When the Thrill is Gone: Endocannbinoids and Chronic Stress Syndrome

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Endocannabinoids in the central nervous system: from neuronal networks to behavior. Fride E. Curr Drug Targets CNS Neurol Disord. 2005 Dec;4(6):633-42.

Retrograde synaptic signaling influences both short-term and long-term plasticity of the brain, in both excitatory and inhibitory synapses. During the last few years it has become apparent that the endogenous ligands for the cannabinoid CB1 receptor, the "endocannabinoids", fulfill an essential role in the brain as retrograde synaptic messengers, in a number of structures including the hippocampus, cerebellum and the limbic and mesocortical systems. This seminal discovery provides a cellular basis for the well known ubiquitous role of the endocannabinoids and their receptors (together, the "ECBR" system) in virtually all brain functions studied.

This review will relate the anatomical distribution of the endocannabinoids and their CB1 receptors to functions of the ECBR system, as much as possible in light of the endocannabinoids as retrograde synaptic messengers.

Functional implications of the high rates of co-localization with cholecystokinin (CCK), will also be considered. The most obvious function to be profoundly affected by the retrograde synaptic role of the endocannabinoids is memory.

Endocannabinoids have addition functions in reward and addiction, motor coordination, pain perception, feeding and appetite, coping with stress, schizophrenia and epilepsy .

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OK, so we have our links.

Serotonin is involved in cannabinoid synthesis and cannabinoids are melatonin nuclear receptor activators. They are involved with gut activation, in bile acid release, in nervous response regulation in the brain, along with pain signal processing and the euphoria, pleasure and reward responses, appetite control, and stress modulation. In their worst deficiencies, they result in seizures and in severe cognitive dysfunction.

At their heart: neuroexcitatory signaling. Glutamate, NMDA and GABA.

Thus, we have our tie in between our indoleamine twins serotonin and melatonin and excitatory reactions and mood, cognitive and social function mediated by endocannabinoids.

This is a story of gene silencing and chemical repression from chronic stress.

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Participation of the Cannabinoid System in the Regulation of Emotional-Like Behaviour. Olga Valverde. Current Pharmaceutical Design 11(26):3411-21 (2005).

The endocannabinoid system has been involved in the control of several neurophysiological and behavioural responses. Indeed, recent studies have suggested that the cannabinoid system could represent an important substrate for the control of emotional behaviour, and further research would probably help to identify new promising therapeutic targets.

Cannabinoid compounds can induce anxiogenic- and anxiolytic-like responses in rodents depending on the experimental conditions. Studies using knockout mice lacking the CB1 cannabinoid receptors have shown the participation of this receptor in several behavioural responses including anxiety- and depressive-like states.

--->Furthermore, the endocannabinoid system regulates the hypothalamic-pituitary adrenal axis, which is involved in providing an appropriate response to stressful situations.

--->Recent studies have also demonstrated that the endocannabinoids can function as retrograde messengers, modulating the release of different neurotransmitter, including opioids, GABA and cholecystokinin (CCK) that have been classically involved in the control of anxiety-like responses.


This paper suggests a role for glutamate/NMDA induced changes in endocannabinoids as a sort of feedback loop modulator (enhancer?) of HPA stimulation. Perhaps leading to norepeinephrine down regulation and adrenal fatigue.

Also recall that excess CCK is linked to GERD/esophageal and intestinal inflammatory disease.