Review
Endocannabinoid system and stress and anxiety responses

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Abstract

Cannabinoid agonists induce complex and often contradictory effects on anxiety in humans and experimental animals. The data from animal tests provide evidence of dose-dependent bidirectional modulation of anxiety by the cannabinoid system and the importance of environmental context. The mechanisms mediating the effects of cannabinoids on anxiety-related responses appear to involve CB1 and non-CB1 cannabinoid receptors. In addition, the CRH, GABAA, cholecystokinin, opioid and serotonergic systems have also been implicated. Brain regions such as the amygdala, hippocampus and cortex, directly involved in the regulation of emotional behavior, contain high densities of CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic-like and depressive-like phenotypes in several tests, as well as profound alterations in their adrenocortical activity. Pharmacological blockade of CB1 receptors induces anxiety in rats, and inhibition of anandamide metabolism produces anxiolytic-like effects. Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states and may constitute a novel pharmacological target for anti-anxiety therapy.

Introduction

Anxiety can be regarded as a “normal” emotion and an adaptive component of the acute stress response under circumstances that threaten the integrity of the individual. However, if anxiety is disproportional in intensity or chronicity, or is not associated with any actual risk, it constitutes a maladaptive response or even a psychiatric disorder. A diversity of mechanisms appears to be involved in the regulation of anxious states, which may contribute to an appropriate emotional response to aversive events. In addition to the GABAergic, serotonergic and noradrenergic systems, many other neurotransmitters and modulators have been implicated. Accordingly, though benzodiazepines and agents acting on serotonergic system are currently the main drugs employed in the management of anxiety disorders, there is considerable scope for the development of alternative therapies (Sandford et al., 2000, Millan, 2003). In this context, there is an increasing interest in the endocannabinoid system as part of the complex circuitry that regulates anxiety. In reviewing the involvement of the endocannabinoid system in the control of anxiety-related responses, the present article focuses on the following points: effects of cannabinoid receptor agonists on anxiety-related responses in humans and experimental animals and the possible mechanisms underlying these effects, results obtained from both pharmacological and genetic strategies that highlight the role of the endogenous cannabinoid system in the regulation of anxiety, interactions between cannabis and other drugs of abuse in the control of anxious states, and the endocannabinoid system as a new pharmacological target for treating anxiety-related disorders.

Section snippets

Effects of cannabinoids on anxiety-related responses

The main feature of the recreational use of cannabis is that it produces a euphoriant effect. This “high” can be accompanied by decreased anxiety and increased sociability. However, cannabis can also produce dysphoric reactions, feelings of anxiety, panic, paranoia and psychosis (Hollister, 1986, Hall et al., 1994, Hall and Solowij, 1998, Ashton, 2001, Patton et al., 2002, Tournier et al., 2003, Dannon et al., 2004). It is possible that the reasons for this lie in bidirectional effects of

Biphasic effects of cannabinoids: proposed hypotheses

As indicated in the previous section, the effects of cannabinoid agonists on anxiety are biphasic, with low doses being anxiolytic and high doses anxiogenic. It is worth noting that, in addition to anxiety, there are other behavioral responses, such as motor activity and exploration (McGregor et al., 1996b, Chaperon and Thiebot, 1999, Marín et al., 2003, Genn et al., 2004a, Marco et al., 2004a) that are affected by cannabinoid agonists in a biphasic manner. In general, low doses are stimulatory

Role of the endocannabinoid system in the regulation of anxiety

The development of knockout mice deficient in CB1 receptors has provided an excellent tool to evaluate the physiological roles of the endocannabinoid system, and in particular its possible implication in the regulation of anxiety (Table 2). The CB1 knockout mice showed an increase in the aggressive response measured in the resident–intruder test and an anxiogenic-like response in the light–dark box. Even more, the mutant mice showed a higher sensitivity to exhibit depressive-like responses in

Interaction between cannabinoids and other drugs of abuse in relation to anxiety

Functional interactions between endogenous systems mediating the effects of drugs of abuse are of special interest in the context of polydrug abuse. Thus, it is conceivable that human addicts use mixtures of drugs either to augment the sensation of pleasure or to reduce the withdrawal and other aversive effects of a given substance. For instance, the drug most commonly taken with MDMA in human users is cannabis. More than 90% of ecstasy users take cannabis regularly (Siliquini et al., 2001,

The endocannabinoid system as a potential pharmacological target for the treatment of anxiety disorders

Marijuana and its derivatives have been used with medicinal purposes for many centuries and during the last years there has been a renewed interest in their possible therapeutic uses. A number of animal studies and clinical trials indicate that cannabinoids may have clinical application in emesis, loss of appetite and nausea associated with AIDS and cancer chemotherapy, neurodegeneration and brain trauma, tumors, spasticity associated with multiple sclerosis, and neuropathic pain (Galve-Roperh

Concluding remarks

During the last few years, the increasing interest in the relationships between cannabinoids and anxiety has led to a number of interesting data derived from animal studies. These results may contribute to understand the underlying mechanisms of complex effects of cannabinoids in humans and certain associations between cannabis abuse and mental disorders.

The use of transgenic mice lacking CB1 receptors and inhibitors of endocannabinoids metabolism has allowed to suggest the existence of an

Acknowledgements

Part of the authors' work has been supported by the Ministerio de Ciencia y Tecnología, grants BFI2000-0611 and BFI2003-03101. Eva M. Marco is a predoctoral fellow of the Ministerio de Educación y Cultura.

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