József Haller

The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxiety

The aim of this study was to compare the effects of the genetic and pharmacological disruption of CB1 cannabinoid receptors on the elevated plus‐maze test of anxiety. In the first experiment, the behaviour of CB1‐knockout mice and wild‐type mice was compared. In the second experiment, the cannabinoid antagonist SR141716A (0, 1, and 3 mg/kg) was administered to both CB1‐knockout and wild type mice. Untreated CB1‐knockout mice showed a reduced exploration of the open arms of the plus‐maze apparatus, thus appearing more anxious than the wild‐type animals, however no changes in locomotion were noticed. The vehicle‐injected CB1‐knockout mice from the second experiment also showed increased anxiety as compared with wild types. Surprisingly, the cannabinoid antagonist SR141716A reduced anxiety in both wild type and CB1 knockout mice. Locomotor behaviour was only marginally affected. Recent evidence suggests the existence of a novel cannabinoid receptor in the brain. It has also been shown that SR141716A binds to both the CB1 and the putative novel receptor. The data presented here supports these findings, as the cannabinoid receptor antagonist affected anxiety in both wild type and CB1‐knockout mice. Tentatively, it may be suggested that the discrepancy between the effects of the genetic and pharmacological blockade of the CB1 receptor suggests that the novel receptor plays a role in anxiety.

Context-dependent effects of CB1 cannabinoid gene disruption on anxiety-like and social behaviour in mice.

Contrasting data were reported regarding the effects of cannabinoids on anxiety and social behaviour in both animals and humans. The cognitive effects of cannabinoids and their interactions with the HPA‐axis raise the possibility that cannabinoid effects are context but not behaviour specific. To assess this hypothesis, we submitted CB1 receptor knock‐out (CB1‐KO) and wild‐type (WT) mice to tests, which involved similar behaviours, but the behavioural context was different. The elevated plus‐maze test was performed under less and more anxiogenic conditions, i.e. under low and high light, respectively. We also compared the social behaviour of the two genotypes in the resident/intruder and social interaction tests. Both tests represent a social challenge and induce similar behaviours, but involve different contexts. The behaviour of CB1‐KO and WT mice was similar under low light, but CB1 gene disruption increased anxiety‐like behaviour under the high light condition. CB1 gene disruption promoted aggressive behaviour in the home‐cage, whereas it inhibited social behaviour in the unfamiliar cage. Thus, the anxiogenic‐like effect was restricted to the more stressful unfamiliar environment. These data suggest that the effects of CB1 gene disruption were context and not behaviour specific. Novelty stress resulted in higher ACTH levels in CB1‐KOs than in WTs, which suggests that context dependency occurred in conjunction with an altered HPA axis function. The present data at least partly explain contrasting effects of cannabinoids in different contexts as well as in different species and strains that show differential stress responses and coping strategies.

Corticosterone response to the plus-maze: High correlation with risk assessment in rats and mice

Exposure to the elevated plus-maze induces behavioural and physiological effects in rodents consistent with fear/anxiety. Maze-naive animals display high levels of risk assessment towards the open arms, and explore these areas less extensively than other parts of the maze while, immediately following the test, pain latencies, skin conductance levels, and plasma corticosterone titres (CORT) are significantly elevated. Although previous research has suggested a link between the plasma CORT response and open-arm exploration, significant elevations in CORT have also been found with restricted exposure to the closed arms. The present study employed ethological measures in an attempt to further characterise the relationship between behavioural and CORT responses to this widely used animal model of anxiety. Our results confirm that, relative to home-cage controls, 5-min exposure to the plus-maze significantly increases plasma CORT levels in test-naive male Wistar rats and male Swiss-Webster mice. Furthermore, in both species, the CORT response was found to be highly correlated with measures of risk assessment (mice: rs = +0.87; rats: rs = +0.58), but not with measures of open-arm activity (entries, time), general locomotor activity, rearing, or head dipping. Findings are discussed in relation to the functional significance of risk assessment in potentially dangerous situations and the potential involvement of glucocorticoids in this process. All rights reserved.

Non-genomic effects of glucocorticoids in the neural system: Evidence, mechanisms and implications

Complementing the classical concept of genomic steroid actions, here we (i) review evidence showing that important neural effects of glucocorticoids are exerted by non-genomic mechanisms; (ii) describe known mechanisms that may underlie such effects; (iii) summarize the functions and implications of non-genomic mechanisms and (iv) outline future directions of research. The role of non-genomic mechanisms is to shape the response of the organism to challenges that require a substantial reorganization of neural and somatic functions and involve massive behavioral shifts. Non-genomic effects may (i) prepare the cell for subsequent glucocorticoid-induced genomic changes, (ii) bridge the gap between the early need of change and the delay in the expression of genomic effects and (iii) may induce specific changes that in some instances are opposite to those induced by genomic mechanisms. The latter can be explained by the fact that challenging situations require different responses in early (acute) and later (chronic) phases. Data show that non-genomic mechanisms of glucocorticoid action play a role in both pathological phenomena and the expression of ameliorative pharmacological effects. Non-genomic mechanisms that underlie many glucocorticoid-induced neural changes constitute a for long overlooked controlling factor. Despite the multitude and the variety of accumulated data, important questions remain to be answered.

Defeat is a major stressor in males while social instability is stressful mainly in females: towards the development of a social stress model in female rats

Social stress models appear useful in elucidating the interrelationship between stress, mood disorders, and drug efficacy. However, reliable social stress models for females are virtually lacking. The aim of this study was to determine stress-related consequences of (a) defeat in aggressive encounters and (b) social instability, in male and female rats. Defeat in male and female subjects was induced by aggressive male residents and female residents made aggressive by surgery (mediobasal hypothalamic lesion [MBHL]), respectively. Aggressiveness of resident males and resident MBHL females was remarkably similar. Alternating isolation and mixed-sex crowding phases with membership rotation were used to induce social instability. Aggression was kept low in the latter paradigm by manipulating crowding group composition. Defeat stress reduced weight gain, and increased both adrenals and plasma corticosterone in males. Only adrenal weight was affected in females. Social instability reduced weight gain, and induced thymus involution, adrenal hypertrophy and elevated plasma corticosterone levels in females. Only weight gain and thymus weights were affected in males. It is concluded that defeat stresses males more than females, while social instability is more stressful for females than for males, if aggressive contacts are low. It is suggested that the social instability model is a good model of social stress in females.

Genomic and non-genomic effects of glucocorticoids on aggressive behavior in male rats.

An increasing body of evidence suggests that glucocorticoids--besides their well-known genomic effects--can affect neuronal function via mechanisms that do not involve the genome. Data obtained mainly in amphibians and birds suggest that such mechanisms play a role in the control of behavior. Acute glucocorticoid treatments increase aggressive behavior in rats, but the mechanism of action has not been investigated to date. To clarify the issue, we have assessed the aggressiveness of male rats after treating them with the corticosterone synthesis inhibitor metyrapone, corticosterone, and the protein synthesis inhibitor cycloheximide. Metyrapone applied intraperitoneally (i.p.) decreased the aggressiveness of residents faced with smaller opponents. Corticosterone administered i.p. 20 or 2 min before a 5-min encounter abolished these changes irrespective of the delay of behavioral testing. Thus, the effects of glucocorticoids on aggressive behavior occurred in less than 7 min (the delay and duration of testing taken together), and lasted more than 25 min. Corticosterone applied centrally (infused into the right lateral ventricle) also stimulated aggressive behavior rapidly, which shows that the effect was centrally mediated. The protein synthesis inhibitor cycloheximide did not affect the aggression-promoting effects of corticosterone when the hormone was injected 2 min before the aggressive encounter. Surprisingly, however, the effects were completely abolished when the hormone was injected 20 min before the encounter. These data suggest that glucocorticoids rapidly increase aggressive behavior via non-genomic mechanisms. In later phases of the aggressive encounter, aggressive behavior appears to be stimulated by genomic mechanisms.

Fast positive feedback between the adrenocortical stress response and a brain mechanism involved in aggressive behavior.

Aggressive behavior induces an adrenocortical stress response, and sudden stressors often precipitate violent behavior. Experiments in rats revealed a fast, mutual, positive feedback between the adrenocortical stress response and a brain mechanism controlling aggression. Stimulation of the aggressive area in the hypothalamus rapidly activated the adrenocortical response, even in the absence of an opponent and fighting. Hypothalamic aggression, in turn, was rapidly facilitated by a corticosterone injection in rats in which the natural adrenocortical stress response was prevented by adrenalectomy. The rapidity of both effects points to a fast, mutual, positive feedback of the controlling mechanisms within the time frame of a single conflict. Such a mutual facilitation may contribute to the precipitation and escalation of violent behavior under stressful conditions.

Stress and the social brain: Behavioural effects and neurobiological mechanisms

Stress often affects our social lives. When undergoing high-level or persistent stress, individuals frequently retract from social interactions and become irritable and hostile. Predisposition to antisocial behaviours — including social detachment and violence — is also modulated by early life adversity; however, the effects of early life stress depend on the timing of exposure and genetic factors. Research in animals and humans has revealed some of the structural, functional and molecular changes in the brain that underlie the effects of stress on social behaviour. Findings in this emerging field will have implications both for the clinic and for society.

Catecholaminergic involvement in the control of aggression: hormones, the peripheral sympathetic, and central noradrenergic systems.

Noradrenaline is involved in many different functions, which all are known to affect behaviour profoundly. In the present review we argue that noradrenaline affects aggression on three different levels: the hormonal level, the sympathetic autonomous nervous system, and the central nervous system (CNS), in different, but functionally synergistic ways. Part of these effects may arise in indirect ways that are by no means specific to aggressive behaviour, however, they are functionally relevant to it. Other effects may affect brain mechanisms specifically involved in aggression. Hormonal catecholamines (adrenaline and noradrenaline) appear to be involved in metabolic preparations for the prospective fight; the sympathetic system ensures appropriate cardiovascular reaction, while the CNS noradrenergic system prepares the animal for the prospective fight. Indirect CNS effects include: the shift of attention towards socially relevant stimuli; the enhancement of olfaction (a major source of information in rodents); the decrease in pain sensitivity; and the enhancement of memory (an aggressive encounter is very relevant for the future of the animal). Concerning more aggression-specific effects one may notice that a slight activation of the central noradrenergic system stimulates aggression, while a strong activation decreases fight readiness. This biphasic effect may allow the animal to engage or to avoid the conflict, depending on the strength of social challenge. A hypothesis is presented regarding the relevance of different adrenoceptors in controlling aggression. It appears that neurons bearing postsynaptic alpha2-adrenoceptors are responsible for the start and maintenance of aggression, while a situation-dependent fine-tuning is realised through neurons equipped with beta-adrenoceptors. The latter phenomenon may be dependent on a noradrenaline-induced corticosterone secretion. It appears that by activating very different mechanisms the systems working with adrenaline and/or noradrenaline prepare the animal in a very complex way to answer the demands imposed by, and to endure the effects caused by, fights. It is a challenge for future research to elucidate how precisely these mechanisms interact to contribute to functionally relevant and adaptive aggressive behaviour.

Effects of Endocannabinoid System Modulation on Cognitive and Emotional Behavior

Cannabis has long been known to produce cognitive and emotional effects. Research has shown that cannabinoid drugs produce these effects by driving the brain’s endogenous cannabinoid system and that this system plays a modulatory role in many cognitive and emotional processes. This review focuses on the effects of endocannabinoid system modulation in animal models of cognition (learning and memory) and emotion (anxiety and depression). We review studies in which natural or synthetic cannabinoid agonists were administered to directly stimulate cannabinoid receptors or, conversely, where cannabinoid antagonists were administered to inhibit the activity of cannabinoid receptors. In addition, studies are reviewed that involved genetic disruption of cannabinoid receptors or genetic or pharmacological manipulation of the endocannabinoid-degrading enzyme, fatty acid amide hydrolase (FAAH). Endocannabinoids affect the function of many neurotransmitter systems, some of which play opposing roles. The diversity of cannabinoid roles and the complexity of task-dependent activation of neuronal circuits may lead to the effects of endocannabinoid system modulation being strongly dependent on environmental conditions. Recent findings are reviewed that raise the possibility that endocannabinoid signaling may change the impact of environmental influences on emotional and cognitive behavior rather than selectively affecting any specific behavior.