Elsevier

Neuroscience

Volume 204, 1 March 2012, Pages 17-30
Neuroscience

Crosstalk Between Endocannabinoids and the Stress Response
Review
Timing is everything: evidence for a role of corticolimbic endocannabinoids in modulating hypothalamic–pituitary–adrenal axis activity across developmental periods

https://doi.org/10.1016/j.neuroscience.2011.10.006Get rights and content

Abstract

Growing evidence suggests that the endocannabinoid system is vital to ensuring normative maturation of the brain into adulthood. Endocannabinoid signaling contributes to guiding pro-neurogenic processes in early life and the development of neurotransmitter systems. Moreover, there is extensive evidence that recruitment of the endocannabinoid system is crucial in the regulation of neuroendocrine responses to stress via the hypothalamic–pituitary–adrenal (HPA) axis, and contributes to subsequent psychopathological consequences associated with emotionality and anxiety. These stress-induced physiological and behavioural sequelae are regulated by neural structures within the corticolimbic circuit, including the amygdala, hypothalamus, hippocampus, and prefrontal cortex. Based on evidence demonstrating endocannabinoid system involvement in both development and stress-induced changes in HPA axis function, it is reasonable to suggest that endocannabinoid signaling is an important mediator of interactions between stress responsivity and maturational stage. In this review, we discuss the ontogeny of the endocannabinoid system in the central nervous system, clinical and rodent models demonstrating short- and long-term effects of stress exposure, regulation of HPA axis responsivity by endocannabinoid signaling, as well as pharmacological and stress models indicating involvement of the endocannabinoid system in early post-natal and adolescent development on stress reactivity of the HPA, the corticolimbic system, and behaviour.

This article is part of a Special Issue entitled: Stress, Emotional Behavior and the Endocannabinoid System.

Highlights

▶The endocannabinoid system serves to regulate normative neurodevelopment. ▶Age-dependent effects have been observed on HPA axis stress responsivity. ▶Endocannabinoid signaling may mediate developmental effects on the HPA axis.

Section snippets

Endocannabinoid system development in the corticolimbic stress circuit

The endocannabinoid system (Fig. 2) interacts with the main psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), to exert its physiological and behavioural effects, and it includes two G-protein coupled receptors, CB1 and CB2. The CB1 receptor is expressed mostly in the brain, primarily on GABAergic and glutamatergic neurons (Freund et al., 2003) while CB2 receptors are predominantly found in peripheral tissues. While CB2 receptors have been detected in the central nervous

HPA axis development and stress responsivity

As mentioned earlier, recruitment of adult eCB signaling is essential to regulation of the neuroendocrine response to stressors via the HPA axis, yet it is not entirely known how this relationship functions in the developing organism. Thus, this section is aimed at describing and considering the existing body of work on HPA axis development and the developmental effects of stress-induced neuroendocrine responses followed by discussion of eCB regulation of stress-induced HPA axis function in the

Endocannabinoid system regulation of the HPA axis and the stress response

The eCB system has been shown to regulate the HPA axis in the maintenance of both basal and stress-induced responses (e.g. Finn, 2010, Hill et al., 2010a, Hill et al., 2010b). For purposes of this review, some key research contributing to our current understanding of eCB system regulation of the HPA axis will be highlighted. However, for a comprehensive review and detailed discussion of this topic, please refer to the review by Jeffrey Tasker and Matthew Hill in this special issue. In general,

Early life stress and cannabinoid treatment engage the endocannabinoid system to modulate HPA functioning

The SHRP coincides with relatively low CB1 receptor density in limbic and midbrain structures (de Fonseca et al., 1993), increasing AEA concentrations that peak at PND 1, and relatively low yet constant 2-AG levels in the whole brain (Berrendero et al., 1999). Due to a lack of empirical data, the exact mechanisms of eCB regulation of HPA axis responsivity in this SHRP are not clearly defined. However, several studies discussed below (see Table 2) have observed that early life stress (∼PND 10)

HPA axis function in adolescence: a role for the endocannabinoid system?

To our knowledge, mechanisms subserving interactions between adolescent development and stress-induced corticolimbic and HPA axis responsivity in relation to the eCB system remain to be determined. Due to restrictions in human research, mostly descriptive rather than experimental evidence has been employed to learn about eCB system regulation of HPA axis functioning and development. Adolescent male cannabis users exhibit region-dependent alterations in thickness of the prefrontal cortex (a key

Long-term consequences of adolescent endocannabinoid system dysregulation on the developing brain and behaviour

Despite several investigations of the short- and long-term impact of adolescent chronic cannabinoid exposure on the adult brain and behaviour, none have assessed HPA axis responsivity. Because the reported long-term neural and behavioural changes produced by adolescent cannabinoid treatment are consistent with the effects of stress, it is conceivable that a paradigm aimed at modeling adolescent cannabis use can also induce dysregulation of HPA axis functioning. In the studies described below,

General discussion

Review of the evidence supports the idea that early life and adolescence are periods of heightened susceptibility to disturbances such as stress, substance use and abuse; yet at the same time, they are very distinct and separate developmental windows. Infancy and childhood are characterized by heavy dependence on parental care for survival and learning of basic skills (e.g. suckling) and are coupled with significant neural changes that facilitate the ability to learn these associations and

Acknowledgments

The authors thank the following sources of funding support: TTYL—Canadian Institutes of Health Research (CIHR; salary); BBG—Operating grants from the Natural Sciences and Engineering Research Council of Canada and CIHR.

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