ReviewEndocannabinoid system and stress and anxiety responses
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.
References (128)
- et al.
Cannabinoid effects on anxiety-related behaviours and hypothalamic neurotransmitters
Pharmacol Biochem Behav
(2001) - et al.
The distribution of cannabinoid-induced Fos expression in rat brain: differences between the Lewis and Wistar strain
Brain Res
(2001) - et al.
A review of central 5-HT receptors and their function
Neuropharmacology
(1999) - et al.
Activation of CB1 cannabinoid receptors in rat hippocampal slices inhibits potassium-evoked cholecystokinin release, a possible mechanism contributing to the spatial memory defects produced by cannabinoids
Neurosci Lett
(2001) - et al.
Functional responses to the cannabinoid agonist WIN 55,212-2 in neonatal rats of both genders: influence of weaning
Pharmacol Biochem Behav
(2004) - et al.
Conditioned place preference induced by the cannabinoid agonist CP 55,940: interaction with the opioid system
Neuroscience
(2001) - et al.
Lack of CB1 cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence
Neuropharmacology
(2002) - et al.
Hippocampal and septal injections of nicotine and 8-OH-DPAT distinguish among different animal tests of anxiety
Prog Neuropsychopharmacol Biol Psychiatry
(2000) - et al.
In adolescence, female rats are more sensitive to the anxiolytic effect of nicotine than are male rats
Neuropsychopharmacology
(2001) - et al.
Mood differences between male and female light smokers and nonsmokers
Pharmacol Biochem Behav
(2002)
Anandamide hydrolysis: a new target for anti-anxiety drugs?
Trends Mol Med
Unconditioned and conditioned anxiogenic effects of the cannabinoid receptor agonist CP 55,940 in the social interaction test
Pharmacol Biochem Behav
A neuroendocrine role in cocaine reinforcement
Psychoneuroendocrinology
The HPA axis and cocaine reinforcement
Psychoneuroendocrinology
5-HT1A and benzodiazepine receptors in the basolateral amygdala modulate anxiety in the social interaction test, but not in the elevated plus-maze
Brain Res
Changes in endocannabinoid contents in the brain of rats chronically exposed to nicotine, ethanol or cocaine
Brain Res
5-Hydroxytryptamine-interacting drugs in animal models of anxiety disorders: more than 30 years of research
Pharmacol Ther
The effects of compounds varying in selectivity as 5-HT1A receptor antagonists in three rat models of anxiety
Neuropharmacology
Anxiolytic effect of cannabidiol derivatives in the elevated plus-maze
Gen Pharmacol
Distinct cannabinoid sensitive receptors regulate hippocampal excitation and inhibition
Chem Phys Lipids
Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus
Neuroscience
Adverse effects of cannabis
Lancet
Enhancement of anxiety-like responsiveness to the cannabinoid CB1 receptor agonist HU-210 following chronic stress
Eur J Pharmacol
Targeted gene mutation approaches to the study of anxiety-like behavior in mice
Neurosci Behav Rev
Dynorphin B and spinal analgesia: induction of antinociception by the cannabinoids CP 55,940, Δ9 THC and anandamide
Brain Res
Conditioned place preference induced by delta 9-tetrahydrocannabinol: comparison with cocaine, morphine, and food reward
Life Sci
Involvement of somatodendritic 5-HT1A receptors in Delta (9)-terahydrocannabinol-induced hypothermia in the rat
Pharmacol Biochem Behav
Opioid and cannabinoid receptor-mediated regulation of the increase in adrenocorticotropin hormone and corticosterone plasma concentrations induced by central administration of Δ9-tetrahydrocannabinol in rats
Brain Res
Pharmacological and biochemical interactions between opioids and cannabinoids
Trends Pharmacol Sci
Involvement of the kappa-opioid receptor in the anxiogenic-like effect of CP 55,940 in male rats
Pharmacol Biochem Behav
Characterization of the acute endocrine actions of (−)-11-hydroxy-delta8-tetrahydrocannabinol-dimethylheptyl (HU-210), a potent synthetic cannabinoid in rats
Eur J Pharmacol
Lack of morphine-induced dopamine release in the nucleus accumbens of cannabinoid CB(1) receptor knockout mice
Eur J Pharmacol
Cannabinoid modulation of rat pup ultrasonic vocalizations
Eur J Pharmacol
Aversive effects of the synthetic cannabinoid CP 55,940 in rats
Pharmacol Biochem Behav
The neurobiology and control of anxious states
Prog Neurobiol
Cannabinoids prevent the acute hyperthermia and partially protect against the 5-HT depleting effects of MDMA (“Ecstasy”) in rats
Neuropharmacology
Blockade of μ- and activation of κ-opioid receptors in the dorsal periaqueductal gray matter produce defensive behavior in rats tested in the elevated plus-maze
Eur J Pharmacol
Cannabinoids modulate neuronal firing in the rat basolateral amygdala: evidence for CB1- and non-CB1-mediated actions
Neuropharmacology
The endocannabinoid nervous system: unique opportunities for therapeutic intervention
Pharmacol Ther
Selective inhibition of sucrose and ethanol intake by rimonabant, an antagonist of central cannabinoid (CB1) receptors
Psychopharmacology
Pharmacology and effects of cannabis: a brief review
Br J Psychiatry
Involvement of the opioid system in the anxiolytic-like effects induced by Delta (9)-tetrahydrocannabinol
Psychopharmacology
Polydrug use at raves by a Western Australian sample
Drug Alcohol Rev
Evidence for a new G protein-coupled cannabinoid receptor in mouse brain
Mol Pharmacol
Behavioral effects of cannabinoid agents in animals
Crit Rev Neurobiol
SR 141716, a central cannabinoid (CB1) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats
Behav Pharmacol
Cannabinoid receptor gene (CNR1): association with i.v. drug use
Mol Psychiatry
Effects of cannabidiol (CBD) on regional cerebral blood flow
Neuropsychopharmacology
Therapeutic potential of cannabinoids in CNS disease
CNS Drugs
Comorbid cannabis use and panic disorder: short term and long term follow-up study
Hum Psychopharmacol
Cited by (400)
Women are taking the hit: Examining the unique consequences of cannabis use across the female lifespan
2023, Frontiers in NeuroendocrinologyCannabinoid treatments for anxiety: A systematic review and consideration of the impact of sleep disturbance
2022, Neuroscience and Biobehavioral ReviewsA review of the effects of acute and chronic cannabinoid exposure on the stress response
2021, Frontiers in Neuroendocrinology