The Emerging Role of LHb CaMKII in the Comorbidity of Depressive and Alcohol Use Disorders

Abstract

Depressive disorders and alcohol use disorders are widespread among the general population and are significant public health and economic burdens. Alcohol use disorders often co-occur with other psychiatric conditions and this dual diagnosis is called comorbidity. Depressive disorders invariably contribute to the development and worsening of alcohol use disorders, and vice versa. The mechanisms underlying these disorders and their comorbidities remain unclear. Recently, interest in the lateral habenula, a small epithalamic brain structure, has increased because it becomes hyperactive in depression and alcohol use disorders, and can inhibit dopamine and serotonin neurons in the midbrain reward center, the hypofunction of which is believed to be a critical contributor to the etiology of depressive disorders and alcohol use disorders as well as their comorbidities. Additionally, calcium/calmodulin-dependent protein kinase II (CaMKII) in the lateral habenula has emerged as a critical player in the etiology of these comorbidities. This review analyzes the interplay of CaMKII signaling in the lateral habenula associated with depressive disorders and alcohol use disorders, in addition to the often-comorbid nature of these disorders. Although most of the CaMKII signaling pathway's core components have been discovered, much remains to be learned about the biochemical events that propagate and link between depression and alcohol abuse. As the field rapidly advances, it is expected that further understanding of the pathology involved will allow for targeted treatments.

Keywords: CaMKII; addiction; alcohol; comorbidity; depression; drugs of abuse; lateral habenula.

Figure 1

The brain network of the lateral habenula (LHb) in alcohol use disorders (AUDs) and its comorbidities. The LHb gets major inputs from the habenula-projecting globus pallidus (GPh), the prefrontal cortex (PFC), and the lateral hypothalamus (LH) and sends projections to dopamine neurons in the ventral tegmental area (VTA)/substantia nigra compacta (SNc) and serotonin neurons in the raphe directly or indirectly through the rostromedial tegmental nucleus (RMTg). The LHb also receives projections from the raphe. LHb’s spike output and glutamatergic transmission are increased in alcohol withdrawal rats and in animal models of depression, suggesting that the LHb plays a key role in AUDs and depressive disorders (DDs) and their comorbidities.

Figure 2

Changes of calcium/calmodulin-dependent protein kinase II (CaMKII) signaling in the LHb glutamatergic neurons in alcohol use disorders (AUDs) and depressive disorders (DDs). Withdrawal from chronic alcohol administration and stress enhance glutamatergic transmission to and the spike output of LHb neurons. This is due in part through phosphorylating serine 831 (Ser831) on the glutamate A1 (GluA1) subunit and activating the CaMKII.