- Email: [email protected]
Functional interaction between dopamine D1 and D2 receptors in rat jaw movements
European Journal of Pharmacology, 201 (1991) 47-5 I 0 1991 Elsevier Science Publishers B.V. OOl4-2999/91/$03.50 ADONIS 003429999100519Q
47
EJP 5 1982
Noriaki Koshikawa, Keiko Kikuchi de B Department of Pharmacology, Nihon Unil,ersity School and
,
Katsunori Tomiyama, Masafumi
Kobayashi
iroy, l-8-13, Kanda-Surugadai, Chiyoda-klc, Tokyo 101, Japan
’ PsychoneuropharmacologicalResearch Whit@lJnil’ersi& of Ngmegen, Nijtnegen, The Nerherlands Received 28 January 1991. revised MS
receivedI MaI, 1991, accepted 21 May 1991
The functional interaction between dopamine D, and D , receptors in dopamine-mediated jaw movements was studied in kctamine-anaesthetized rats after Cl spinal transection. JacW movements were recorded by means of a light-emitting diode attached to the mandible; the method permits a detailed qua italive and quantitative analysis of jaw movements. D, stimulation with SKF38393 (10 mg/kg i.v.1 produced frequent bursts f teeth chattering, which were abolished by pretreatment with SW23390 (0.25 mg/kg i.v.1. D, stimulation by quinpirole Cl-10 mg/kg i.v.1 produced infrequent bursts of jaw movements, which were characterized by low frequency jaw opening and sure movements from the rest position of the jaw, and absence of tongue protrusions. An additional stimulation of D, recept bygiving SKF38393 30 min later produced an almost continuous pattern of jaw openings but less closure movements from rest position, and the openings were accompanied by frequent tongue protrusions. These results clearly demonstrate that type of oral behaviour produced by stimulation of D, and D,
receptors together is qualitatively different from that prOdWed bystimulation of either D1 or D, receptors alone. Oral movements; Electromyographic activity; SK&F 38393; Quinpiro!e; Dopamine D,/D,
1. Introduction There have been several reports of synergism between dopamine D, and D, receptors in producing dopamine-mediated behaviour. For example, the selective D, agonist SKF38393 increases turning elicited by the Dz agonist quinpirole in a dose-dependent manner (Braun et al., 1986). A similar synergistic effect on typical oral stereotyped behaviour has also been reported (Arnt et al., 1987; 1988; Meller et al., 1988). The foregoing results suggest that D, receptors play an ‘enabling’ or ‘permissive’ role in permitting the full expression of D, receptor-stimulated behaviours (Melloy et al., 1986; Waddington, 1986; Longoni et al., 1987a,b). This D,/D, interaction profile has also been found in electrophysiological studies (White, 1987; Walters et al., 1988). The present study demonstrates that the type of oral behaviour produced by stimulation of D, and D, receptors together is qualitatively different from that evoked by stimulation of either D, or D, receptors only.
Correspondence to: N. Koshikawa, Department Nihon University School of Dentistry, l-8-13. Chiyoda-ku, Tokyo 101, Japan.
of’ Pharmacology, Kanda-Surugadai,
receptor interaction; (Rat)
Jaw movements were recorded by means of a lightemitting diode attached to the mandible of anaesthetized rats with spinal transection at Cl. This method permits a more detailed qualitative and quantitative analysis of jaw movements. We believe that this method will help to further elucidate fundamental principles in the organization of the neural mechanisms responsible for the generation of behaviours involving jaw move-
ments.
2. 21.
Materials and methods Animals
and surgery
Male Sprague-Dawley rats (270-350 g) were anaesthetized with ketamine HCI (10 mg/kg i.p.) supplemented during surgery with halothane (OS-4%). After surgery the ar:imals were maintained under anaesthesia with an i.v. infusion of ketamine (10 mg/kg). Recordings of jaw movements were made as described previously (Koshikawa et al., 1989). Artificial respiration (60 strokes/min, 5 m! stroke volume) was commenced and the spinal cord was transected at Cl. Bipolar electrodes were placed under the mystacial
masseter muscles to d into the digastric C) activity. A small e~e~tro~~yographic ( e was attached to the mandible: the s held in a constant position relative to a ~~g~t-se~s~~~ve transducer by cementing the skull to a ame (to avoid the use of ear bars). LignoCi (2%) gel was applied periodically to all Rectal temperature was maintained at 37 o C tatically controlled heating pad. Vertical movements of &e mandible were detected by the t~~~s~~cer and displayed on a polygraph for counting ses. The number of jaw openings greater than 1 pu mm (measured from the diode displacement) were counted during consecutive 5-min periods. Other orofacial behaviours, such as tongue protrusion and teeth chattering, were also assessed in individual rats. Rats were rated for the presence or absence of the items; data are expressed as the number of rats in each treatment group (n = 6) exhibiting each sign. Animals were used only ante.
SKF38393 HCI (Smith Kline Beecham), SCH23390 maleate (Schering Co.) and quinpirole HCI (LY 171555, Eli Lilly & Co.) were dissolved in saline (0.9% NaCl VI immediately before use and given i.v. via a jugucannula. Solutions of SKF38393 were made and
2.3. Statistical analysis The data for jaw movements are expressed as means k S.E.M. Statistical analysis was done with a two-way analysis of variance (ANOVA). The data for total jaw movements were analysed with a one-way ANOVA followed by Dunc&s multiple range test. The data for teeth chattering and tongue protrusion were analysed with Fisher’s exact probability test. A P value of less than 0.05 was considered statistically significant.
SU?W93 (1, 2 and 3 kg/mg) produced slightly more jaw movements than saline alone (fig. 1). A few brief episodes of teeth chattering were seen, but these became more frequent when a high dose (10 mg/kg) of SKF38393 was given. Quinpirole (1, 2 and 3 mg/kg) induced infrequent bursts of jaw movements, each consisting of a small number of jaw openings and closures which were characterized by a low frequency or abSence of tongue protrusions. The overall number of Wtpirole-induced jaw movements remained rather low (fig. 11, even when the dose of quinpirole was increased to LOrag/kg: the latter dose produced a pattern which
SKF
’
l A
Fig. 1. Jaw movements evoked by i.v. injection of saline, SKF3823 CXF). quinpirole (Quin) or SW38393 and quinpirole together. The data are expressed as the mean number of total jaw movements in a 30-min observation period (six rats). Vertical bars indicate S.E.M. * P < 0.05 (Duncan’s multiple range test).
did not differ from that elicited by 3 mg/kg (n = 6, fig. 4). However, when the same doses of SKF38393 and quinpirole were administered in combination, there was an immediate and dramatic dose-dependent increase in the number of jaw movements (fig. 1). Figure 1 shows the total jaw movements occurring in the first 30 min, but the effects of SKF38393 and quinpirole together persisted for more than 2 h. The openings were greater in magnitude than those occurring after quinpirole alone and were accompanied by frequent tongue protrusions. Figure 2 shows that a reciprocal potentiation occurred when SKF38393 (2, 3 mg/kg) and quinpirole (2, 3 mg/kg) were administered 30 min apart, although the potentiation was greatest when quinpirole was administered first (P < 0.01, hvo-way ANOVA). A similar difference in potentiation was also found with smaller doses (2 mg/kg each) after a shorter (10 min) interval (data not shown). The change in the pattern of jaw movements occurring after administration of both agonists is illustrated in fig. 3A. It can be seen that quinpirole (2 mg/kg) alone induced bursts of jaw movements, each consisting of jaw openings and closures from the rest position of the jaw and accompanied by lateral movements from the midline. The movements were dramatically changed by an additional administration of SKF38393 (2 mg/kg) 30 min later: there was an almost continuous pattern of rapid jaw openings but less closures from the rest position. The movements were associated with a more pronounced increase in the activity of the digastric (jaw-opener) muscle than the increase seen in the masseter (jaw-closer) muscle. Infrequent episodes of teeth chattering were seen about 30 min after SKF38393 (fig. 3A) and this became more frequent at later observation periods. Movement of the vibrissas
49
Fig. 2. Time course of jaw movements evoked by intravenous injections of saline, SKF38393 WW and quinpirole (Quin). The arrows indicate the time of injection. The jaw movements are the means from 6 animafs. Vertical bars indicate S.E.M.
was also activated by quinpirole and was further activated by additional SELF38393 (fig. 3A). Figure 3B shows the effects induced by SKF38393 (10 mg/kg). Teeth chattering was accompanied by very rapid closing movements of the jaw (fig. 3B: upper trace) as well as by very high activity in the masseter muscles. Movements were accompanied by sounds made by the tapping of the teeth. The trace of jaw movements in the horizontal dimension shows that the frequency of lateral movements during teeth chattering was almost half of that of vertical movements, which means that during teeth chattering each cycle of vertical jaw movement was associated with the movement of the mandible to either the Ieft or right side of the midline. Movement of the vibrissas was aIso activated by SKF38393, but the magnitude seemed smaller than that seen after quinpirole alone or two drugs together (fig. 3.4,B). Occasiona1 tongue protrusions were also seen in some of the intervals between the teeth clattering bursts. These
fess. ImV]
Vb.
1mV ] 10s
Fig. 3. Records of jaw movements (JM) and of electromyographic activity from the right anterior digastric muscle (Dig.), right masseter mu& (Mass.) and vibrissas (Vib.) induced by SW38393 and quinpirole. Vertical (VERT) and horizontal (HOR) movements of the diode attached to the mental protuberance are shown together with EMG recordings. In (A), SICF38393 (2 mg/kg i.v.1 was given (arrow) to rats pretreated with quinpirole (2 mg/kg ix.1 30 min earlier. (B) shows the effects induced by SKF38393 (10 m&kg i.v.1.
Fig. 4. Overall picture of drug effects upo11 vertical jaw movC.?xfits after systemic injections of saline, quinpirole, SKF38393 or a combination of the two drugs.
Pretreatment
None
Treatment tm_e/kgb
Saline
Teeth chattering Tongue protrusion Dominant muscle
SCH233W SKF3839.7
1 l/6 O/h -
6/h O/h M
2 6/6 O/h M
3 6/6 I/6 M
None
None
Quinpirole
SKF38393 + quinpirole
1
10
10
6/6 6/6 M
O/h *’ O/h * _
O/6 O/h _
z O/6 I/6 _
3 l/6 l/6 _
IO
1
2
3
O/6 l/6 _
2/h
3/6 6/6 D
2/6 6/6 D
4/6 D
-LP = O.001 Fisher’s xrct prohahility ted of SKF3X393 (10 mg/kp) versus SKF3ti39.7 (IO mg/kg) ptdreated with SCH233YO (0.25
of SKFX733 (10 mg/kgl were COt’tIPh2iY aboiished by pretreatment with SCH23390 to.25 mg/kgl 5 min before (table 1).
&em
The present study provides clear evidence that costimulation of D, and D, receptors is essential for full expression of dopamine-mediated jaw movements in rats. The selective D, agonist quinpiroie given alone produced a smaller number of jaw opening movements, while the selective D, agonist SKF35393 was almost inert when given alone in a dose range of l-3 mg/kg. From these results it can he concluded that D, stimuiation enhances the production of jaw movements induced by D, stimulation in terms of the number of jaw opening movements only. However, it is clear from the trace of jaw movements and the EMG activities of digastric (jaw-opener) and masseter (jaw-closer) muscles that the pattern of the behaviour induced by co-stimulation of D, and D, receptors was completely different from that induced by D, receptor stimulation alone. The trace shows very clearly that the pattern of jaw movements induced by quinpiroie alone changed dramatically after the additional injection of SKF38393. Thus, the predominant jaw movements produced after concurrent D, and D, stimulation were jaw openings, whereas the jaw was opened and closed equally when only Dz receptors were stimulated. These results indicate that D, stimulation together with D, stimulation produces changes in jaw movements not only in a quantitative but also in a qualitative way. The jaw movements induced by simultaneous activation of both D, and D, receptors were different from those induced by D, receptor stimulation alone. In this respect the present results are not in line with the general idea that D, receptors always play an enabling or permissive role in permitting the full expression of D2 receptorstimulated behaviour (Moiioy et al., 1986; Waddington, 1986; Longoni et al., 1987a,b). In fact, the present study shows that this idea does not hold for the inter-
mg/kg) 5 min
action between D, and D, receptors in the preparation used. Although the preparation used differs in many respects from more conventional animal models such as the tube-test of Eiiison (Eiiison et al., 19871, it has previously been shown that this model provides reievant insights into the mechanism of action underlying apomorphine-induced oral stereotypy (Koshikawa et al., 19891. The extent to which the present findings can be generalized to other animal models of oral stereotypy remains to be shown. The reciprocal potentiation seen when SKF38393 (2 or 3 mg/kg) and quinpiroie (2 or 3 mg/kg) were administered 30 min apart was greater when quinpiroie was given first. The reason why smaller effects were obtained when SKF38393 was given first is not well understood, but the results may suggest that either SKF38393 has a shorter duration of action than quinpirole or that a sufficient stimulation of Dz receptors is required to produce full expression of the jaw movements mediated by stimulation of D, receptors. However, the former seems less likely since simultaneous injection of both agonists (2 mg/kg each) produced a smaller number of jaw movements than those produced by giving quinpiroie first. Several studies have indicated that D, agonists can induce syndromes of typical behaviours in their own right (Moiioy and Waddington, 1984, 1987; Starr and Starr, 1986; Murray and Waddington, 1989). One of these behaviours, which is commonly described as purposeless or vacuous chewing, has been observed with SKF38393 (Rosengarten et al., 1983; Collins et al., 1989). There are difficulties with regard to the terminology of orofaciai movements; in a critical review Waddington (1990) suggested that the phenomenoiogy of the movements should be described in more detail. In the present study it appears that the teeth chattering induced by a high dose (10 mg/kg iv.1 of SKF38393 might be a D,-stimulated behaviour with a pattern of jaw movements quite distinct from that induced by either D, stimulation alone or concurrent stimulation of both types of dopamine receptors. Furthermore, none of the three types of behaviour observed in this study could be considered as being identical to the
51
previously reported ‘purposeless or vacuous chewing’ (Rosengarten et al., 1983; Collins et al., 1989). To what extent these differences are due to differences in the experimental set-ups remains to be investigated. The teeth chattering induced by SKF38393 (10 mg/kg i.v.) was completely abolished by pretreatment with SCH23390 (0.25 mg/kg i-v.). The reason why a high dose of SKF38393 was needed to induce these effects might be that SKF38393 is a partial D, receptor agonist. Very recently, D, receptors have been subdivided into two subtypes (i.e. new Dz and D3 receptors), based on cloning experiments (Sokoloff et al., 1990). The study shows that quinpirole can act at both subtypes but is more active at D, than D, subtypes. The complication of the functional D,/D, receptor interaction on behaviour, i.e. a cooperative and an oppositional interaction (Johansson et al., 1987; Murray and Waddington, 1989; Waddington and 0’ Boyle, 1989; Koshikawa et al., 19901,might be well explained by the subdivision of the D, receptors. The introduction of selective compounds for these receptors is desirable for the further characterization of perioral behaviours related to these dopamine receptor subtypes, as is a description of the behaviour in more detail.
This work was supported by the Satoh foundation (Japan). We thank the pharmaceutical companies listed in Methods for the gifts of their compounds.
References Arm, J., J. Hyttel and J, Perregard, 1987, Dopamine D-l receptor agonists combined with the selective D-2 agonist, quinpirole, facilitate the expression of oral stereotyped behaviour in rats, European J. Pharmacol. 133. 137. Arm, J., J. Hyttel and E. Meier, 1988, inactivation of dopamine D-l or D-2 receptors differentially inhibits stereotypies induced by dopamine agonists in rats, European J. Pharmacol. 1.5537. Braun, A.R., P. Barone and T.N. Chase, 1986, Interaction of D-1 and D-2 dopamine receptors in the expression of dopamine agonist induced behaviours, in: Neurobiology of Central DrDopamine Receptors, Advances in Experimental Medicine and Biology, Vol. 204, eds. G.R. Breese and 1. Creese fPlenum Press, New York and London) p. 151. Collins, P., C.L.E. Broekkamp, P. Jenner and CD. Marsden, 1989, D, or Dz receptor-induced purposeless chewing in rats is differentially modulated by choiinergic drugs, Br. J. Pharmacol. 98 &lppl.), 815p. Ellison, G,, R. See, E. Levin and J. Kinney, 1987, Timorous mouth movements in rats administered chronic neuroleptics, Psychopharmacology 92, 122. Johansson, P., E. Levin, L. Gunne and G. Ellison. 1987, Opposite effects of a Dl and a D2 agonist on oral movements in rats, European J. Pharmacol. 134,83. Koshikawa, N., S, Aoki, M. Hiruta, K. Tomiyama, M. Kobayashi. Y.
Tsuboi. K. Jwata, R. Sumino and J.D. Stephenson, 1989, Effects of intrastriatal injections of selective dopamfne D-1 and D-2 agonists and antagOnists on jaw movements of rats, European J. Pharmacoi. 163,227. Koshikawa, N., K. Tomiyama, K. Omiya, K. Kikuchi de Beltran and M, Kabayashi, 1QQO.Dopamine D-l but not D-2 receptor stimulation Of the dorsai striatum potentiates apomorpbine-induced jaw movements in rats, European J. Pbarmacol. 178,189. Longoar, R.. L. Spina and G. Di Chiara, 1987a, Permissive rote of D-l receptor stimulation for the expression of D-2 mediated behavior& responses: a quantitative phenomenologica~ study in rats, Life Sci. 41,2135. Longoni, R., L. Spina and G. Di Chiara, 1987b, Permissive role of D-1 receptor stimulation by endogenous dopamine for the expression of postsynaptic D-2-mediated behaviouraf responses. Yawning in rats, European J. Pharmacol. 134, 163. Meller, E., F. Bordi and K. Bohmaker, 1988, Enhancement by the D-J dopamine agonist SKF38393 of specific components of StereOtypy elicited by the D-2 agonists LX71555 and RLJ24213, Life Sci. 42, 2561. Molloy, A.G., K.M. O’Boyle, M.T. Pugh and J.L. Waddington, 1986. Locomotor behaviours in response to new selective D-l and D-2 dopamine receptor agonists, and the influence of selective antagonists, Pharmacol. Biochem. Behav. 25,249. Molloy, A.G. and J.L. Waddington, 1984, Dopaminergic behaviour stereospecifically promoted by the D-l agonist R-SK&F 38393 and selectively blucked by the D-l antagonist SCH 23390, Psychopharmacology 82,409. Moiloy, A.G. and J.L. Waddington, 1987, Assessment of grooming and other behavioural responses to the D-l dopamine receptor agonist SK&F 38393 and it R- and S-enantiomen in the intact adult rat, Psychopharmacology 92, 164. Murray, A.M. and J.L. Waddington, 1989, The induction of grooming and vacuous chewing by a series of selective D-l dopamine receptor agonists: two directions of D-l: D-2 interaction, European J. PharmacoL 160,377. Rosengarten, H., J.W. Schweitzer and A.J. Friedhoff, 1983, Jnduction of oral dyskinesias in native rats by D, stimulatjun, Life Sci. 33, 2479. Sokoloff, P., B. Giros, M.-P. Martres, M.-L. Bouthenet and J.-C. Schwartz, 1990, Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for nemoleptics, Nature 347, 146. Starr, B.S. and M.S. Starr, 1986, Differential effects of dopamine D-l and D-2 agonists and antagonists on velocity of movement. rearing and grooming in the mouse, Neuropha-macology 25.455. Waddington, JL., 1986, Bromocriptine, selective L-2 dopamine receptor agonists and D-l dopaminergic tone, Trends Pharmacol. Sci. 7, 223. Waddington, J.L., 1990, S~ntaneous orofacial movements induced in rodents by very long-term neuroleptic drug administration: phenomenolo~, ~athophysiology and putative relationship to tardive dyskinesia, Psychopharmacology 101,431. Waddington, J,L. and KM. G’Boyle, 1989. Drug action on brain dopamine receptors: a conceptual re-evaluation five Years after the first selective D-l antagonist, Pharmacol. Thor. 43, 1. Walters, J.R., J.H. Carlson, B.G. Weick and D.A. ~rgstrom. 1988, Neurophysiologiral examination of the role of D-l dopamine receptors in the regulation of neuronal activity in the basar ganglia, in: Central D, Dopamine Receptors, Advances in Experimental Medicine and Biology, Vol. 235, eds. M. Goldstein. K Fuxe and 1. Tabachnick (Plenum Press, New York and London) p. 145. White, F.J. 1987, D-1 dopamine receptor stimulation enabkzs the inhibition of nucleus accumbens neurons by a D-2 receptor agonist, European J. Pharmacol. 13% 101.
47
EJP 5 1982
Noriaki Koshikawa, Keiko Kikuchi de B Department of Pharmacology, Nihon Unil,ersity School and
,
Katsunori Tomiyama, Masafumi
Kobayashi
iroy, l-8-13, Kanda-Surugadai, Chiyoda-klc, Tokyo 101, Japan
’ PsychoneuropharmacologicalResearch Whit@lJnil’ersi& of Ngmegen, Nijtnegen, The Nerherlands Received 28 January 1991. revised MS
receivedI MaI, 1991, accepted 21 May 1991
The functional interaction between dopamine D, and D , receptors in dopamine-mediated jaw movements was studied in kctamine-anaesthetized rats after Cl spinal transection. JacW movements were recorded by means of a light-emitting diode attached to the mandible; the method permits a detailed qua italive and quantitative analysis of jaw movements. D, stimulation with SKF38393 (10 mg/kg i.v.1 produced frequent bursts f teeth chattering, which were abolished by pretreatment with SW23390 (0.25 mg/kg i.v.1. D, stimulation by quinpirole Cl-10 mg/kg i.v.1 produced infrequent bursts of jaw movements, which were characterized by low frequency jaw opening and sure movements from the rest position of the jaw, and absence of tongue protrusions. An additional stimulation of D, recept bygiving SKF38393 30 min later produced an almost continuous pattern of jaw openings but less closure movements from rest position, and the openings were accompanied by frequent tongue protrusions. These results clearly demonstrate that type of oral behaviour produced by stimulation of D, and D,
receptors together is qualitatively different from that prOdWed bystimulation of either D1 or D, receptors alone. Oral movements; Electromyographic activity; SK&F 38393; Quinpiro!e; Dopamine D,/D,
1. Introduction There have been several reports of synergism between dopamine D, and D, receptors in producing dopamine-mediated behaviour. For example, the selective D, agonist SKF38393 increases turning elicited by the Dz agonist quinpirole in a dose-dependent manner (Braun et al., 1986). A similar synergistic effect on typical oral stereotyped behaviour has also been reported (Arnt et al., 1987; 1988; Meller et al., 1988). The foregoing results suggest that D, receptors play an ‘enabling’ or ‘permissive’ role in permitting the full expression of D, receptor-stimulated behaviours (Melloy et al., 1986; Waddington, 1986; Longoni et al., 1987a,b). This D,/D, interaction profile has also been found in electrophysiological studies (White, 1987; Walters et al., 1988). The present study demonstrates that the type of oral behaviour produced by stimulation of D, and D, receptors together is qualitatively different from that evoked by stimulation of either D, or D, receptors only.
Correspondence to: N. Koshikawa, Department Nihon University School of Dentistry, l-8-13. Chiyoda-ku, Tokyo 101, Japan.
of’ Pharmacology, Kanda-Surugadai,
receptor interaction; (Rat)
Jaw movements were recorded by means of a lightemitting diode attached to the mandible of anaesthetized rats with spinal transection at Cl. This method permits a more detailed qualitative and quantitative analysis of jaw movements. We believe that this method will help to further elucidate fundamental principles in the organization of the neural mechanisms responsible for the generation of behaviours involving jaw move-
ments.
2. 21.
Materials and methods Animals
and surgery
Male Sprague-Dawley rats (270-350 g) were anaesthetized with ketamine HCI (10 mg/kg i.p.) supplemented during surgery with halothane (OS-4%). After surgery the ar:imals were maintained under anaesthesia with an i.v. infusion of ketamine (10 mg/kg). Recordings of jaw movements were made as described previously (Koshikawa et al., 1989). Artificial respiration (60 strokes/min, 5 m! stroke volume) was commenced and the spinal cord was transected at Cl. Bipolar electrodes were placed under the mystacial
masseter muscles to d into the digastric C) activity. A small e~e~tro~~yographic ( e was attached to the mandible: the s held in a constant position relative to a ~~g~t-se~s~~~ve transducer by cementing the skull to a ame (to avoid the use of ear bars). LignoCi (2%) gel was applied periodically to all Rectal temperature was maintained at 37 o C tatically controlled heating pad. Vertical movements of &e mandible were detected by the t~~~s~~cer and displayed on a polygraph for counting ses. The number of jaw openings greater than 1 pu mm (measured from the diode displacement) were counted during consecutive 5-min periods. Other orofacial behaviours, such as tongue protrusion and teeth chattering, were also assessed in individual rats. Rats were rated for the presence or absence of the items; data are expressed as the number of rats in each treatment group (n = 6) exhibiting each sign. Animals were used only ante.
SKF38393 HCI (Smith Kline Beecham), SCH23390 maleate (Schering Co.) and quinpirole HCI (LY 171555, Eli Lilly & Co.) were dissolved in saline (0.9% NaCl VI immediately before use and given i.v. via a jugucannula. Solutions of SKF38393 were made and
2.3. Statistical analysis The data for jaw movements are expressed as means k S.E.M. Statistical analysis was done with a two-way analysis of variance (ANOVA). The data for total jaw movements were analysed with a one-way ANOVA followed by Dunc&s multiple range test. The data for teeth chattering and tongue protrusion were analysed with Fisher’s exact probability test. A P value of less than 0.05 was considered statistically significant.
SU?W93 (1, 2 and 3 kg/mg) produced slightly more jaw movements than saline alone (fig. 1). A few brief episodes of teeth chattering were seen, but these became more frequent when a high dose (10 mg/kg) of SKF38393 was given. Quinpirole (1, 2 and 3 mg/kg) induced infrequent bursts of jaw movements, each consisting of a small number of jaw openings and closures which were characterized by a low frequency or abSence of tongue protrusions. The overall number of Wtpirole-induced jaw movements remained rather low (fig. 11, even when the dose of quinpirole was increased to LOrag/kg: the latter dose produced a pattern which
SKF
’
l A
Fig. 1. Jaw movements evoked by i.v. injection of saline, SKF3823 CXF). quinpirole (Quin) or SW38393 and quinpirole together. The data are expressed as the mean number of total jaw movements in a 30-min observation period (six rats). Vertical bars indicate S.E.M. * P < 0.05 (Duncan’s multiple range test).
did not differ from that elicited by 3 mg/kg (n = 6, fig. 4). However, when the same doses of SKF38393 and quinpirole were administered in combination, there was an immediate and dramatic dose-dependent increase in the number of jaw movements (fig. 1). Figure 1 shows the total jaw movements occurring in the first 30 min, but the effects of SKF38393 and quinpirole together persisted for more than 2 h. The openings were greater in magnitude than those occurring after quinpirole alone and were accompanied by frequent tongue protrusions. Figure 2 shows that a reciprocal potentiation occurred when SKF38393 (2, 3 mg/kg) and quinpirole (2, 3 mg/kg) were administered 30 min apart, although the potentiation was greatest when quinpirole was administered first (P < 0.01, hvo-way ANOVA). A similar difference in potentiation was also found with smaller doses (2 mg/kg each) after a shorter (10 min) interval (data not shown). The change in the pattern of jaw movements occurring after administration of both agonists is illustrated in fig. 3A. It can be seen that quinpirole (2 mg/kg) alone induced bursts of jaw movements, each consisting of jaw openings and closures from the rest position of the jaw and accompanied by lateral movements from the midline. The movements were dramatically changed by an additional administration of SKF38393 (2 mg/kg) 30 min later: there was an almost continuous pattern of rapid jaw openings but less closures from the rest position. The movements were associated with a more pronounced increase in the activity of the digastric (jaw-opener) muscle than the increase seen in the masseter (jaw-closer) muscle. Infrequent episodes of teeth chattering were seen about 30 min after SKF38393 (fig. 3A) and this became more frequent at later observation periods. Movement of the vibrissas
49
Fig. 2. Time course of jaw movements evoked by intravenous injections of saline, SKF38393 WW and quinpirole (Quin). The arrows indicate the time of injection. The jaw movements are the means from 6 animafs. Vertical bars indicate S.E.M.
was also activated by quinpirole and was further activated by additional SELF38393 (fig. 3A). Figure 3B shows the effects induced by SKF38393 (10 mg/kg). Teeth chattering was accompanied by very rapid closing movements of the jaw (fig. 3B: upper trace) as well as by very high activity in the masseter muscles. Movements were accompanied by sounds made by the tapping of the teeth. The trace of jaw movements in the horizontal dimension shows that the frequency of lateral movements during teeth chattering was almost half of that of vertical movements, which means that during teeth chattering each cycle of vertical jaw movement was associated with the movement of the mandible to either the Ieft or right side of the midline. Movement of the vibrissas was aIso activated by SKF38393, but the magnitude seemed smaller than that seen after quinpirole alone or two drugs together (fig. 3.4,B). Occasiona1 tongue protrusions were also seen in some of the intervals between the teeth clattering bursts. These
fess. ImV]
Vb.
1mV ] 10s
Fig. 3. Records of jaw movements (JM) and of electromyographic activity from the right anterior digastric muscle (Dig.), right masseter mu& (Mass.) and vibrissas (Vib.) induced by SW38393 and quinpirole. Vertical (VERT) and horizontal (HOR) movements of the diode attached to the mental protuberance are shown together with EMG recordings. In (A), SICF38393 (2 mg/kg i.v.1 was given (arrow) to rats pretreated with quinpirole (2 mg/kg ix.1 30 min earlier. (B) shows the effects induced by SKF38393 (10 m&kg i.v.1.
Fig. 4. Overall picture of drug effects upo11 vertical jaw movC.?xfits after systemic injections of saline, quinpirole, SKF38393 or a combination of the two drugs.
Pretreatment
None
Treatment tm_e/kgb
Saline
Teeth chattering Tongue protrusion Dominant muscle
SCH233W SKF3839.7
1 l/6 O/h -
6/h O/h M
2 6/6 O/h M
3 6/6 I/6 M
None
None
Quinpirole
SKF38393 + quinpirole
1
10
10
6/6 6/6 M
O/h *’ O/h * _
O/6 O/h _
z O/6 I/6 _
3 l/6 l/6 _
IO
1
2
3
O/6 l/6 _
2/h
3/6 6/6 D
2/6 6/6 D
4/6 D
-LP = O.001 Fisher’s xrct prohahility ted of SKF3X393 (10 mg/kp) versus SKF3ti39.7 (IO mg/kg) ptdreated with SCH233YO (0.25
of SKFX733 (10 mg/kgl were COt’tIPh2iY aboiished by pretreatment with SCH23390 to.25 mg/kgl 5 min before (table 1).
&em
The present study provides clear evidence that costimulation of D, and D, receptors is essential for full expression of dopamine-mediated jaw movements in rats. The selective D, agonist quinpiroie given alone produced a smaller number of jaw opening movements, while the selective D, agonist SKF35393 was almost inert when given alone in a dose range of l-3 mg/kg. From these results it can he concluded that D, stimuiation enhances the production of jaw movements induced by D, stimulation in terms of the number of jaw opening movements only. However, it is clear from the trace of jaw movements and the EMG activities of digastric (jaw-opener) and masseter (jaw-closer) muscles that the pattern of the behaviour induced by co-stimulation of D, and D, receptors was completely different from that induced by D, receptor stimulation alone. The trace shows very clearly that the pattern of jaw movements induced by quinpiroie alone changed dramatically after the additional injection of SKF38393. Thus, the predominant jaw movements produced after concurrent D, and D, stimulation were jaw openings, whereas the jaw was opened and closed equally when only Dz receptors were stimulated. These results indicate that D, stimulation together with D, stimulation produces changes in jaw movements not only in a quantitative but also in a qualitative way. The jaw movements induced by simultaneous activation of both D, and D, receptors were different from those induced by D, receptor stimulation alone. In this respect the present results are not in line with the general idea that D, receptors always play an enabling or permissive role in permitting the full expression of D2 receptorstimulated behaviour (Moiioy et al., 1986; Waddington, 1986; Longoni et al., 1987a,b). In fact, the present study shows that this idea does not hold for the inter-
mg/kg) 5 min
action between D, and D, receptors in the preparation used. Although the preparation used differs in many respects from more conventional animal models such as the tube-test of Eiiison (Eiiison et al., 19871, it has previously been shown that this model provides reievant insights into the mechanism of action underlying apomorphine-induced oral stereotypy (Koshikawa et al., 19891. The extent to which the present findings can be generalized to other animal models of oral stereotypy remains to be shown. The reciprocal potentiation seen when SKF38393 (2 or 3 mg/kg) and quinpiroie (2 or 3 mg/kg) were administered 30 min apart was greater when quinpiroie was given first. The reason why smaller effects were obtained when SKF38393 was given first is not well understood, but the results may suggest that either SKF38393 has a shorter duration of action than quinpirole or that a sufficient stimulation of Dz receptors is required to produce full expression of the jaw movements mediated by stimulation of D, receptors. However, the former seems less likely since simultaneous injection of both agonists (2 mg/kg each) produced a smaller number of jaw movements than those produced by giving quinpiroie first. Several studies have indicated that D, agonists can induce syndromes of typical behaviours in their own right (Moiioy and Waddington, 1984, 1987; Starr and Starr, 1986; Murray and Waddington, 1989). One of these behaviours, which is commonly described as purposeless or vacuous chewing, has been observed with SKF38393 (Rosengarten et al., 1983; Collins et al., 1989). There are difficulties with regard to the terminology of orofaciai movements; in a critical review Waddington (1990) suggested that the phenomenoiogy of the movements should be described in more detail. In the present study it appears that the teeth chattering induced by a high dose (10 mg/kg iv.1 of SKF38393 might be a D,-stimulated behaviour with a pattern of jaw movements quite distinct from that induced by either D, stimulation alone or concurrent stimulation of both types of dopamine receptors. Furthermore, none of the three types of behaviour observed in this study could be considered as being identical to the
51
previously reported ‘purposeless or vacuous chewing’ (Rosengarten et al., 1983; Collins et al., 1989). To what extent these differences are due to differences in the experimental set-ups remains to be investigated. The teeth chattering induced by SKF38393 (10 mg/kg i.v.) was completely abolished by pretreatment with SCH23390 (0.25 mg/kg i-v.). The reason why a high dose of SKF38393 was needed to induce these effects might be that SKF38393 is a partial D, receptor agonist. Very recently, D, receptors have been subdivided into two subtypes (i.e. new Dz and D3 receptors), based on cloning experiments (Sokoloff et al., 1990). The study shows that quinpirole can act at both subtypes but is more active at D, than D, subtypes. The complication of the functional D,/D, receptor interaction on behaviour, i.e. a cooperative and an oppositional interaction (Johansson et al., 1987; Murray and Waddington, 1989; Waddington and 0’ Boyle, 1989; Koshikawa et al., 19901,might be well explained by the subdivision of the D, receptors. The introduction of selective compounds for these receptors is desirable for the further characterization of perioral behaviours related to these dopamine receptor subtypes, as is a description of the behaviour in more detail.
This work was supported by the Satoh foundation (Japan). We thank the pharmaceutical companies listed in Methods for the gifts of their compounds.
References Arm, J., J. Hyttel and J, Perregard, 1987, Dopamine D-l receptor agonists combined with the selective D-2 agonist, quinpirole, facilitate the expression of oral stereotyped behaviour in rats, European J. Pharmacol. 133. 137. Arm, J., J. Hyttel and E. Meier, 1988, inactivation of dopamine D-l or D-2 receptors differentially inhibits stereotypies induced by dopamine agonists in rats, European J. Pharmacol. 1.5537. Braun, A.R., P. Barone and T.N. Chase, 1986, Interaction of D-1 and D-2 dopamine receptors in the expression of dopamine agonist induced behaviours, in: Neurobiology of Central DrDopamine Receptors, Advances in Experimental Medicine and Biology, Vol. 204, eds. G.R. Breese and 1. Creese fPlenum Press, New York and London) p. 151. Collins, P., C.L.E. Broekkamp, P. Jenner and CD. Marsden, 1989, D, or Dz receptor-induced purposeless chewing in rats is differentially modulated by choiinergic drugs, Br. J. Pharmacol. 98 &lppl.), 815p. Ellison, G,, R. See, E. Levin and J. Kinney, 1987, Timorous mouth movements in rats administered chronic neuroleptics, Psychopharmacology 92, 122. Johansson, P., E. Levin, L. Gunne and G. Ellison. 1987, Opposite effects of a Dl and a D2 agonist on oral movements in rats, European J. Pharmacol. 134,83. Koshikawa, N., S, Aoki, M. Hiruta, K. Tomiyama, M. Kobayashi. Y.
Tsuboi. K. Jwata, R. Sumino and J.D. Stephenson, 1989, Effects of intrastriatal injections of selective dopamfne D-1 and D-2 agonists and antagOnists on jaw movements of rats, European J. Pharmacoi. 163,227. Koshikawa, N., K. Tomiyama, K. Omiya, K. Kikuchi de Beltran and M, Kabayashi, 1QQO.Dopamine D-l but not D-2 receptor stimulation Of the dorsai striatum potentiates apomorpbine-induced jaw movements in rats, European J. Pbarmacol. 178,189. Longoar, R.. L. Spina and G. Di Chiara, 1987a, Permissive rote of D-l receptor stimulation for the expression of D-2 mediated behavior& responses: a quantitative phenomenologica~ study in rats, Life Sci. 41,2135. Longoni, R., L. Spina and G. Di Chiara, 1987b, Permissive role of D-1 receptor stimulation by endogenous dopamine for the expression of postsynaptic D-2-mediated behaviouraf responses. Yawning in rats, European J. Pharmacol. 134, 163. Meller, E., F. Bordi and K. Bohmaker, 1988, Enhancement by the D-J dopamine agonist SKF38393 of specific components of StereOtypy elicited by the D-2 agonists LX71555 and RLJ24213, Life Sci. 42, 2561. Molloy, A.G., K.M. O’Boyle, M.T. Pugh and J.L. Waddington, 1986. Locomotor behaviours in response to new selective D-l and D-2 dopamine receptor agonists, and the influence of selective antagonists, Pharmacol. Biochem. Behav. 25,249. Molloy, A.G. and J.L. Waddington, 1984, Dopaminergic behaviour stereospecifically promoted by the D-l agonist R-SK&F 38393 and selectively blucked by the D-l antagonist SCH 23390, Psychopharmacology 82,409. Moiloy, A.G. and J.L. Waddington, 1987, Assessment of grooming and other behavioural responses to the D-l dopamine receptor agonist SK&F 38393 and it R- and S-enantiomen in the intact adult rat, Psychopharmacology 92, 164. Murray, A.M. and J.L. Waddington, 1989, The induction of grooming and vacuous chewing by a series of selective D-l dopamine receptor agonists: two directions of D-l: D-2 interaction, European J. PharmacoL 160,377. Rosengarten, H., J.W. Schweitzer and A.J. Friedhoff, 1983, Jnduction of oral dyskinesias in native rats by D, stimulatjun, Life Sci. 33, 2479. Sokoloff, P., B. Giros, M.-P. Martres, M.-L. Bouthenet and J.-C. Schwartz, 1990, Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for nemoleptics, Nature 347, 146. Starr, B.S. and M.S. Starr, 1986, Differential effects of dopamine D-l and D-2 agonists and antagonists on velocity of movement. rearing and grooming in the mouse, Neuropha-macology 25.455. Waddington, JL., 1986, Bromocriptine, selective L-2 dopamine receptor agonists and D-l dopaminergic tone, Trends Pharmacol. Sci. 7, 223. Waddington, J.L., 1990, S~ntaneous orofacial movements induced in rodents by very long-term neuroleptic drug administration: phenomenolo~, ~athophysiology and putative relationship to tardive dyskinesia, Psychopharmacology 101,431. Waddington, J,L. and KM. G’Boyle, 1989. Drug action on brain dopamine receptors: a conceptual re-evaluation five Years after the first selective D-l antagonist, Pharmacol. Thor. 43, 1. Walters, J.R., J.H. Carlson, B.G. Weick and D.A. ~rgstrom. 1988, Neurophysiologiral examination of the role of D-l dopamine receptors in the regulation of neuronal activity in the basar ganglia, in: Central D, Dopamine Receptors, Advances in Experimental Medicine and Biology, Vol. 235, eds. M. Goldstein. K Fuxe and 1. Tabachnick (Plenum Press, New York and London) p. 145. White, F.J. 1987, D-1 dopamine receptor stimulation enabkzs the inhibition of nucleus accumbens neurons by a D-2 receptor agonist, European J. Pharmacol. 13% 101.