Review
Aggression and defeat: persistent effects on cocaine self-administration and gene expression in peptidergic and aminergic mesocorticolimbic circuits

https://doi.org/10.1016/j.neubiorev.2003.11.005Get rights and content

Abstract

The question of how ostensibly aversive social stress experiences in an aggressive confrontation can persistently increase intense drug taking such as cocaine ‘bingeing’ needs to be resolved. The biology of social conflict highlights distinctive behavioral, cardiovascular and endocrine profiles of dominant and subordinate animals, as seen also in rodents and primates under laboratory conditions. In contrast to continuous subordination stress that produces chronic pathophysiological consequences and often is fatal, animals adapt to brief episodes of social defeat stress, but show enduring functional activation in mesocorticolimbic microcircuits. Uncontrollable episodes of social defeat stress produce long-lasting tolerance to opiate analgesia and, concurrently, behavioral sensitization to challenges with either amphetamine or cocaine. One week after a single social defeat stress, cross-sensitization to cocaine is evident in terms of enhanced motor activity as well as in terms of increased Fos labeling in the periaqueductal grey area, the locus coeruleus, and the dorsal raphe nuclei. When challenged with a low amphetamine dose, the behavioral and neural effects of repeated brief episodes of social defeat stress persist for months. Previous exposure to social defeat stress can (1) significantly shorten the latency to acquire cocaine self-administration, (2) maintain this behavior at low cocaine unit doses, (3) significantly increase the levels of cocaine taking during a 24 h binge of continuous drug availability, (4) dysregulate the timing of consecutive infusions, and (5) abolish the circadian pattern of self-administration. Amygdaloid modulation, especially originating from central and basolateral nuclei, of dopaminergic pathways via peptidergic and glutamatergic neurons appears to be a key mechanism by which social defeat stress affects cocaine self-administration. Social stress alters the feedback from prefrontal cortex and thereby may contribute to the dysregulation of dopaminergic activity that is necessary for cocaine self-administration.

Introduction

Aggressive confrontations, like other salient life experiences, profoundly change neural activity in mesocorticolimbic circuits via genomic and non-genomic action [1], [2], [3], [4], even in adulthood when the stress-sensitive developmental period has long elapsed. Molecular biology tools make it possible to trace how specific experiential factors impact translational and transcriptional activity and eventually alter protein synthesis in specific mesocorticolimbic cells [5], and this cellular activity presumably influences the probability of future behavior during social conflict, affiliation and attachment [6], [7], [8], [9]. The feedback from salient social experiences to intracellular events in discrete neural circuits complements the constitutive tonic activity in these circuits.

The experience of offensive aggressive behavior and defeat is linked to cellular activation in neural circuits that are also critical in several stress disorders such as psychosis and post-traumatic stress disorder, and also in drug abuse [10], [11], [12]. This latter link has attracted considerable attention since it is the euphorogenic effects of drugs that are thought to lead to their self-administration, at least initially, which contrast with the ostensibly aversive nature of social stress. Even though aggressive confrontations are extremely stressful as indicated by endocrine and cardiovascular indices [13], [14], [15], individuals seek out the opportunity to engage in certain aggressive acts, and the performance of aggressive behavior can serve as a potent positive reinforcing event [16], [17], [18], [19]. Conversely, even though drugs such as cocaine are thought to be potent positive reinforcers under many circumstances [20], its anxiogenic effects have also been demonstrated under certain conditions [21], [22], [23]. One of the conceptual challenges is to delineate the neural integration of processes that are activated by apparently aversive stimulation such as social stress with those subserving the intensely rewarding stimulation by self-administered psychomotor stimulants.

Biologically significant and rewarding social interactions such as social bonding, sexual intercourse and aggressive behavior engender large and enduring changes in the cascade of protein synthesis starting at the transcriptional level. For example, when social attachment in a species with strong bonds is disrupted as during maternal separation, transcriptional factors are activated in discrete diencephalic and hippocampal neurons [24], [25]. The salience of sexual experiences at the cellular level is illustrated by transcriptional activation in the region of the extended amygdala and preoptic area [6], [26]. A further example is provided by behavior in social conflict, the offensive aggressor versus the defender who is eventually defeated, and the impact of these experiences on transcription and translation in mesocorticolimbic neurons, as reviewed below.

From a behavioral perspective, the term ‘social stress’ has been applied to both responses emerging from a discrete, brief confrontation between two individuals and, alternatively, to a more pervasive pattern of continuous interactions with the prevailing individual being referred to as dominant and the yielding individual as subordinate. In socially organized species such as certain insects, fish, and mammals, aggressive confrontations are rare; they are frequent and intense only during the establishment of a dominance hierarchy and during the breeding season [27], [28]. Once a hierarchy is established, the most dominant animal differs fundamentally from subordinate members in its behavioral, physiological and neurochemical responses to a stressor, even though the actual number of intense aggressive episodes remains relatively low.

The physiological cost of being subordinate is evident in various endocrine, immune and cardiovascular parameters, and in some species such as, for example, the tree shrew (Tupaia belangeri) the prognosis for survival of subordinates is poor [29], [30]. The presence of a dominant individual is sufficient to precipitate a deterioration of cardiovascular and endocrine regulation, and many submissive animals die within 2 weeks. Similarly, when longhaired rats (Rattus villosissimus) were introduced into an existing colony, about a third of the new members died after being attacked and threatened by the resident members, although no major wounds were detected [31]. Even in small breeding colonies of laboratory rats that are provisioned with clumped sources for food and water, subordinate members need to be rescued periodically in order to ensure their survival [32], [33]. When previously isolated CBA mice are aggregated in population cages, they show evidence for essential hypertension, develop sustained elevation in systolic blood pressure and renal failures [34]. Repeated conflict in unstable social groups results in increased risk of injuries, exposes the combatants to predatory attack, compromises the immune response to pathogens, diverts energies from reproductive activities and foraging, disrupts their circadian physiological rhythms, places prolonged demands on endocrine functions that result in gonadal atrophy and adrenal hypertrophy, and ultimately, shortens the lifespan [35], [36]. These risks are weighed against the potential benefits of access to fit mating partners with high reproductive success rate, high-quality diet and protected niches. As noted early on, aggressive behavior is present in all phyla, representing the behavioral tools with which individuals of different species achieve dispersion or aggregation [37].

An elaborate species-typical behavioral repertoire consisting of threat displays, pursuits, attack bites, and aggressive postures has evolved for the execution of offensive aggressive behavior. A distinctively separate pattern of behavior comprises defensive, submissive and flight responses. For example, when flight is barred, a rat defends and eventually assumes the submissive supine posture and emits loud and frequent ultrasonic distress calls, whereas a mouse displays an upright posture with the head angled upward, ears retracted, and forepaws limp (Fig. 1) [38], [39], [40], [41], [42], [43]. Mice and rats differ in their social organization, with the former living in aggregated colonies, and the latter patrolling, marking and defending territorial boundaries [44], [45]. Individuals differ considerably in how they respond to threats and aggressive displays by a dominant group member, with active and passive ‘coping styles’ having been characterized as the prevalent modes of behavior [46]. Even after having been attacked a single time, mice begin to show evidence for conditioning in their display of submissive responses even when interacting with non-aggressive animals [47].

But it is not solely the physiological burden that leads to the morbid course of subordinate animals; they are literally scared to death. It is the neural mechanisms that control the physiological and behavioral response patterns to the aggressive displays by dominant group members that have become the focus of investigation. Chronically subordinate rats and monkeys have begun to be characterized in terms of their monoaminergic, peptidergic and steroid systems [33], [48], [49], [50], [51]. Beginning with whole brain assays and progressing to assays of discrete brain regions, the early goal of deciphering a distinctive profile of catecholamine, serotonin, GABA and acetylcholine activity in dominant versus subordinate animals was not adequately realized at the mammalian level [52].

Brain serotonin is by far the most intensively studied neurochemical system that has been linked to dominance aggression and subordination stress as well as other forms of behavior in situations of social conflict [53], [54]. Studies from lobsters, crayfish, fire ants, and electric fish as well as vervet monkeys, rhesus macaques, talapoin monkeys and squirrel monkeys provides evidence for increased serotonergic activity but also for deficits in serotonin turnover, or no reliable changes both in the aggressing dominant and in the defending and submitting species member [55], [56], [57], [58], [59]. Long-term changes in peptidergic and aminergic receptors are induced by subordination stress as, for example, illustrated by significant reductions in the mRNA for mineralocorticoid and glucocorticoid receptors and lower 5-HT1A receptor density [33], [60]. One implication of long-term changes in receptor regulation due to subordination stress is their potential role in rendering an individual more or less vulnerable or resilient to environmental challenges or drug taking.

Under controlled laboratory conditions, it is possible to construct a history of salient social defeat experiences, and thereby to learn about the emerging neural changes that develop as a function of accruing defeat experiences without risking morbidity. This approach relies on the species-typical salient responses in a brief confrontation with an aggressive opponent such as specific defeat postures and vocalizations without fatal consequences. Continuous behavioral and physiological measurements indicate that the elevated glucocorticoid activity, tachycardia and hyperthermia take hours to recover after a brief confrontation with an aggressive opponent [15], [61]. Moreover, brief episodes of social defeat stress induce enduring neuroadaptations that are evident weeks and months after termination after the stress experiences.

During defeat in a brief aggressive confrontation a very large sympathetic and adrenocortical activation is evident, followed by a parasympathetic rebound [13]. Both the attacking and the defending combatants are tachycardic, hypertensive, and hyperthermic in the initial phase of the confrontation. The defeated individual incurs these physiological costs much longer than the winning opponent. It requires ca. 3–4 h for a defeated rat to recover normal heart rate and core temperature after a 10-min confrontation with an aggressive resident rat (Fig. 2) [61]. When a rat experiences social defeat stress on repeated occasions, there is no indication of adaptation to the tachycardic or hyperthermic response [62]. During the first half-hour of the confrontation, plasma corticosterone levels in the resident aggressive rat increase at a rate that is similar to that in the defeated opponent. Thereafter, corticosterone continues to rise in the defeated rat and requires 24 h to recover baseline levels. By contrast, corticosterone levels in the aggressive animal return to the normal range within a few hours after the confrontation [15]. The prolonged glucocorticoid activation due to brief episodes of social defeat stress is also accompanied by reduced antibody production indicating a compromised immune system [63], [64].

Social defeat stress in a brief confrontation profoundly impacts on aminergic and peptidergic systems in the brain. For example, early evidence pointed to noradrenergic activation in the cortex after episodes of intense fighting in mice [65]. Considerable post-mortem assay data indicate that dopamine turnover in limbic forebrain structures is increased in mice and rats that defend against attacks [66], [67], [68]. Using in vivo microdialysis, the rise in accumbal and cortical, but not striatal, dopamine was seen in rats that were threatened by an aggressive opponent (Fig. 3) [69]. Notably, a similar rise in accumbal and cortical dopamine is seen in resident rats that engage in attack and threat behavior [2]. Neither the increases in cortical norepinephrine nor in dopamine appear to be specific markers for defensive or submissive behavior, but rather indicate a role in arousal, attention, and preparation for salient events. Substantial rises in serotonin turnover and in the firing rate of 5-HT-containing raphe cells were recorded during intense defensive reactions by tree shrews (T. belangeri) [70], [71]. Increased 5-HT release in hippocampal, amygdaloid and prefrontal cortical 5-HT and 5-HIAA was also evident in rats reacting to a potential predator, but similar increases accompanied responses to various challenges such as, for example, stress-induced feeding [72]. It is evident that social stress profoundly alters the activity in aminergic neurons, but a variety of salient events produce similar changes in catecholaminergic and serotonergic pathways indicating that these changes are not specific to the initiation of aggressive behavior or social stress responses.

Section snippets

Aggressive experiences and immediate early gene expression

The propensity to engage in aggressive behavior is influenced by genes, as demonstrated by classic strategies of selective breeding, strain comparisons, and quantitative trait loci analyses [73], [74], [75]. Superimposed on the complex traits for different kinds of aggressive behavior are the experiential factors that contribute to the display of these behaviors. Evidence is accruing to show that both the individual initiating and winning an aggressive confrontation as well as the defending and

Acknowledgements

The authors would like to thank Mr J. Thomas Sopko for his exceptional technical assistance. Preparation of this review and the original research from our own laboratories were supported by USPHS research grants AA13983, DA02632, a grant from the Alcoholic Beverage Medical Research Foundation (KAM, PI), DA14327 (EMN) and MH066954 (RPH).

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