et al. 1984; Heilig et 1984), and it has been proposed that the amygdala codes 111989).In the conflict test, however, NPY also pro­ the stressful affect of aversive inputs. The central nu­ daceda smaller increase of unpunished responding, cleus of the amygdala in particular may be the point I188fStingthat increased appetite could contribute to of output to areas controlling visceral responses to such llirapparentanxiolytic-like action of NPY in this test. information (Henke 1988). The central nucleus receives Anxiolytic-likeeffects of ICV NPY have previously a dense network of NPY -ergic terminals (Chronwall et beenrepor ted in the Vogel punished drinking test and al. 1985), which innervate neurons projecting to the i�theelevated P-maze (Heilig et al. 1989). These two dorsal vagal complex (Gray et al. 1986). Neuropeptide modelsdo not rely on food reward, and are therefore V-positive terminals in the central nucleus originate at �.sensitive to false-positive results due to effects on least in part from cell bodies in the nucleus of the soli- NEUROPSYCHOPHARMACOLOGY 1993-VOL. 362 M. Heilig et al. 8, NO.1

175 ,-----,,-----,-----r----,----y------r--,----, quired the full amino acid sequence of NPY for activation, although Y2 receptors could also be activated

by shorter, C-terminal fragments of NPY, such as NPY13-36 (Wahlestedt et al. 1986). Evidence fromfunc· 150 tional studies as well as binding experiments (Heilig et al. 1988; Wahlestedt et al. 1990; Aicher et al. 1991) confrrmed that a similar heterogeneity of NPY recep­ tors was also present in the brain. In a previous study, 125 ICV administration of NPY produced anxiolytic-like effects, and NPY13-36 was ineffective. Based on this negative evidence, it was hypothesized that anxiolytic­ like actions ofNPY are likely to be mediated by Y1 recep­ 100 tors (Heilig et al. 1989). Recently, a selective Y1 agonist, p[Leu31,Pro34]NPY became available (Fuhlendorffet al. 1990). In the present study, the Y1 agonist was approx­ imately equipotent with native NPY in producing are­

75 L-_l...-_l...-_l...-_l...-_l...-_L-_L------I lease of punished responding, and NPY 13-36 was o 100 200 o 100 200 markedly less potent. Such a hierarchy of potencies is characteristic of the recently cloned Y1 receptor NPY 13-36 (pmol/side) (Larhammar et al. 1992). These results thereforerepre­ Figure 6. Unpunished and punished responding after in­ sent the frrst positive evidence that the anxiolytic-like jection of vehicle, or the selective NPY- Y2 agonist, NPY13-36 action of NPY is mediated by Y1 receptors. In periph­ (100 to 200 pmol/side) into the central nucleus of the amyg­ eral sympathetic neuroeffectorjunctions, NPY coexists dala. ThefIgure illustrates the lower potency of the Y2 agonist, with norepinephrine, and potentiates postsynapticac­ which reqUired a dose of 200 pmol/side to produce a margi­ tions of the latter transmitter by activating Y1 recep­ nally signifIcant increase of punished responding. Respond­ tors (Wahlestedt et al. 1990). Since a similar colocaliza. ing is expressed as described in legend to Figure 1. Values are means of 8 to 10 animals, and error bars represent SEM. tion seems to be present in the central amygdaloid For statistical analysis, see Results. (., unpunished; ... ,pun­ nucleus (Zardetto-Smith and Gray 1990; Riche et al. ished.) 1990), NPY could exert its anxiolytic-like effecton this structure in an analogous manner. However, NPYin the amygdala also coexists with somatostatin and tary tract. In a vast majority (80%) of these afferents, gamma-aminobutyric acid in a population of intrinsic NPY is colocalized with norepinephrine (Zardetto­ interneurons similar to those seen in the neocortex and Smith and Gray 1990, Riche et al. 1990). striatum (McDonald 1989; McDonald and Pearson In the present study, doses of NPY as low as 50 1989). It remains to be established whether brain-stem pmol/side injected into the amygdala produced a max­ afferents, local interneurons, or both are involved in imal anxiolytic-like effectin the conflict test. No effects mediating the anxiolytic-like effects of NPY. on the nonspecmc, unpunished component of the test It has been reported that the concentration of NPY­ were seen. In a separate experiment, a higherNPY dose like immunoreactivity is decreased in the cerebrospi­ (100 pmol/side) did not increase food intake in free­ nal fluid of depressed patients (Wider16v et al. 1988) feeding rats after microinjection into the central nucleus. and in brain tissue of suicide victims (Widdowson eI These observations are in agreement with studies by al. 1992), suggesting thatNPY could be involved in the others. It has previously been shown that doses in this pathogenesis of the depressive syndrome, or parts range increase food intake after injection into the thereof. Interestingly, in the depressed patient popu­ hypothalamic paraventricular nucleus (Stanley and lation, a negative correlation between NPY-like im­ Leibovitz 1985), but are without effecton this parame­ munoreactivity and anxiety scores was observed. Fur· ter after administration into the amygdala (Stanley et thermore, high-performance liquid chromatography al. 1985). The results of the present study support the analysis of the immunoreactive material revealed that hypothesis that the anxiolytic-like action of NPY is in­ only a single peak, coeluting with native NPY was pres­ dependent of the peptide's orexigenic effects, that the ent in the controls, whereas peaks representing im­ two effects are mediated by different anatomic struc­ munoreactive material of smaller molecular size were tures, and that the central amygdaloid nucleus, at least also detected in the patients (Heilig and Widerlov 1m). in part, mediates the anxiolytic-like effects of NPY. The results of the present study suggest that activation A heterogeneity ofNPY receptors was initially pro­ of Y1 receptors is required to produce antianxietyeffects posed in the peripheral nervous system. It was sug­ of NPY. Such an activation would require the fullse­ gested that one receptor population, termed Y1, re- quence of NPY. An increased processing and/or me- D)PSYCHOPHARMACOLOGY 1993-VOL. NO. 4 8, Anxiolytic-Like Action of Neuropeptide Y 363

Ildismof NPY to shorter fragments could therefore amygdala and stress ulcers. Neurosci Biobehav Rev 12:143-150 matean important endogenous antianxiety signal, IIIthusmight contribute to anxiety symptoms seen Jansen PAJ (1963): The inhibitory effectof fentanyl and other I depression. morphine-like analgesics on the warm water-induced tail withdrawal reflex in rats. Arzheirnittel Forsch 13:502-507 Larhammar D, Biomqvist AG, Yee F, JazinE, Yoo H, Wahle­ stedt C (1992): Cloning and functional expression of a ACKNOWLEDGMENTS human neuropeptide Y /peptide YY receptor of the Y1 type. J BioI Chern267:10935-10938 I lleiligwas sponsored by a fellowship from the UCLA Pro­ Levine AS, Morley JE (1984): Neuropeptide Y: A potent in­ ,.forPsychoneuroimmunology. This work was supported ducer of consummatory behavior in rats. Peptides 5: �NIDDKGrant AM 26741 (GFK), and a VA Merit Award 1025-1029 111).This manuscript is 7486-NP from The Scripps Research McDonald AJ (1989): Coexistence of somatostatin with neu­ IIdDte.Dr. E.M. Pich is gratefully acknowledged for con­ liatingto creating an intellectually rich environment, and ropeptide Y, but not with cholecystokinin or vasoactive -rother things. intestinal peptide, in neurons of the rat amygdala. Brain Res 500:37-45 McDonald AJ, Pearson JC (1989): Coexistence of GABA and REFERENCES peptide immunoreactivity in non-pyramidal neurons of the basolateral amygdala. Neurosci Lett 100:53-58.

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