Drug discovery strategies that focus on the endocannabinoid signaling system in psychiatric disease

Abstract

Introduction: The endocannabinoid (eCB) system plays an important role in the control of mood, and its dysregulation has been implicated in several psychiatric disorders. Targeting the eCB system appears to represent an attractive and novel approach to the treatment of depression and other mood disorders. However, several failed clinical trials have diminished enthusiasm for the continued development of eCB-targeted therapeutics for psychiatric disorders, despite the encouraging preclinical data and promising preliminary results obtained with the synthetic cannabinoid nabilone for treating post-traumatic stress disorder.

Areas covered: This review describes the eCB system's role in modulating cell signaling within the brain. There is a specific focus on eCB's regulation of monoamine neurotransmission and the stress axis, as well as how dysfunction of this interaction can contribute to the development of psychiatric disorders. Additionally, the review provides discussion on compounds and drugs that target this system and might prove to be successful for the treatment of mood-related psychiatric disorders.

Expert opinion: The discovery of increasingly selective modulators of CB receptors should enable the identification of optimal therapeutic strategies. It should also maximize the likelihood of developing safe and effective treatments for debilitating psychiatric disorders.

Keywords: CB1 receptors; anxiety; clinical trials; depression; hypothalamic–pituitary–adrenal axis; monoamines; post-traumatic stress disorder; stress response.

Figure 1

Schematic diagram depicting cannabinoid-adrenergic interactions in stress-integrative circuitry. The basolateral complex of the amygdala (BLA) has been implicated in the consolidation of emotionally arousing experiences and involves glucocorticoid-mediated increases in eCB release and interactions with norepinephrine [146]. (1) eCBs are posited to increase BLA activity by decreasing GABAergic neurotransmission [147]. (2) Disinhibition of GABAergic interneurons results in an increase of glutamatergic signaling in the central nucleus of the amygdala (CNA), a source of excitatory afferents to the LC [148]. (3) Activation of the LC causes an increase in noradrenergic signaling and norepinephrine (NE) release in postsynaptic targets, such as the prefrontal cortex (PFC). Given that the PFC represents a critical region in mediating the extinction of traumatic/aversive memories, treatments involving the eCB system that target this region may help alleviate symptoms of anxiety disorders by increasing extinction of such memories. For example, (4) CBs have been shown to inhibit monoamine oxidase (MAO), representing another mechanism in which CB signaling can regulate NE levels. (5) Targeting GABAergic projections to the LC with CB ligands can potentially modulate LC afferent activity to the PFC. Achieving the proper balance in frontal cortical activity by targeting cannabinoid-adrenergic interactions may result in enhancing extinction of aversive memories and diminish anxiety-like behaviors that are precipitated by stress.