Dolor

Volume 3, pages 277-288

©1977 Alan R. Liss, Inc.

The Medial Amygdala: Serotonergic Inhibition of Shock-Induced Aggression and Pain Sensitivity in Rats

R. J. Rodgers

Postgraduate School of Studies in Psychology. University of Bradford.

Bradford, England

Abstract

Two aspects of the amygdaloid complex (corticomedial and basolateral) were examinedwitli reference to serotonergic inliibition of shock-induced aggression.

Fighting was significantly depressed by serotonergic stimulation (5-MT, 10 u% bilateral)in the cortieomedial amygdala while serotonergic blockade (metliysergide,5 tigbilateral) in this region increased levels of fighting. No consistent effects wereobtained with serotonergic manipulation of the basolateral amygdala.

Further investigation revealed that the stale of serotonergic activity in medialamygdaloid sites was associated with concomitant alterations in the animals'sensitivity to footshock. Results are discussed in relation to a) a general inhibitoryrole of serotonin irbehavioural mechanisms and b) a dopaminergic-serotonergicbalance for behavioural arousal involving medial amygdaloidnudei.

Key words: rat, shock-induced aggression, pain sensitivity, amygdala, serotonin, inhibition

INTRODUCTION

In recent years, central serotonergic (5-HT) mechanisms have been implicatedin the inhibitory control of various fomis of aggressive behaviour. Reductions ofserotonergic activity by PCPA injection have been reported to increase inter-malefighting in mice (Essman et al, 1974), irritability (Koe and Weissman, 1966) andhome-cage aggression (Sheard, 1973) in rats, and predatory attack in both cats(Ferguson et al, 1970)and rats(DiChiaraet al, 1971; Eichelman and Thoa, 1973;Manuscript received January 20, 1977; accepted February 9. 1977Address reprint requests to R. J. Rodgers, Postgraduate School of Studies in PsychologyKarli et al. 1969; McLain et al, 1974; Miczek et al. 1975; Vergnes. Mack et al,1974b). 

Similarly, lesions of the serotonin-containing cell bodies in the raphe systemincrease home-cage aggression (Sheard, 1973) and muricidebehaviour (Grantet al, 1973; Vergnes, Mack et al, 1974b; Vergnes, Boehrer et al. i974a) in rats.Conversely, increased serotonergic activity by injection of the 5-HT precursor,dl-5HTP, inliibits isolated-induced fighting in mice (Hodge and Butcher, 1974)and rat muricidalbehaviour (DiChiaraetal. 1971; Kulkarni, 1968 and 1970;Miczek et al, 1975; Vergnes, Mack et al, 1974b).

Less consistent results have been obtained in studies on shock-induced aggression(SIA). Depletion of brain serotonin by PCPA has been reported to increase(Butcher and Dietrich, 1974; Ellison and Bresler. 1974), have no effect on (Conneret al, 1970; Eichelman and Thoa, 1973; McLain et al, 1974) or to decrease(Anandet al, 1976) levels of SIA. Lesionsof the dorsal, but not the medial, raphenuclei increase SIA by 83% over control levels of fighting (Jacobs and Cohen, 1976).

The amygdaloid complex has long been known to exert an importantmodulatory influence upon aggressive behaviour in many species (rat: Eichelman,1971; hamster: Bunnell et al, 1970; cat: Kaada, 1969; monkey: Rosvoldetal,1957; man: Mark and Ervin. 1970). Most of these reports have suggested that theamygdala facilitates aggressive responding, with lesions resulting in a "tamingeffect." However, data exists indicating that the amygdala may also exett aninhibitory influence over certain forms of aggressive behaviour, lesions resultingin increased aggression (Bard and Mountcastle, 1948; Schreiner and Kling, 1953;Utsin, 1965; Wood, 1958). This apparent confusion may be explained by stressingthe fact that the amygdala is a nonhomogenous structure, consisting of a complexof nuclei with differing afferent and efferent connections (Hall. 1972; Lammers.1972;deOlinos. 1972).

Earlier reports have implicated cholinergic facilitation of SAI in the basolateralaspect of the amygdaloid complex (Rodgers and Brown. 1976). Since evidenceexists for serotonergic terminals in both aspects of the amygdaloid complex(Aghajanian, 1976. Eidelberg et al. 1967; Saavedra et al, 1974).the present paperinvestigates the possibility that 5-HT may exert its inhibitory effect upon SIAthrough this complex sub-cortical structure. Indeed, two procedures known to increase muricidebehaviour in the rat, olfactory bulbectomy and raphe lesions,decrease serotonin in the amygdaloid area (Karli et al, 1969; Vergnes. Mack et al,1974b), perhaps reflecting decreased inhibition of aggressive responding.

MATERIALS AND METHODS

Animals

Adult male Sprague-Dawley rats, ftom Bradford University colony, were usedin this study. Subjects were individually housed with food and water available adlibitum. All animals were maintained on a 12-hr light-dark cycle and testing was performed under red light during the dark phase of the cycle, i.e., 7 p.m. onwards.

Surgery

Subjects were bilaterally implanted with guide cannulae under Equithesinanaesthesia (Jensen-Salsbery Lab., Inc.). Cannulae consisted of a 0.6-mm o.d.stainless-steel guide, fitted with a 0.3-mm o.d. stylet. During injection, styletswere replaced by 0.3-mm injection cannulae. Guides were constructed such thateach terminated 2 mm dorsal to the desired injection site; injection cannulae weredesigned to protrude 2 mm beyond the tip of the guides. After surgery, eachanimal received an intramuscular injection of penicillin (50.000 units) andallowed at least 10 days postoperative recovery.

Stereotaxic Coordinates

Implantation co-ordinates were based on adjusted calculations derived fromthe atlas on Konig and Klippel (1963): Basolateral amygdala (+5.2, ± 5.0.8.5down) and corticomedial amygdala (+5.0, ± 4.0,9.5 down). Anterior-posteriorvalues were calculated with reference to stereotaxic zero.

Apparatus

A modified rat operant station (manipulanda removed, flat interface). Measuring 23.5 X 22 X 22 cm served as the test chamber for both the aggressionand pain sensitivity tests. The chamber was opaque apart from the perspex doorwhich also served as an observation window. An Aim Biosciences shock generator(model 507) and programming equipment supplied scrambled electric shock ofspecified intensity, duration, and frequency to the grid floor of the test chamber.

Drugs

Serotonin creatininesulphate complex (Sigma Chemical Co.) was used in asolution of 10 mg/ml. Methysergidebimaleate (Sandoz Products Ltd.) was usedin a solution of 5 mg/ml. Serotonin was dissolved in distilled water. Distilled waterwas used as the control injection. To aid the solubility of methysergide, 1 dropof 5 N HCl was added to the distilled water, a similar solution being used forthe control injection.

Histology

Before sacrifice, animals received bilateral injection of 0.1 /iltrypan blue toaid localization of injection sites. Animals then received an overdose of Nembutaland were perfused with physiological saline followed by 10% formal saline. Brainswere removed, hardened in formalin, and examined for injection sites followingsectioning on a freeze microtome.

EXPERIMENT 1 - SHOCK INDUCED AGGRESSION

Subjects

Twenty rats were randomly divided into two equal groups. One group servedas unoperated fight opponents while the other group was subdivided into twooperation groups. Group I (n = 5) was bilaterally implanted with guide cannulaeaimed at the basolateral amygdala (BLA) and Group II (n = 5) was implanted inthe corticomedial amygdala (CMA).

Procedure

Operated animals and unoperated fight opponents were matched for weightand fighting pairs placed in the test chamber where they were allowed 5 min explorationbefore testing commenced. Sixty pre-injection shocks (2 mA intensity;0.5 sec duration, 6/min) were delivered to the grid fioor in order to establishbaseline levels of responding. The responses were recorded as a) no response,b) upright threat posture, and c) fight/attack response. An attack response was recorded when one animal made a directed forward movement towards anopponent either by lunging with its whole body or by striking with the forepaws.

On four separate occasions (48 hr intersession interval) baselines wereestablished for each fighting pair, after which they received 1 {A bilateral injectionof either serotonin (10 jUg), serotonin vehicle, methysergide (5 )jg), or methysergidevehicle and were immediately retested with a further 60 shocks. All treatmentswere administered in a randomized sequence.

Results

Data was analysed using 2-tailed correlated t tests, comparing baseline againstresponse.

Had any consistent effect upon levels of SIA, when injected into the BLA animals.However, when injected into the CMA, serotonin produced a 40% decrease in SIA(p < 0.001), while vehicle was without effect. Conversely, methysergide injectioninto the CMA produced a 46% increase in levels of SIA (p < 0.01). Again. Vehicle was without effect.

Figure 2 gives histological summaries of the area covered by injection sites ineach of the two amygdala groups. Although one set of CMA injections were veryclose to the ventral surface of the brain, the results were in the same direction asthe rest of the group and were included in the data analysis.The results of this experiment indicate that serotonergic inhibition of SIAoperates through a forebrain system involving the corticomedial, but not thebasolateral, amygdala. However, since changes in 5-HT in the forebrain have beenlinked to alterations in pain sensitivity (Lints and Harvey, 1969; Yunger andHarvey, 1973), it was considered appropriate to perform another experiment to test the possibility that the present effects on aggression were merely secondaryto changes in pain sensitivity.

 

CORTICOMEDIAL BASOLATERAL

AMYGDALA SITE

Fig, 1. Mean attack frequencies {t standard deviation) for injected animals under various

surgical and drug conditions. B) baseline, S) serotonin (10 /igbilat), M) methysergide

(5 Hg bilat), V) appropriate vehicle control injection.     

 

EXPERIMENT 2 - PAIISI SENSITIVITY

Subjects and Procedure

Five naive rats were bilaterally implanted with guide cannulae aimed at thecorticomediai amygdala.Pain thresholds were measured using a modified "flinch-jump" threshold test(Evans, 1961; Rodgers and Brown, 1976). Animals were placed individually inthe test chamber and received 6 series of 8 shocks (0.5 sec duration) delivered at10 sec intervals to the grid floor. Shock series were administered in ascendingand descending order with intensities ranging betweeti 0.16-1.3 mA in eiglitsteps. Only jump thresholds (the intensity at which the animals' hind feet leavethe grid floor) were recorded since it has been suggested that flinch thresholdsare unreUable indicators of pain sensitivity (Evans, 1961). Thresholds weredetermined for each shock series and an overall mean value calculated to yield a pre-injection basehne.

Ajiimals then received bilateral injections of either serotonin (10 jUg), orserotonin vehicle, methysergide (5 /ig), or methysergide vehicle and wereimmediately retested. Each animal received all injections over a period of 10 days.All treatments were administered in a randomized sequence.

Results

Data was analyzed using 1-tailed correlated t tests, comparing baseUnesagainst responses.Injections of serotonin into the CMA resulted in a significant elevation in jumpthresholds (Baseline 0.81 ± 0.04 mA/Response 0.87 ± 0.05 mA; t =-8.25, df = 4,p < 0.005) whereas vehicle was without effect (Baseline 0.80 ± 0.04 mA/Response 0-82 ±0,03 mA; t =-1.31, n.s.).Conversely, methysergide injection into CMA produced a significant decreasein jump thresholds (Baseline 0.77 ±0.05 mA/Response 0.69 ±0.05 mA; t =2.81,df = 4, p < 0.05) while vehicle was ineffective (Baseline 0.77 ± 0.04 mA/Response0.78 ± 0.04 mA;t =-1.96, n.s.).Histological examination indicated that injection sites were indistinguishablefrom those reported in Experiment 1 (Eig. 2). Results from this experiment strongly suggest that serotonergic manipulationof the amygdala ahers aggression indirectly via changes in the animals sensitivityto electric shock.

DISCUSSION

This study suggests that within the amygdaloid complex, 5-HT mediates aninhibitory influence over aggressive responding and shock sensitivity. Although5-HT is equally distributed in the amygdaloid nuclei (Saavedra et al., 1974),these particular behavioural effects are seen specifically in relation to the corticomediaiaspect of this complex. Present data are in agreement with earlier findingsand related hypotheses concerning the role of 5-HT in other forms of aggressivebehaviour: Vergnes, Boehrer et al (1974a) and Kulkarni (1968) have independentlysuggested that the amygdala may be the critical focus for the mediation ofserotonergic inhibition of muricide while Sheard (1969) proposed the amygdalaas important in the increased irritability and aggressiveness seen in rats followingPCPA injection. Further confirmation of serotonergic inliibition in the amygdalahas been provided by the electrophysiological studies of Eidelberg et al (1967)

andAghajanian (1976).However, caution should be exercised with respect to the overall interpretationof all these results. A major complicating factor in studies of serotonergic inhibitionof aggression is that this transmitter system appears to exert a general inliibitoryeffect upon behaviour and that its depletion leads to heightened reactivity(commented upon at length by Vergnes, Boehrer et al, 1974a). Depletion of forebrain5-HT by medial forebrain bundle (MFB) lesions {Harvey and Lints, 1965,1971; Lints and Harvey, 1969; Yunger and Harvey, 1973) or PCPA injection(Harvey and Lints, 1971; Tenen, 1967, 1968) increases responsiveness to painfulstimulation. Similarly, raphe lesions also increase responsiveness to pain (Blasiget al, 1973; Proudfit and Anderson, 1975), but reports also exist indicating noeffeet of such lesions on pain responses (Hole and Lorens, 1975; Jacobs and Cohen,1976). Median raphe lesions increase open-field activity and etnotionality (Jacobsand Cohen, 1976; Vergnes, Boehrer et al, 1974a).Evidence for central serotonergic inhibition of behaviour also derives fromcentral injection studies. Intraventricular injection of 5-HT inhibits the startleresponse to air puffs (Geyer et al, 1976), intrahypothalamic 5-HT inhibitsaversive responding (LeRoux and Myers, 1975) and wliileintraseptal 5-HTinhibits pain sensitivity, injections of the 5-HT blocker, cinnanserin, into thesame area increases pain sensitivity (Persip and Hamilton, 1973).

The results of the present experiment appear to fit the general framework ofthese findings. Serotonergic stimulation of the corti come dial amygdala inhibitsnot only aggression but also pain sensitivity while serotonergic blockade(methysergide) has the opposite effect.It has earlier been reported that dopaminergic stimulation in the corticomedialamygdala facilitates SIA and pain sensitivity, an effect perhaps related to generaldopaminergic facilitation of behavioural arousal (Rodgers et al, 1976). Currentdata indicate serotonergic inhibition of the same behaviours within the sameamygdaloid region. Together, these findings may implicate the amygdala as acritical focus for the serotonergic inhibition of catecholamine-induced arousal(Mabry and Campbell, 1973). In view of the extensive sensory contribution tothe amygdala (Gloor, 1960; Goddard, 1964), it may be the case that a "balance"between 5-HT and dopamine in the corticomedial amygdala (dependent uponsensory input?) determines the threshold for release of aggression by thecholinergic basolateral amygdala. This infiuenee may be mediated to lower midbraineffector meehanisms(Bandler, 1973) via the ventral amygdalofugal pathway,lateral hypothalamus, and associated descending MFB connections, all of whichcontain cholinergic components implieated in the control of aggression (seeRodgers and Brown, 1976). Electrolytic lesions of all these structures decreaseaggression (Eichelman, 1971; Hilton and Zbrozyna, 1963; Karli et al, 1969;Miczek et al, 1974; Rodgers and Brown, 1976; Ursin and Kaada, 1960a, b).Alternatively, the serotonergie inhibitory influence tnay be mediated via themore indirect striaterminalis route through the ventromedial hypothalamus tothe lateral hypothalamus. Lesions of the striaterminalis (Mabry and Campbell,1975; Ursin, 1965) and ventromedial hypothalamus (Adams, 1971; Eclancher andKarli, 1971; Eichelman, 1971; Grossman, 1972; Panksepp, 1971) are known to

increase aggression, presumably through disinhibition. Present results do notallow the selection of either alternative hypothesis. However, Bell (personalcommunication) has found that serotonergic inhibition within the lateral hypothalamusresults in increased levels of SIA and pain sensitivity, while serotonergiestimulation decreases both of these behaviours. This would indicate that thesecond alternative is the more likely explanation at the moment.

ACKNOWLEDGMENTS

The author wishes to thank Sandoz Products Ltd., for their kind gift of !methysergidebimaleate. Thanks also to Mike Crowley, Dick Goundry, andPenny Walker for invaluable technical and secretarial assistance during this study.

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BIBLIOGRAFIA

Rodgers, R. (1977). The Medial Amygdala: Serotonergic Inhibition of Shock-Induced Aggression and Pain Sensitivity in Rats.  Liss, Inc. Volume 3, pages 277-288. Bradford, England