Involvement of the nucleus accumbens in oral behaviour in the freely moving rat

European Journal of Pharmacology, 233 (1993) 151-156

151

© 1993 Elsevaer Science Pubhshers B V All rights reserved 0014-2999/93/$06 00

EJP 52967

Involvement of the nucleus accumbens in oral behaviour in the freely moving rat P a u l K o e n e a, E r i c P M P r m s s e n b a n d A l e x a n d e r R. C o o l s b "Ammal Husbandry, Section Ethology Agricultural Unwerstty Wagenmgen, P 0 Box 338, 6700AH Wagenmgen, Netherlands and b PsychoneuropharmacologlcalResearch Umt, Unwersttyof Ntlmegen, P 0 Box 9101, 6500 HB Nomegen, Netherlands

Received 22 July 1992, rewsed MS recewed 18 December 1992, accepted 22 December 1992

The role of the nucleus accumbens in oral behavaour was examined by intra-accumbens injections of a single dose of a selectwe dopamlne D I receptor agonlst (SKF 38393 5 /xg/side), a selectwe dopamine D 2 receptor agonist (qumplrole 10 /zg/side), and their combination in freely moving rats Principal factor analysis revealed four factors to be involved in the scored behavlours, two of which concerned oral behavlour a chew factor, comprising the behawours chew, tongue protrusion, yawn and lick, and a groom factor, with high factor loadings of tremor and groom The two remaining factors were the circle factor comprising circle, walk and rear, and the stuff factor comprising sniff, yawn and rear Two-way ANOVA (Independent variable Da with H 2 0 and SKF 38393 level, Independent variable D 2 with H 2 0 and quinpirole level) of the factor scores revealed that SKF 38393 and quinpirole had similar or opposite effects which were addltwe or antagonistic, depending on which behavlour was studied This study demonstrates that (a) the nucleus accumbens plays a major role in the oral behaxaour of freely moving rats, and (b) an integrated study of all oral behavioural elements IS necessary to describe the effects of drugs on oral behavlour Dopamlne D I receptor agonlsts, Dopamlne 0 2 receptor agonlsts, Nucleus accumbens, Oral behaviour, Principal factor analysis, SK&F 38393, Quinplrole

1. Introduction The result of behawoural studies suggest that d o p a m m e D 1 and D 2 receptors are involved in various oral actwltles in the rat Oral behavlour can be ehcited by dopamine D 1 receptor agonists and d o p a m m e D 2 receptor antagonists (Rosengarten et a l , 1983), although the dopamine D 1 receptor-mediated effect is not always found (Murray and Waddmgton, 1989) The number of d o p a m m e D 2 receptors has been found to be negatwely correlated with the number of repeated jaw movements (Rosengarten et a l , 1986) However, the function of d o p a m m e D 2 receptor agonlsts in oral behavlour remains obscure O o p a m m e 0 2 receptor agomsts alone have b e e n reported to Inhibit (Elhson et a l , 1987), not to influence (Arnt et al., 1987) and to elicit oral movements (Moody and Spear, 1989, Johansson et a l , 1987, Collins et a l , 1991), they can also induce yawning behavlour (Longonl et a l , 1987) The

Correspondence to A R Cools, Psychoneuropharmacologlcal Research Umt, Unwerstty of N0megen, P O Box 9101, 6500 HB N0megen, Netherlands Tel 31 80-613 693, fax 31 80-540 576

dose of the drug injected is important m this respect A low dose of the d o p a m m e D E receptor agomst quinplrole has b e e n found to suppress all activity In contrast, a high dose of qumplrole has been found to elicit sniffing and head movements, but to suppress oral movements Extremely high doses of the doparnlne D 1 receptor agomst SKF 38393 have been found to increase general activity (Molloy and Waddington, 1985), whereas intermediate doses have been found to Induce grooming selectively (MoUoy and Waddmgton, 1984) D o p a m i n e D 1 and D E receptors have been suggested to mediate opposite effects on vacuous chewing (Rosengarten et al 1983, Murray and WaddIngton, 1989, Johansson et a l , 1987) Dopamine D I and D E receptors are also known to act cooperatively m grooming and m a variety of other motor behavaours (Arnt et a l , 1987, Braun and Chase, 1986, Robertson and Robertson, 1987, Murray and Waddmgton, 1989) Apparently, the balance between d o p a m m e D 1 and D E receptors seems to determine the behavloural outcome (Rosengarten et a l , 1988) The above-mentioned studles reveal that differences in the terminology and the definition of oral behavaour make comparisons difficult (see also Waddmgton, 1990) The site for these

152 dopammergic actions may be the striatum, more specifically the ventrolateral striatum and the nucleus accumbens Pharmacological activation of the dopamlnergIc ventrolateral strIatum ehcits oral behaviour in rats (Kelley et al, 1988, Koshikawa et al, 1989, Dells and Kelley, 1990) A dopamInergic stnatal subregion is also involved in oral behavlour in cats (Spooren et al, 1990) In ketamine anaesthetised rats with a spinal C1 transection Koshikawa et al (1990) have found that combined administration of the dopamine D I receptor agonist SKF 38393 (5/zg//slde InJected bilaterally) and the dopamlne D 2 receptor agonlst qulnpirole (10 /zg/slde) into the nucleus accumbens increases rhythmic jaw movements The goal of the present study was to investigate whether the nucleus accumbens also plays a major role in oral behaviour in freely moving rats The dopamlne D 1 receptor agonist SKF 38393 and the dopamine D 2 receptor agonlst qumpirole were administered into the nucleus accumbens of freely moving rats, either alone or in combination The doses - 5 /zg SKF 38393 and 10 /zg quinplrole - were selected on basis of the study of Koshlkawa et al (1990) It was decided to perform an integrated study by measuring oral behavlour and gross motor behavlour and by recording muscle movements with the aid of E M G The E M G results are published elsewhere (Prmssen et al, 1992)

2. Materials and methods

2 1 Subjects Naive, male Wistar rats (n = 34, Central Animal Laboratory, Nijmegen) were used Before operation they weighed between 175 and 190 g Rats were individually housed and kept on a 12-h day/night cycle with lights on at 8 00 a m and off at 8 00 pm Food and water were available ad hbitum

2 2 Surgery Animals were anaesthetised with sodium pentobarbltal (Narcovet, 60 m g / k g l p ) Stereotaxlc Implantation of guide cannulas into the nucleus accumbens (Konig and Khppel (1963) anterior 9.8, vertical 2 7, lateral 1 2) was done according to previously described procedures (Prinssen et al, 1992) via guide cannulas (5 mm length, 0 65 mm outer diameter, 0 30 mm inner diameter) 5 mm above the skull The cannulas were angled 11 degrees from the mid sagIttal plane to avoid the ventrlcular system and to leave space for an E M G connector Cannulas were fixed to the skull with dental cement (Durelon, ESPE, carboxylate cement) and two screws Electrodes were placed m the musculus masseter and dlgastrIcus after the skin over the cheek and

lower mandible had been opened (for details see PrInssen et al, 1992) The 5-pole E M G connector was attached to the skull with dental cement

2 3 Apparatus Rats were observed in a 25 × 25 × 35 cm cage of Plexaglas A mirror (angled at 45 degrees) was mounted beneath the cage to allow the precise recording of behavlour, especially of oral movements Behaviour was registered on a protocol panel with 16 channels The E M G signals (via a swwel, pre-amphfier, 50 Hz filter) and the behavioural responses were recorded on an instrumentation recorder (Hewlett Packard 3960, 3968A with Agfa Professional PEM 639 tape)

2 4 Procedure After surgery the rats were housed Individually in the original stockroom and allowed to recover from operation for at least one week Non-habituated, drug-naive rats were observed immediately after inJection Bilateral injections were given by means of a 5/zl Hamilton syringe with a 0 25 mm needle that extended into the brain tissue 2 mm below the tip of the permanently embedded cannula The injection volume was 0 5 /zl per side injected over a 10 s period, and the needle was left in situ for another 10 s to mlnlmlse diffusion along the needle tract After the cord had been connected to the swivel the subjects were placed in the middle of the observation cage, and recording started immediately The injection sites were identified histologically, and only data from subjects with Injections made into the desired sites were analysed further Testing lasted 60 min per animal and took place between 9 00 and 17 00 h

2 5 Behavtoural observattons For observation of behawour the following ethogram of behavloural elements was defined (1) tremor (rhythmic movements, rapid oscillations of cheek a n d / o r lower jaw), (2) chew (movement of the lower jaw vertical a n d / o r lateral in a single or repeated fashion with or without an object between the teeth), (3) tongue protrusion (not aimed at an object), (4) yawn (wide opening of the lower jaw with bare teeth), (5) lick (repeated tongue protrusion aimed at an object), (6) groom (face washing, licking the fur and scratching), (7) walk (diverse locomotion), (8) sniff (exploratory behavIour with moving vlbrlssas), (9) rear (standing upon hind paws freely a n d / o r against a wall), (10) circle (turning in one direction during locomotion) and (11) immobility (absence of any displacement of three or four paws) Rapid chains of identical elements of behavlour (bouts) were scored as single occurrences,

153

7222

:'1112":

iiii'!:!:i iii!iiiii

7o-j 60-

403O 20

2161 101

10

82

0

,7

is

I

tongue

yawn

tick

i

i

rct~n

w~k

Sniff

rear

.

i

arc~

,

i

imrt'~llt,

Fig 1 Behavloural profile The relative differences between the H20 group (open area), SKF 38393 group (wide striped area), qulnplrole group (netted area) and SKF 38393 +qulnplrole group (striped area) are shown The absolute mean frequency per hour (tongue protrusions, yawn, orcle) or duration in seconds (tremor, chew, hck, groom, walk, sniff, rear and lmmobihty) of the behawoural elements are given m the columns

this was espectally true for tremor and chew which occurred too rapidly to record single movements Durattons (tremor, chew, lick, groom, walk, sniff, rear, immobility) or frequenoes (tongue protrusion, yawn, circle) are analysed and presented

erally in an amount of 5 ~ g / 0 5/xl SKF 38393 and 10 p . g / 0 5 ~1 qulnplrole Four groups were formed one group recelvmg control injections of distilled water, one group receiving SKF 38393, one group receivmg quinplrole and one group receiving the combinatton of SKF 38393 and qumplrole

2 6 Drugs 2 7 Statistical analysts (__)-SKF 38393 hydrochlorlde (Research Blochemlcals Inc USA) and qulnplrole (Eli Lilly and Co ) were dissolved m distilled water Drugs were injected btlat-

For analysis, data for the duration or frequency of the 11 behavloural elements, recorded over 1 h, were

TABLE 1 Factor loadlngs of the rotated factor pattern after principal factor analysis w,th varimax rotation of behavloural elements of 34 rats treated w~th H 20, SKF 38393, qulnplrole and SKF 38393 + quinpirole Between parentheses the rotated factor pattern of the partial correlation matrix ~s shown controlled for the effect of the Independent variables D 1 and D 2'ExplaIned %' shows the percent variance explained by the factor, 'cumulatwe %' is the summation of explained variance over the factors, starting with factor 1 Factor

Tremor Chew Tongue protrusion Yawn Lick Groom Walk Stuff Rear Circle Immobihty Elgenvalue Explained % Cumulative % Label

1

2

3

4

0 08 (0 24) 0 87 a (0 88) a 0 84 a (0 77) a 0 71 a (0 81) a 063a (062) a -004 (-003) 0 22 (0 13) 000 ( - 0 0 2 ) 0 10 ( - 0 03) 003 ( - 0 0 8 ) 008 (008) 3 13 (2 71) 28 (25) 28 (25) Chew

- 0 01 (0 19) 0 12 (0 01) 0 22 (0 17) 0 03 (0 05) -009 (-037) -016 (-011) 0 84 a (0 80) a -012 (-052) a 0 67 a (0 29) 086 a (081) a - 0 5 0 a ( - 0 10) 2 11 (2 02) 19 (18) 48 (43) Circle

- 0 19 (0 17) 0 12 (0 00) - 0 13 (0 14) --0 17 (0 13) 052a(-033) -005 (-002) - 0 18 (0 04) 087a(-066) 0 44 a ( _ 0 65) 003 ( - 0 1 7 ) - 0 7 6 a (087) 1 67 (1 70) 15 (15) 63 (58) Sniff

082 a (0 55) a 011 (0 11) 012 (0 3o) - 0 5 1 a ( - 0 o8) -009 ( - 0 04) 086 a (0 92) a - 0 06 (0 13) - 0 15 ( - 0 16) 0 03 (0 39) -015 ( - 0 o9) 0 09 (0 23) 1 48 (1 28) 14 (12) 76 (70) Groom

a Slgmfic~mt factor loading (P < 0 01)

154

transformed loganthmxcally (duration) or by taking the square root (frequency) Principal factor analysis with v a n m a x rotation was done to reveal the factor structure underlying the dependent variables (procedure Factor of SAS, 1991) This was done also on the partial correlations, with the correlations being controlled for the m d e p e n d e n t variable labelled D1 (with H 2 0 and SKF 38393 level) and the independent variable labelled D 2 (with H 2 0 and qulnpirole level) Factor scores of extracted factors were analysed in a two-way analysis of variance with the independent variables D~ and D 2 (see Prlnssen et al, 1992) In short, main effects found in thts analysis indicate that SKF 38393 a n d / o r quinpirole have effects in the four groups An interaction between the Independent variables D a and D z indicates that the combination of SKF 38393 and qulnplrole has synergistic or antagonisUc effects, the absence of an interaction indicates that the main effects are additive Duncan post-hoc tests were done to determine differences among the four groups

3. Results

3 1 General results The behavloural elements observed were tremor, chew, tongue protrusion, yawn, lick, groom, walk, sniff, rear, c~rcle and immobility The effects of admimstratIon of H 2 0 , SKF 38393, qulnplrole and SKF 38393 + qumpirole on these behavioural elements are shown in fig 1 The total sum of the means per group per hour was set at 100% to facilitate comparison between the effects of the different drugs SKF 38393 seemed to increase tremor, while qulnplrole seemed to decrease tremor and groom, but increased yawn, walk and circle were increased after administration of SKF 38393 + qulnpirole

3 2 Prmctpal factor analysts of behautour Different oral behaviours can a p p e a r in sequences (Spooren et a l , 1990) and hence are correlated to each other To investigate this possibihty, principal factor analysis was done with the 11 behavloural elements selected in this study Four factors were found that explained 76% of the variance (table 1) To control for correlations directly caused by the drugs and thus rule out the influence of the d o p a m m e D~ receptor agomst and the dopamIne D 2 receptor agomst, a second principal factor analysis was done on the partial correlations between the variables, controlhng for the rodependent variables D 1 and D z (results are presented between parentheses m table 1) Again, four orthogonil factors were found to explain 70% of the varmnce The factors were similar to those found in the uncor-

15 a 10 05

La

O0

10a 15

Chew

Circle

Factor

Sniff

Groom

Fig 2 Mean factor scores on the four factors 'chew', 'circle', 'sniff' and 'groom' G r o u p identification HEO group (open area), SKF 38393 group (wide striped area), qumplrole group (netted area), and SKF 38393+qulnplrole group (striped area) S E M s are gwen S~gnlficant differences with respect to the H 2 0 group are shown in the figure ( a p < 0 05) See text for all significant differences between groups

rected analysis Further analyses were based on the factor scores of the uncorrected prmclpal factor analysis The first factor found explained 28% of the variance and had significant loadlngs of chew, tongue protrusion, yawn and lick The second factor, which explained 19% of the variance, comprised walk, rear and circle, and had a negatwe loading of lmmoblhty The third factor explained 15% of the variance and had significant loadings of sniff, lick and rear, and a negatwe loading of Immobility The fourth factor explained 14% of the variance and had significant Ioadings of tremor and groom and a negatwe loading of yawn The factors were labelled according to the behavlour with the highest loading (1) chew, (2) circle, (3) stuff, (4) groom The mean factor scores for these four factors are shown In fig. 2 Analysis of variance of the factor scores showed a stgnificant mteractton effect of the independent variables D 1 and D 2 on the chew factor (F(1, 30) = 10 31, P = 0 003) Duncan post-hoc analysis showed that the chew factor scores of the SKF 38393 and qumplrole group were significantly higher than those of the H z O group (fig 2, P < 0 05), while the scores of the SKF 38393 + quInplrole group were significantly lower than those of the quinp~role group (fig 2, P < 0 05) The scores of the circle factor showed sigmficant effects of the independent variable D~ (F(1, 30) = 9 16, P = 0 005) and the independent variable D 2 (F(1,30) = 9 34, P = 0 005) Duncan post-hoc test shows that the scores of the SKF 38393 + qump~role group were significantly higher than those of the three other groups (fig 2, P < 0 05) On the sniff factor a significant effect of the independent variable D 1 was found (F(1, 30) = 4 56, P = 0 041) However, Duncan post-hoc analysis showed no significant differences between groups Both the Independent variables D 1(F(1, 30) = 5 60, P = 0 025) and D 2 (F(1, 30) = 18 70,

155 P = 0 000) had a significant effect on the groom factor Duncan post-hoc analysis showed that the groom factor scores of the SKF 38393 group were significantly higher than those of the quinplrole and SKF 38393 + qulnpIrole groups (fig 2, P < 0 05), and that the scores of the H 2 0 group were significantly higher than those of the qumplrole group (fig 2, P < 0 05)

4. Discussion

4 1 Methodology Oral behavlour can be registered accurately in fLxed (Elhson et al, 1987) or fLxed and anaesthetised (Koshikawa et al, 1990) rats The results obtained are different from those found with freely moving animals (Johansson et al, 1987) In this study we investigated the effects of local administration of a dopamlne D 1 receptor agomst (SKF 38393) and a dopamlne D E receptor agonlst (quinpIrole) in the nucleus accumbens on oral behavlour of freely moving rats in a new environment Although we were primarily interested in oral behaviour, we also recorded the effects on more general motor behaviour to detect a possible interaction with oral behavlour Scoring the behavlour of a freely moving animal in a restricted environment was facilitated by placing a mirror under the cage to see jaw movements from underneath and by using an ethogram together with EMG, the results of which are presented elsewhere (Prlnssen et al, 1992) Principal factor analysis of the oral behaviour revealed important relations between the different behavloural elements Accounting for these relations by means of factor scores provided information about the complexlty of oral behaviour and highlighted the risk of concentrating on only one behavloural element The most important finding is that the behavloural elements chew and tremor loaded on separate factors In many studies only one of these behaviours was studied or both were combined (see Waddington, 1990) on the assumption that there is a direct relation between the two behavlours The results of this study show that chew and tremor must be interpreted separately Although combined administration of SKF 38393 and quinpirole did not increase oral behavlour (cf Koshikawa et al, 1990), it is possible that an effect was not seen because of the increase in the behavioural elements circle and rear This increase in activity could have hampered the observation of oral behavlour However, the E M G registrations did not reveal an increase m rhythmic oral muscle discharges when SKF 38393 and qulnpirole were administered in combination (Prinssen et al, 1992) It is therefore likely that oral behavlour did not occur during the circle and rear activity

4 2 Nucleus accumbens The results obtained after lntra-accumbens inJections unambiguously show the involvement of the nucleus accumbens in oral behavlour The dopamme D 1 receptor agonist SKF 38393 and the dopamine D 2 receptor agonist qulnplrole had antagonistic effects on the chew factor SKF 38393 and qulnpirole both significantly increased chew factor scores, but SKF 38393 and qulnplrole antagonised each other when administered together (cf Uchlmura et al, 1990) These data are not in agreement with the results of Koshikawa et al (1990) who showed that rhythmic jaw movements were increased significantly by the combination of SKF 38393 and qulnplrole However, the latter authors found that their synergistic effects occurred only after a latency of about 60 mln Because we analysed the initial 60 mln, we may have overlooked this effect Still, it cannot be excluded that differences in the experimental set-up (splnahsed and anaesthetlsed rats vs freely moving rats) underlie this discrepancy SKF 38393 and qulnplrole had opposite effects on the groom factor Whereas SKF 38393 increased groom factor scores, qulnplrole decreased groom factor scores The increase in grooming behaviour after SKF 38393 admlmstratlon is in agreement with reports in the literature (Molloy and Waddington, 1984, 1985, Murray and Waddmgton, 1989) SKF 38393 and qulnplrole had additive effects in the same direction on the circle factor, i e both increased the occurrence of the behavlours that loaded positively on this factor Use of principal factor analysis revealed the presence of four separate principal factors, two of which consist of oral behavlour The first factor, i e the chew factor represents related behaviours, viz chew, tongue protrusion, yawn and lick, that load on the same factor In contrast, the second factor, 1 e the groom factor, represents tremor and groom, in which tremor appears to have a common basis with groom The effects of SKF 38393 and qumpirole on the chew factor were antagonistic and were opposite on the groom factor Thus administration of these dopamlne D i and D 2 receptor agonlsts Into the nucleus accumbens results in a complex pattern of oral behaviour (chew, tongue protrusion, yawn and tremor) Since only a single dose of each drug was tested, it is evident that the above-mentioned effects of SKF 38393, qulnpirole and their combination are insufficient for drawing conclusions about the interaction between the dopamlne D 1 and D 2 receptor systems in the nucleus accumbens Both dose-response studies and studies analysing receptor specificity are required The present study clearly demonstrated that SKF 38393 and qumplrole have slmdar or opposite effects which are additive or antagonistic depending on the behavlour studied and that the nucleus accumbens plays a major role in the oral behaviour of freely moving rats The results

150

also show that an mtegrated study of all oral behawoural elements ts necessary to describe the effects of drugs on oral behawour

Acknowledgements The authors thank Dick Heeren for support with programming, Will Spooren for reformation concerning OFD attacks m cats and Bart Ellenbroek for instruction on the operatton techniques and for critically reading the manuscript

References Arnt, J , J Hyttel and J Perregaard, 1987, Dopamme D-1 receptor agomsts combined with the selective D-2 agomst qulnpirole faclhtate the expressmn of oral stereotyped behavlour, Eur J Pharmacol 133, 137 Braun, A R and T N Chase, 1988, Behavloural effects of chronic exposure to selective D-1 and D-2 dopamlne receptor agomsts, Eur J Pharmacol 147, 441 Collins, P , C L E Broekkamp, P Jenner and C D Marsden, 1991, Drugs acting at D-1 and D-2 dopamme receptors induce identical purposeless chewing in rats which can be differentiated by chohnerglc mampulat~on, Psychopharmacology 103, 503 Delfs, J M and A E Kelley, 1990, The role of D 1 and D 2 dopamlne receptors m oral stereotypy induced by dopammerglc stimulation of the ventrolateral strlatum, Neurosclence 39, 59 Elhson, G , R See, E Levln and J Kinney, 1987, Tremorous mouth movements m rats administered chromc neuroleptlcs, Psychopharmacology 92, 122 Johansson, P , E Levm, L Gunne and G Elhson, 1987, Opposite effects of a D1 and a D2 agomst on oral movements in rats, Eur J Pharmacol 134, 83 Kelley, A E , C G Lang and A M Gauthier, 1988, Induction of oral stereotypy following amphetamine mlcrolnjection into a &screte subregion of the strmtum, Psychopharmacology 95, 556 Konlg, F R J and R A Khppel, 1963, The Rat Brain (Williams and Wllkms, Baltimore) Koshlkawa, N , S Aokl, M Hiruta, K Tomiyama, M Kobayashl, Y Tsuboi, K Iwata, R Summo and J D Stephenson, 1989, Effects of mtrastrmtal rejections of selectwe dopamme D-1 and D-2 agomsts and antagonists on jaw movements of rats, Eur J Pharmacol 163, 227 Koshtkawa, N , F Koshikawa, K Tomlyama, K Kakuchi de Beltran, F Kamimura and M Kobayashi, 1990, Effects of dopamme D1 and D2 agonlsts and antagomsts injected into the nucleus accum-

bens and globus palhdus on jaw movements o! rats, Eur J Pharmacol 182, 375 Longonl, R , L Spma and G D~ Ch~ara, 1987, Permissive role of D-1 receptor stlmulatton by endogenous dopamme for the expression of postsynaptlc D-2-medlated behavloural responses Yawning m rats, Eur J Pharmacol 134, 163 Molloy, A G and J L Waddmgton, 1984, Dopammerglc behavlour stereospeclfically promoted by the D1 agomst R-SK&F 38393 and selectively blocked by the D1 antagonist SCH 23390, Psychopharmacology 82, 400 Molloy, A G and J L Waddmgton, 1985, Stuffing, rearing and locomotor responses to the D-1 dopamme agomst R-SK&F 38393 and to apomorphme differential mteractlons w~th the selective D-1 and D-2 antagomsts SCH 23390 and metoclopramlde, Eur J Pharmacol 108, 305 Moody, C A and L P Spear, 1989, The D e agonlst qumplrole induces non-&rected and directed chewing m weanhng rats, Soc Neuroscl Abstr 15, 518 6 Murray, A M and J L Waddmgton, 1989, The reduction of groommg and vacuous chewing by a series of selective D-1 dopamme receptor agomsts two directions of D-1 D-2 interaction, Eur J Pharmacol 160, 377 Prlnssen, E P M , P Koene, D J Heeren and A R Cools, 1992, Jaw muscle activity, the nucleus accumbens and dopammerglc agorests a new approach, Brain Res Bull 28, 775 Robertson, G S and H A Robertson, 1987, D1 and D2 dopamme agomst synergism separate sites of action 9, Trends Pharmacol Scl 8, 295 Rosengarten, H , J W Schweitzer and A J Frledhoff, 1983, Inductmn of oral dysloneslas m naive rats by D1 stimulation, Life Sc~ 33, 2479 Rosengarten, H , J W Schweltzer and A J Frledhoff, 1986, Selective dopamme D2 receptor reduction enhances a D1 mediated oral dyskmesm m rats, Life Scl 39, 29 Rosengarten, H , J W Schweltzer, M Egawa and A J Fnedhoff, 1988, Diminished D2 dopamme receptor function and the emergence of repetitive jaw movements, m Central D-1 Dopamme Receptors, eds M Goldstem, K Fuxe and I Tabachmk (Plenum, New York) p 159 SAS User's Guide Statistics, Version 6 Edition, 1990 (SAS Institute Inc ) Spooren, W P J M , E Cuypers and A R Cools, 1989, Oro-faclal dyskmesia and the sub-commissural part of the globus pallldus in the cat role of acetylchohne and its interaction with GABA, Psychopharmacology 99, 381 Uchlmura, N , H Hlgashl and S Nmhl, 1986, Hyperpolarlzlng and depolarizing actions of dopamme via D-1 and D-2 receptors on nucleus accumbens neurons, Brain Res 375, 368 Waddmgton, J L, 1990, Spontaneous orofacml movements reduced In rodents by very long-term neurolept~c drug administration phenomenology, pathophyslology and putative relatmnshlp to tardwe dyskmesla, Psychopharmacology 101, 431