Elsevier

Pharmacological Research

Volume 56, Issue 5, November 2007, Pages 428-442
Pharmacological Research

Review
Short- and long-term plasticity of the endocannabinoid system in neuropsychiatric and neurological disorders

https://doi.org/10.1016/j.phrs.2007.09.002Get rights and content

Abstract

The activity of the endocannabinoid system, in terms of the levels of the endocannabinoids and of cannabinoid receptors, or of the functional coupling of the latter to a biological response, undergoes to remodelling during pathological conditions. In the CNS, these changes, depending also on the nature of the disorder, can be transient or long-lasting, occur only in those tissues involved in the pathological condition and usually aim at restoring the physiological homeostasis by reducing excitotoxicity, inflammation and neuronal death. However, during chronic disorders, prolonged activation of the endocannabinoid system might also contribute to the symptoms of the pathology. Whilst acute changes of the tissue levels of the endocannabinoids reflect the “on demand” nature of their biosynthesis and release, and hence are effected mostly through regulation of the biosynthetic enzymes, chronic changes seem to be mostly due to longer-lasting alterations in the expression of anabolic and catabolic enzymes. The possibility of obtaining therapeutic advantage from endocannabinoid plasticity in neuropsychiatric and neurological disorders is discussed in this review article.

Section snippets

Introduction—“on demand” or “long-term” regulation of endocannabinoid levels

The regulation of the tissue concentrations of the endogenous agonists of cannabinoid receptors, or endocannabinoids, and the nature of the signal that they convey is strongly determined by their chemical nature. In fact, the two most studied endocannabinoids, anandamide and 2-arachidonoyl-glycerol (2-AG), are lipophilic compounds produced from the remodelling of membrane phospholipids, and as such are not stored into vesicles to be released following exocytosis. Instead, they are made “on

“On demand” or “long-term” activation of the EC system in stress and emotions

Increasing evidence is accumulating to suggest that endocannabinoid plasticity occurs following conditions of mild or strong stress in laboratory animals. In fact, if one looks at the pharmacological actions associated with stimulation of cannabinoid CB1 and CB2 receptors, they all fit very well with a possible general function of the endocannabinoid system as a “stress-recovery” mechanism. Two experimental conditions that resemble acute stressful stimuli are brief food deprivation and

“On demand” activation of the EC system in acute neurological conditions

Some acute pathological conditions of the CNS offer ideal examples of the “on demand” regulation of endocannabinoid biosynthesis [92]. In the hippocampus, glutamate-induced neuronal depolarisation and/or Gq/11-mediated intracellular Ca2+ mobilization cause excitotoxicity along with transient elevations of the levels of endocannabinoids, which can then be released and act retrogradely to inhibit glutamate release from principal neurons [19], thus dampening neuronal excitability [7], [21], [93],

Short- and long-term activation or impairment of the endocannabinoid system in chronic or degenerative neurological disorders

During neurodegenerative disorders, the “output” of the endocannabinoid system appears to become either permanently activated or impaired. The role of endocannabinoids and cannabinoid CB1 and CB2 receptors in these disorders, which are characterized by distinct aetiologies and progress, but present several common features, have been recently the subject of comprehensive reviews [122], [123]. There is increasing evidence that, in animal models of either Parkinson's disease (PD) (reserpine-,

Conclusions—new therapeutic avenues from the endocannabinoid system

From the several experimental studies reviewed in this article, the general scenario emerges of an endocannabinoid system undergoing profound changes in the central nervous system during most of the neurological and psychiatric disorders investigated to date. The protective function of an elevated endocannabinoid tone in some cases (e.g., in models of multiple sclerosis, epilepsy, neuropathic pain, head trauma, ALS) is supported by overwelming data obtained using biochemical, genetic and

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