Angiotensin II-induced rhythmic jaw movements in the ketamine-anesthetized guinea pig

Brain Research, 478 (1989) 233-240 Elsevier

233

BRE 14193

Angiotensin II-induced rhythmic jaw movements in the ketamine-anesthetized guinea pig Geoffrey E. Gerstner, Louis J. Goldberg and Korina De Bruyne Department of Oral Biology, School of Dentistry, Departmentof Kinesiology, and the Brain Research Institute, Universityof California, Los Angeles, Los Angeles, CA 90024 (U.S.A.) (Accepted 12 July 1988) Key words: Jaw movement; Masticatorymuscle; Drinking; Angiotensin II; Electromyography;Guinea pig

The EMG activity of the left anterior digastric muscle as well as associated jaw movements were studied in ketamine-anesthetized guinea pigs that had received i.v. infusions of angiotensin II (ANG-II). Rhythmicjaw movements with two distinct movement profiles were associated with ANG-II infusion. One movement profile was typified by vertical jaw opening and closing movements with little or no associated horizontal movement. The second rhythmical jaw movement profile was unlike the first in that jaw closingwas accompanied by a significant horizontal deflection of the jaw. Both jaw movement profiles were similar in that little or no horizontal movement occurred during jaw opening. Tongue protrusions were also observed during jaw opening in both cases. The results show that ANG-II induces rhythmic jaw movements in anesthetized guinea pigs. ANG-lI-induced jaw movement profiles and digastric muscle EMG activity are similar to those seen after an i.v. injection of apomorphine in the anesthetized guinea pig, and to those associated with lapping in the awake animal. INTRODUCTION Dopamine agonists delivered intravenously (i.v.), intraventricularly (i.v.t,), or intraperitoneally (i.p.) increase drinking in awake animals 4-7"9"!°'25'29"31. It has recently been reported that the dopamine agonist, apomorphine, induces rhythmic jaw movements accompanied by rhythmical bursting in jaw opener and closer muscles in ketamine-anesthetized guinea pigs 2. These apomorphine-induced rhythmic jaw movements (ARJMs) have since been analyzed in detail 3'21"22, as have the jaw movements and masticatory muscle EMG activities associated with drinking in the awake animal 12, and it has been shown that ARJMs have jaw movement profiles and jaw muscle EMG activity that are similar to lapping or drinking in awake guinea pigs 12. Drinking behavior has also been reported to occur in awake, freely behaving animals in response to centrally or peripherally administered angiotensin lI (ANG-II) 7.9-11"15"19"23. ANG-II is a powerful dipso-

gen and is believed to exert its effect through the subfornical organ when administered i.v. and through tissue surrounding the anteroventral third ventricle when administered i.v.t. (see refs. 16, 23, 24 for reviews). Dopaminergic pathways are probably involved in ANG-II-induced drinking, because selective destruction or blockade of dopamine systems blocks the ANG-II effect 10"11'14'16-20'33-35'37.The nigrostriatal and mesolimbic dopaminergic pathways as well as neural circuits within the lateral hypothalamus are the neural systems most probably involved in drinking behavior 6-s'19'2°'25'27'30'36-38'4°. If ANG-ll-induced drinking in awake animals results, at least in part, from a direct influence on motor systems, then ANG-II may be capable of producing drinking-like rhythmic jaw movements in the anesthetized animal. The purpose of the present study was to determine whether administration of ANG-II to the anesthetized guinea pig would produce rhythmic jaw movements similar to those occurring during drinking in the awake animal and ARJMs in the anes-

Correspondence: G.E. Gerstner, Department of Oral Biology, School of Dentistry, Universityof California, Los Angeles, Los Angeles, CA 90024, U.S.A. 0006-8993/89/$03.50 © 1989Elsevier Science Publishers B.V. (Biomedical Division)

234 thetized preparation. Some of the results of this study have been reported elsewhere z3. MATERIALSAND METHODS

Animals Five adult male guinea pigs weighing 450-600 g were used in this study.

Drugs Atropine sulfate (0.1 mg, i.p.) and chlorpromazine HCI (5 rag, i.m.) were administered prior to an anesthetic dose of ketamine HCI (100 mg/kg, i.m.). A Sage infusion pump delivered a total dose of 1/~g of ANG-II (Hypertensin II, Sigma) dissolved in sterile 0.9% NaCl through the jugular cannula (see below) at a rate of 0.02 ml/min or 50 ng ANG-ll/min. At this rate, the iefusion was completed after 20 min. This protocol for i.v. ANG-II is similar to that used to elicit drinking in awake animals 32, and the dose is in the mid-range of that used by Robinson and Evered 32. At the termination of the experiments, the animals were sacrificed with a lethal dose of sodium pentobarbital.

Experiments The surgical procedure and experimental setup are detailed elsewhere 22. Briefly, a midline incision was made from the sternum to the mental symphysis on the inferior surface of the mandible. The right external jugular vein and trachea were cannulated. The anterior belly of the left digastric muscle was exposed, and bipolar EMG recording electrodes, consisting of a pair of wires (0.127 mm outside diameter, enamel coated except for 1-2 mm at the tip), were inserted using a 25-gauge hypodermic needle. The tip of each electrode was bent into a hook, allowing it to remain embedded in the muscle after the needle was removed. Electrode locations were verified post mortem. A hole was drilled in the ventral aspect of the mandible 2 mm lateral to the mandibular symphysis, and a small tungsten light bulb was screwed into this hole. This light served as a source for a photosensitive movement transducer that recorded jaw movements in the horizontal and vertical axes after the method of Byrd, et al. 1. After the EMG electrodes and tungsten light bulb were in place, lidocaine was infiltrated around the external auditory meatus, and then the

animal was placed in a Kopf stereotaxic instrument with the use of ear bars and the tooth plate. A lightsensitive transducer was placed 3-4 cm in front of the tungsten light bulb; one output of the transducer was proportional to the vertical, and the other to the horizontal mandibular movements. One to 2 h after the initial anesthetic dose of ketamine, the animals began to exhibit spontaneous rhythmic jaw movements (SRJMs), as has been previously reported 22. As soon as the SRJMs began, the ANG-II infusion was initiated. (In previous studies, supplemental anesthetic doses were not needed until 3-4 h after the initial anesthetic dose22.) During this period, SRJMs were the only movements observed, and the animals remained unresponsive to pinching of the ear or limb. In the current study, the ANG-II infusion lasted 20 min, and the animals were observed for a maximum time of 130 min after the observation of SRJM onset. Consequently, no supplemental anesthetic doses were needed during the experiments in the present study.

Data analysis Jaw movement trajectories and EMG activity were recorded on a Vetter FM tape recorder (0-2500 Hz frequency response) beginning 5 rain prior to ANG-II delivery, during the 20 rain of ANG-II infusion, and for 10-110 rain following the termination of ANG-II infusion. The data were subsequently recorded on a Grass polygraph. The polygraph record was divided into 2 min segments, with the onset of ANG-II infusion defining time zero. Each rhythmical jaw movement cycle was visually scored using vertical and horizontal movement criteria described in the Results section. Data segments, 10-120 s in length, were digitized (1 ms bin width) in a C~,mpaq Deskpro personal computer. The EMG data were full-wave rectified and filtered (80 Hz, low-frequency cutoff) by computer software (Run Technologies). Averaging of vertical and horizontal outputs of the movement transducer and jaw muscle EMG activities were performed with software developed by Run Technologies. RESULTS

SRJMs associated with ketamine anesthesia were observed in all animals. It has been hypothesized that

235 S l u M s are related to jaw movements occurring during mastication in the a w a k e animal ~2. S l u M s have been analyzed in detail elsewhere 22, but will be included here for comparison purposes. Fig. 1A shows 6 cycles of S l u M s . The uppermost trace in Fig. 1A shows the horizontal component of jaw movement, the middle trace the vertical component of jaw movement, and the bottom trace the E M G activity in the left digastric muscle. It is evident from Fig. 1A that S R J M s were characterized by prominent lateral jaw

movement trajectories as seen in the uppermost tiace. It is also evident from Fig. 1A that this horizontal movement was associated with both jaw opening and jaw closing movements. The horizontal movement occurred on the left side of the midline on some S l U M cycles and to the right side on others (note the dotted line depicting the midline in Fig. 1A). The 6 cycles shown in Fig. 1A show a regular pattern of alternation; the first cycle occurs on the left side of the midline, the next cycle on the right,

B

A

I '°°-v C

0

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O.S I

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Fig. 1. Relationship between jaw movement trajectories and EMG activity in the left digastric muscle during three separate rhythmic jaw movement profiles. Although A - F represent results from one animal, similar results were obtained from all animals. A: 6 spontaneous rhythmic jaw movements (SluMs) are displayed. Vertical and horizontal jaw movements are shown along with rectified EMG recordings from the left digastric muscle. B: averages of 49 left-sided SlUM cycles, including those from A. The trigger level occurs at the crossing of the vertical bar with the horizontal movement trace. C: 6 cycles of ANG-II-induced RJMs. The first 5 cycles have no horizontal jaw movement and are designated VRJMs (see text). D: averages of 47 VluM cycles, including the first 5 shown in C. The trigger level occurs at the crossing of the vertical bar with the EMG trace. E: 5 cycles of a second jaw movement profile associated with ANG-II infusion, the altered rhythmic jaw movements or ALT. F: averages of 16 ALT cycles including those shown in E. The trigger level occurs at the crossing of the vertical bar with the horizontal movement trace. The time calibration bars shown below E and F are the same for all traces in the respective columns. Arrows to the right of A, C, and E are equal to a 1 mm deflection in the adjacent vertical or horizontal jaw r "ovement trace.

236 etc., with a total of 3 cycles occurring on the left side, and 3 on the right side. In Fig. 1B, a total of 49 SRJM cycles from one animal, including those in Fig. 1A, were averaged. This average was obtained by triggering the averaging program on the horizontal component of the mandibular movement trajectory. The trigger level was adjusted to detect only horizontal movements to the left of the midline. SRJM cycles with horizontal movements to the right side were, consequently, excluded from this analysis. The trigger level is indicated by the intersection point of the vertical reference line and the horizomal movement trace (i.e. the top trace of Fig. 1B). The other two traces in Fig. 1B were also averaged with respect to that trigger. Note that the horizontal movement began at or near the initiation of jaw opening (Fig. 1B). The only rhythmic jaw movements (RJMs) associated with ketamine anesthesia were SRJMs (see also ref. 22). As soon as SRJM onset was observed, the angiotensin (ANG-II) infusion was begun. Six to 7 min after the ANG-II infusion was begun, SRJMs were gradually replaced by two novel rhythmic jaw trajectory, profiles; one of these profiles is shown in Fig. 1C,D, the other profile is shown in Fig. 1E,F. All 5 animals receiving the ANG-II infusion exhibited these two novel jaw movement profiles. Fig. 1C depicts 6 RJMs obtained from one animal approximately 6 min after the initiation of the ANG-II infusion. The data in this figure are in the same format as those in Fig. 1A. The first 5 cycles in Fig. 1C show a jaw trajectory profile that is characterized by vertical jaw movements with little or no horizontal jaw movement component, whereas the last cycle shows a jaw deflection in the horizontal trace as well as an increased deflection in the vertical trace. Because of the lack of horizontal movements, the particular profile typified by the first 5 cycles in Fig. 1C will be referred to as vertical-only rhythmic jaw movements (VRJMs). Fig. 1D shows the average of 47 VRJM cycles taken from the same animal as the data in Fig. 1C. Cycles with a horizontal movement component similar to that seen in the sixth cycle of Fig. 1C were excluded from this analysis. The format used in Fig. 1D is similar to that used in Fig. lB. The data shown in Fig. 1D were obtained by triggering the averaging program on the onset of digastric muscle E M q activity. The vertical reference line that intersects the EMG trace in Fig. 1D represents the trigger level.

The second of the two ANG-II-associated jaw trajectory profiles appears in Fig. 1E,F and is referred to as altered rhythmic jaw movements (ALT). The respective formats used in Fig. 1E,F are the same as those used in Fig. 1A,C and Fig. 1B,D. Fig. 1E depicts 5 cycles of the second ~orm of ANG-ll-induced jaw movements. Unlike VRJMs, the ALT profile had a significant horizontal movement component associated with it (top trace, Fig. 1E). Note that the horizontal movement occurred to the left side of the midline in each of the five iall cycles shown. Approximately 50% of the cycics of this jaw movement profile had such left-sided jaw trajectories and the other 50% were right-sided. However, unlike SRJMs 22, ALTs often had more tb~.~ three consecutive cycles occurring on the same s~de of the midline, as the examples in Fig. 1E,F show. In Fig. 1F, 16 consecutive left-sided cycles, including those shown in Fig. 1E, were averaged. The averaging program was set to trigger on the horizontal component of the mandibu-

A

C

t close right ~: 11 mm

Fig. 2. X - Y plots of the horizontal and vertical jaw movement components of three separate rhythmic jaw movement profiles of one animal. Thin arrows indicate the direction of jaw movement in A and B. The vertical arrow under A and B indicates the midlinc. Calibration bars arc the same for A-C. A: jaw trajectories of the SRJM profile. The dots on each side of the midline emphasize the lateral deviation of the jaw at maximum opening (see text). B: jaw trajectories of the ALT profile. C: jaw trajectories of the VRJM profile.

237 lar movement trajectory. The trigger was adjusted to detect only horizontal excursions to the left side of the midline. The intersection of the vertical reference line and the horizontal movement trace indicates the trigger level. Note that there was no horizontal movement associated with the onset of jaw opening, as was the case in SRJMs (Fig. 1A,B). The horizontal movement in ALTs occurred soon after the initiation of jaw closure. The jaw opening phase of both VRJMs and ALTs had little or no associated horizontal movement (Fig. 1D,i~). Also, prominent tongue protrusions were visually observed during the jaw opening phase of VRJMs and ALTs. Tongue protrusion was not observed during SRJMs. Rhythmical EMG activity in the left digastric muscle is seen in all three profiles (Fig. 1A,C,E). The horizontal and vertical jaw movement components associated with SRJMs, VRJMs, and ALTs were combined in X - Y plots to make the displays shown in Fig. 2. These plots correspond to a frontal plane view of each of the profiles. Although the data in Fig. 2 are from one animal, the same profiles were observed in all animals. The calibration bars are the same for Fig. 2A-C. Fig. 2A shows the jaw trajectories for SRJMs. The key feature of this jaw movement profile was the lateral excursion of the mandible that occurred during both the jaw opening and jaw closing phases of the cycle. Two dots on each side of the midline arrow in Fig. 2A emphasize the fact that there was a significant lateral deviation from the midline associated with maximum jaw opening. Fig. 2B shows the ALT jaw movement profile. As Fig. 2B demonstrates, there were no significant horizontal mandibular movements during jaw opening in ALTs, and at maximum jaw opening, there was no significant lateral deviation of the jaw. However, there was a prominent horizontal mandibular movement associated with jaw closing in ALTs, which was similar to that seen in SRJMs. Fig. 2C shows the VRJM profile. From this figure, it is apparent that relatively little or no lateral excursion of the jaw occurred in association with either jaw opening or closing movements. The jaw movements of this profile always occurred near the midline. Fig 3 demonstrates that VRJMs and ALTs increased in frequency of occurrence and then decreased as the ANG-II infusion progressed. The horizontal axis of Fig. 3 shows the number of minutes

lOO

13S~M

MALT

EEwJM

80. 60. 4o, 20, o 2

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6

8

10

12

14

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Fig. 3. The percentage of the total number of cycles represented by each of the three jaw movement profiles for twenty minutes after the initiationof ANG-II infusion. SRJMsare represented by striped bars, ALTs are represented by stippled bars, and VILIMsare represented by black bars. The frequency of occurrence of each jaw movementprofile is expressed as the percentage of total jaw movement cyclesoccurring in two min bins. The X axis shows the number of min after the initiationof the ANG-II infusion, the Y axis shows the percentage of total jaw movementcycles. Data were collected from 5 animals(see text). Lines above the bars represent 1 S.E.M.

after the initiation of the ANG-II infusion, and the vertical axis depicts the mean number of SRJM, VRJM, and ALT jaw movement cycles per 2 min bin expressed as a percentage of the total jaw movement cycles per bin. The bars represent the mean percentages for 5 animals, and the extensions above the bars represent 1 S.E.M. Fig. 3 was constructed by dividing the 20 min of ANG-II infusion into ten 2 rain bins. For individual animals, the total SRJM, VRJM and ALT cycles occurring in each 2 min bin were expressed as percentages of the total jaw movement cycles occurring in the appropriate bin. The group mean and standard error were then calculated from the means of the individual animals. Fig. 3 shows that during the first 4 min after ANG-II infusion initiation, only SRJMs were observed. By 5-6 min into the ANG-11 infusion, VRJM and ALT jaw movement cycles began to occur. Thereafter, both VRJM and ALT jaw movement cycles increased in occurrence, reached their maximum values between 9 and 14 min into the ANG-11 infusion, and then gradually decreased in occurrence. By rain 19 of the ANG-II infusion, only SRJMs were observed. The ANG-II infusion ended at min 20, a~d although all animals were observed for up to 130 rain following initiation of ANG-II infusion, only SRJMs were observed during the 19-130 rain time period.

238 DISCUSSION The results of the present study demonstrated that i.v. ANG-II infusion elicited RJMs in the anesthetized guinea pig. Two jaw movement profiles were associated with ANG-II infusion, one profile was characterized by the absence of significant horizontal jaw movements during both jaw opening and closing (VRJMs). The second profile (ALT) was characterized by the absence of significant horizontal deviations of the jaw during jaw opening and by large horizontal jaw movement deflections during jaw closing. The ALT profile was very similar to a jaw movement profile observed after a 2 mg/kg i.v. dose of apomorphine. ALTs are similar to VRJMs during the jaw opening phase of the cycle, and similar to spontaneous rhythmic jaw movements (SRJMs) during the jaw closing phase of the cycle (Figs. 1 and 2). It is possible that ALTs are a mixture of VRJMs and SRJMs. Further analysis of apomorphine- and ANGIf-induced ALTs will provide evidence to test this hypothesis. The VRJM profile was similar both to a jaw movement profile induced by i.v. apomorphine administration 22, and to jaw movements associated with drinking in the awake guinea pig 12. In a previous study 22, it was reported that apomorphine injections induced RJMs that were characterized by the absence of horizontal jaw movements during jaw opening and jaw closing phases of the cycle. It was subsequently established that the jaw movement profile associated with drinking in the awake guinea pig also lacked horizontal jaw movements and were similar to the apomorphine-induced jaw movements 12. Based on these results, it was hypothesized that apomorphine was activating brain dopaminergic circuits associated with drinking 12. The fact that apomorphine could induce drinking-like jaw movements in anesthetized animals indicated that these dopaminergic circuits were probably involved directly in the motor aspects of drinking, a finding supported by previous work done with awake animals 7,1s.3s. It was further hypothesized that dipsogens such as ANG-II could evoke drinking-like jaw movements in the anesthetized guinea pig ~2. It had already been shown in many studies that ANG-II was a powerful dipsogen 9-11'19. However, these studies all used awake animals, and it was difficult from such prepa-

rations to determine what specific aspects of drinking behavior (e.g. arousal, motivational, motor, etc.) were being influenced by the administration of ANGIf. In the anesthetized preparation, neural systems that contribute to arousal, and other motivational variables are presumably decoupled from motor systems; consequently, if a motor response is observed, this is strong preliminary evidence that the effects of ANG-II and apomorphine do not require reward or motivational brain states. Furthermore, the expression of this drinking-like response occurs without an appropriate environmental substrate at which to direct the behavior. The fact that ANG-II-induced jaw movements and ARJMs occur under these conditions lends considerable support to the hypothesis that ANG-II and dopamine play a direct role in activating ~eural circuits that produce the characteristic oral motor patterns associated with drinking. A future line of research will be to determine the mechanism underlying the induction of drinking behavior by dopamine and ANG-II. Currently, it is believed that nigrostriatal and mesolimbic dopaminergic systems, as well as neural circuits in the lateral hypothalamus are involved in the initiation and maintenance of drinking 6-8"19'2°'25'27'36-38'4°. It is also known that ANG-II binding sites are located in the subfornical organ as well as the anteroventral hypothalamus (AV3V) 11"15-17"23'26"35 (however, see ref. 39). It has been proposed that subfornicai organ cells project to the median preoptic nucleus area of the AV3V and use ANG-II as their neurotransmitter 23. The median preoptic nucleus also receives and integrates sensory information from several brainstem systems regarding body fluid states and projects, among other places, to the ventral tegmental area ~5-17' 23,28,35. The ventral tegmental area is the origin of the mesolimbic dopaminergic system, one of the systems thought to be involved with drinking initiation and maintenance 35, and inhibition of ventral tegmental area neurons by GABA has been shown to block ANG-lI-induced drinking 19'2°. At present, it is not known how these circuits are involved in the motor programs associated with drinking; however, it has already been determined that lesioning the superior colliculus disrupts apomorphine-induced rhythmic jaw movements, but spares rhythmic jaw movements evoked by electrical stimulation of the masticatory area of the cortex 2. It has yet to be determined

239 whether VRJMs or ALTs will be similarly disrupted by lesions in the superior colliculus, and what specific tract this lesion interrupts. Finally, future research will be needed to determine whether other bioactive compounds associated with drinking facilitation and water balance (e.g. antidiuretic hormone, acetylcholine, the other catecholamines, aldosterone, etc.) play a role in ANG-ll-induced drinking-like jaw movements. In conclusion, the results of the present study show that ANG-II infusion evokes drinking-like jaw movements that are similar to those previously observed following apomorphine administration in the anes-

thetized guinea pig22, and to those associated with

REFERENCES

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drinking in the awake animal 12. This finding supports the hypothesis that dopaminergic and angiotensinergic systems are involved in activating m o t o r system networks that produce jaw movements associated with drinking 7.12.14.18,22.28.

ACKNOWLEDGEMENT

This project was supported by the National Institute of Dental Research, Research Grant R01DE4166.

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