Involvement of the Dorsal Vagal Complex in Alcohol-Related Behaviors

Abstract

The neurobiological mechanisms that regulate the development and maintenance of alcohol use disorder (AUD) are complex and involve a wide variety of within and between systems neuroadaptations. While classic reward, preoccupation, and withdrawal neurocircuits have been heavily studied in terms of AUD, viable treatment targets from this established literature have not proven clinically effective as of yet. Therefore, examination of additional neurocircuitries not classically studied in the context of AUD may provide novel therapeutic targets. Recent studies demonstrate that various neuropeptides systems are important modulators of alcohol reward, seeking, and intake behaviors. This includes neurocircuitry within the dorsal vagal complex (DVC), which is involved in the control of the autonomic nervous system, control of intake of natural rewards like food, and acts as a relay of interoceptive sensory information via interactions of numerous gut-brain peptides and neurotransmitter systems with DVC projections to central and peripheral targets. DVC neuron subtypes produce a variety of neuropeptides and transmitters and project to target brain regions critical for reward such as the mesolimbic dopamine system as well as other limbic areas important for the negative reinforcing and aversive properties of alcohol withdrawal such as the extended amygdala. This suggests the DVC may play a role in the modulation of various aspects of AUD. This review summarizes the current literature on neurotransmitters and neuropeptides systems in the DVC (e.g., norepinephrine, glucagon-like peptide 1, neurotensin, cholecystokinin, thyrotropin-releasing hormone), and their potential relevance to alcohol-related behaviors in humans and rodent models for AUD research. A better understanding of the role of the DVC in modulating alcohol related behaviors may lead to the elucidation of novel therapeutic targets for drug development in AUD.

Keywords: alcohol use disorder; gut-brain axis; interoception; nucleus of the tractus solitarius; vagus nerve.

FIGURE 1

Neuronal types and subtypes in the NTS. Schematic coronal medullary section showing the diversity of cell types located within the NTS. Peptide and transmitter expression includes NE, norepinephrine, which is made up of cellular subtypes hoxb1 and krox2; prolactin-releasing peptide, PrRP which also has a population of neurons that co-express NE; GLP-1, glucagon-like peptide 1; POMC, pro-opiomelanocortin; GABA, gamma-aminobutyric acid; CCK, cholecystokinin; TRH, thyrotropin-releasing hormone; Galanin; NT, neurotensin. Other peptides shown to be in the DVC but not depicted include Met-enkephalin, Dynorphin, Substance P, calcitonin gene related peptide and Neuropeptide Y. NTS, nucleus of the tractus solitarius; DMV, dorsal motor nucleus of the vagus nerve; AP, area postrema. Sizes not to scale or indicative of typical location within a caudal DVC section.

FIGURE 2

Schematic of DVC projections hypothesized to be involved in central homeostatic systems and AUD. The origin and distribution of central neurotransmitter and peptide pathways participating in consumption behaviors and energy homeostasis and potentially involved in AUD. Peptide and transmitter systems include NE, norepinephrine; GLP-1, glucagon-like peptide 1; GABA, gamma-aminobutyric acid; POMC, pro-opiomelanocortin; CCK, cholecystokinin; TRH, thyrotropin-releasing hormone; Galanin. These projections are derived from the NTS, nucleus of the tractus solitarius; and project to multiple nuclei in the hypothalamus including the PVN, paraventricular nucleus, and the ARC, arcuate. The general area delineating the hypothalamus is denoted with dashed lines. Note that the specific hypothalamic regions that NTS POMC neurons project to is not yet defined, thus nerve endings are shown to terminate in the general hypothalamic region. CCK neurons are shown to project to the PBN, parabrachial nucleus, which also projects heavily to the hypothalamus. Dashed lines indicate that projections have been identified, but functionality and relevance to AUD is not known. Question marks indicate that immunohistochemically, neurotransmitters or peptide are present however, the termination of the projections have not been identified. DMV, dorsal motor nucleus of the vagus nerve; AP, area postrema.

FIGURE 3

Schematic of DVC projections hypothesized to be involved in central stress systems and AUD. The origin and distribution of DVC neurotransmitter and peptide pathways involved in stress and implicated in AUD. Peptide and transmitter systems include NE, norepinephrine; PrRP, prolactin releasing peptide; GLP-1, glucagon-like peptide 1; GABA, gamma-aminobutyric acid. Dotted lines indicate that projections have been identified, but functionality and relevance to AUD is not known. Note that most of these projections arise from the caudal NTS, nucleus of the tractus solitarius. Also, efferent motor projections from the DMV, dorsal motor nucleus of the vagus nerve, are included to highlight their importance in physiological responses to stress in AUD. BNST, Bed nucleus of the stria terminalis; PVN, paraventricular nucleus of the hypothalamus; CeA, central amygdala; AP, area postrema.

FIGURE 4

Schematic of DVC projections hypothesized to be involved in central reward systems and AUD. The origin and distribution of central neurotransmitter and peptide pathways hypothesized to be involved in rewarding properties of alcohol. Peptide and transmitter systems include NE, norepinephrine and GLP-1, glucagon-like peptide 1 and neruotensin. These projections are derived from the NTS, nucleus of the tractus solitarius; and project to mesolimbic regions including the NAc, nucleus accumbens, and the VTA, ventral tegmental area. Question marks indicate that immunohistochemically, neurotransmitters or peptide are present, however, the termination of the projections have not been identified. DMV, dorsal motor nucleus of the vagus nerve; AP, area postrema.