Pharmacolog) Btochemtstr) & Beha~zor. Vol 38, pp .1-63-465 v Pergamon Press plc, 1991 Pnnted m the U S A 0091-3057/91 $3 00 + 00

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Neurotensin Selectively Antagonizes Apomorphine-Induced Stereotyped Climbing 1

B. JOLICOEUR, 2 M. A. GAGNE, R. RIVEST, A. D R U M H E L L E R A N D S. S T - P I E R R E

Departments of Psvchiatr 3' and Pharmacology, Facult 3, of Medicine UniversiD' of Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4

R e c e i v e d 26 S e p t e m b e r 1990

JOLICOEUR, F B , M A GAGNE, R. RIVEST, A DRUMHELLER AND S ST-PIERRE Neurotensin selecnvely antagomzes apomorphme-mduced stereoO,ped chmbmg PHARMACOL BIOCHEM BEHAV 38(2) 463-465, 1991 --In order to better charac- terize the neuroleptlc properties of neurotensm, the dose-related effects of the pept~de on stereotyped chmbmg, sniffing and licking induced by 0 6 mg/kg apornorphme were examined The following doses of the peptide were injected lntravenmcularly 30 mm prior to apomorphlne admlmstraUon 0 9, 3 75, 30 0 and 60 Ixg Results indicate that, whereas oro-facml stereotypies remained unaffected by the peptlde, stereotyped chmbmg was slgmficantly decreased with the two largest doses of neurotensm These findings mthcate that the profile of neurotensm's neurobehavloral effects is more alan to that of atypical than typical neuroleptlcs

Neurotensln Apomorphme Stereotypy Chmbmg Sniffing Licking

SIMILARITIES between the neurobehavioral effects of the tri- decapepttde neurotensin and classic neurolepttcs were remarked upon early in the hterature on the pepttde (10). At the time, com- parisons were made wlth typical neuroleptics (phenothiazmes and butyrophenones) and, similarly to these substances, neurotensln was found to decrease body temperature, muscle tone and motor activity of antmals. Later studtes added support to ttus parallel- ism by demonstratmg that the peptlde also decreased rates of self- sttmulation in animals and reduced the behaworal hyperactlvtty induced by a variety of dopamme-stimulating drugs (2, 5, 8). However, as the research on neurotensin progressed, important differences between the actions of the pepUde and classic neuro- lepttcs emerged. For example, contrary to typtcal neuroleptics, neurotensln did not induce catalepsy in rats (4) nor affect oral stereotyptes produced by dopamlnergtc stimulation (2,5). Because of these differences, 1t has been proposed that neurotensm's pro- file of neurobehavioral effects ts more akin to that of so-called atyptcal neuroleptics such as sulpiride and clozapme (7). These drugs, while capable of producing all the aforementtoned effects of typical neurolepucs, also display weak cataleptogemc proper- ties and are relatwely ineffective m affectmg stereotyped be- haviors

Recently, the examination of the effects of drugs on lndlwd- ual components of apomorphme-induced stereotyped behaviors has been shown to be a vahd procedure to detect potential neuro- leptlcs and to differenttate reliably between typical and atypical

antipsychotlcs (3,9). Whereas typical neuroleptics decrease both stereotyped climbing and oro-factal stereotyptes at similar doses, atypical neuroleptics are markedly more potent m reducing the former than the latter stereotyped behaviors (3,9). In order to better characterize the neurolept~c-hke properties of neurotensln, we have examined in the present study the dose-related effects of the peptide on climbing, sniffing and licking mduced by 0 6 mg/ kg apomorphme.

METHOD Ammals

Male hooded rats (250-300 g) were obtained from Canadian Breeding Farm (St-Constant, Quebec). They were housed m a temperature-controlled room havmg a 12-h hght/dark cycle. Food (Punna rat chow) and water were available ad hb. Under pento- barbital anesthesia, animals were implanted with a 23-ga stainless steel indwellmg guide cannula 2 mm above the left lateral ventri- cle according to our previously published procedure (6). Animals were allowed at least four days of recovery before the beginning of experimentation

Procedure

Neurotensm was dissolved in 0 9% NaCI and the volume of rejection was 10 p,l administered over a 30-s period by means of a 50 Ixl Hamilton syringe. Apomorphme hydrochloride was ob- tained from Research Btochemlcals Incorporated, &ssolved m an

IThls work was supported by Grant MT 9101 of the Me&cal Research Councd of Canada. 2Requests for repnnts should be addressed to Dr Francois B Johcoeur, Department of Psychiatry, CHUS, Sherbrooke, Quebec, Canada JIH 5N4

463

464 JOLICOEUR ET AL.

TABLE 1

EFFECTS OF NEUROTENSIN ON APOMORPHINE-INDUCED SNIFFING AND ORAL STEREOTYPIES*

Dose (p,g) Sniffing L,ckmg

00 237 ± 26 127 ± 99 09 24.9 - 42 190 ± 109 375 247--- 17 1 7 9 ± 91 300 256-4- 1 3 165 +- 102 600 279 ±- 26 178 --- 30

*Each value represents the mean and standard devmuon obtained in each group (n= 7) dunng the 1-h test period No significant differences between controls and neurotensm-treated animals were found

oxygen free boded 0.9% NaCl solution containing 0.1% ascorblc acid. and administered m a volume of 1 ml/kg.

Data obtained for each behavior were analyzed by individual ANOVA's Each dose administered constituted one level of the main factor. Following a significant main effect, individual group comparisons between controls and neurotensxn-treated animals were performed by means of Dunnett tests.

RESULTS

As expected, the administration of 0.6 mg/kg apomorphine induced stereotyped climbing, sniffing and hckmg in ammals Data analysis revealed that none of the doses of neurotensm ad- ministered significantly affected the number of either sniffing or licking episodes. These results are presented in Table 1 where mean and standard deviations of both sniffing and licking fre- quencies obtained m each group are given

On the other hand, chmblng behavior decreased hnearly as a function of dose and statistically significant reductions were ob- tained with 30.0 and 60.0 Ixg of neurotensm. These results are illustrated m Fig. 1 where chmblng frequency ts presented as a function of dose of neurotensin administered.

DISCUSSION

The results of the present study clearly demonstrate that neu- rotensin can antagomze apomorphme-induced chmbing This ef- fect cannot be attributed to a nonspeclfiC motor impmrment effect of the peptlde since we have shown previously that 60.0 Ixg of neurotensm, the most effective dose in reducing climbing, does not affect motor activity nor muscle tone of animals (4). Also, careful observation of the ammals dunng the course of this study &d not reveal any behavioral abnormalities. Finally, the mainte- nance of oral stereotypies in the experimental animals is further in&cation that inhibition of chmbing Is not due to a generalized sedative effect of the peptlde.

The present results demonstrate for the first time that neuro- tensm can affect stereotyped behavior induced by a dopamine agomst. Untd now examination of the possible influence of the peptide on stereotypy reduced by dopaminergic stimulation has been limited to oro-factal stereotyples and a complete lack of ef-

25- (5 Z

20.

, ,J 0 c~ 1 5 - IM 0 ~ 10 . Z

0 a. 5

0

/ / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / i

/ / / / / /

0 0

I

0.9

I 1 3.75 30.0 60.0

NT (lag)

FIG. 1 Dose-related effects of neurotensm on chmbmg reduced by 0 6 mg/kg apomorphme Statistically stgmficant differences from controls as revealed by Dunnett tests are m&cated by *p<0 05, **p<0 01

fect of the peptide on these behaviors has been reported (2,5). This was confirmed in the present study as both sniffing and lick- ing remained unaffected by neurotensln. The selective Inhibitory effect of the peptide on stereotyped climbing is therefore interest- mg, although the exact mechanism underlying this action is &ffi- cult to explain at the present time. The neuronal substrates of apomorphme-induced climbing in rats are essentially unknown but they do not seem to be located in either the smatum or the nucleus accumbens as lesions of these regions do not alter climb- lng ( l 1 ). The dopamine receptors implicated in this behavior also remain to be clearly idenufied (3,9). However, the fact that neu- rotenstn affected chmblng but not oro-facial movements indicates that &stmct receptors and/or neurophyslological processes under- he these different apomorphine-induced stereotyped behaviors.

Together the present findings lend support to the suggestion that neurotensln's profile of neurobehavioral effects is more akin to atypical than typical neuroleptics. Similarly to atypical anti- psychotics neurotensin was much more efficient m reducing chmb- ing than oro-facml stereotypies. Actually, the &ssociation of the lnhthitory effects on the two types of stereotyped behaviors is even more evident with neurotensm than ~t is with atypical neu- roleptics such as sulpirlde and clozapme, which can, at relatively large doses, attenuate oro-facial stereotyples (3,9). Neurotensln, on the other hand, failed completely to attenuate oro-facial ste- reotypies at the doses utilized in this study. Furthermore, we have observed that a 120.0 Ixg dose of the peptide, the largest subtoxtc dose we could utlhze, is also ineffective m altenng oro-faclal stereotyples (unpubhshed observations).

In summary, the results of this study demonstrate that neuro- tensin can selectively affect specific stereotyplc manifestations produced by a dopamlne agomst. The dffferentml effects of the pepttde on stereotyped climbing and oro-facml movements indi- cate that the peptide possesses atypical neuroleptic-hke properties.

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