Pre-clinical models of reward deficiency syndrome: A behavioral octopus

Abstract

Individuals with mood disorders or with addiction, impulsivity and some personality disorders can share in common a dysfunction in how the brain perceives reward, where processing of natural endorphins or the response to exogenous dopamine stimulants is impaired. Reward Deficiency Syndrome (RDS) is a polygenic trait with implications that suggest cross-talk between different neurological systems that include the known reward pathway, neuroendocrine systems, and motivational systems. In this review we evaluate well-characterized animal models for their construct validity and as potential models for RDS. Animal models used to study substance use disorder, major depressive disorder (MDD), early life stress, immune dysregulation, attention deficit hyperactivity disorder (ADHD), post traumatic stress disorder (PTSD), compulsive gambling and compulsive eating disorders are discussed. These disorders recruit underlying reward deficiency mechanisms in multiple brain centers. Because of the widespread and remarkable array of associated/overlapping behavioral manifestations with a common root of hypodopaminergia, the basic endophenotype recognized as RDS is indeed likened to a behavioral octopus. We conclude this review with a look ahead on how these models can be used to investigate potential therapeutics that target the underlying common deficiency.

Keywords: APOSUS; Addiction; Alcohol use disorder; Alcohol-preferring P rat; Animal models of reward deficiency; Compulsive eating disorder; Dopamine; Early life stress; Gambling disorder; Helpless mouse (HL); Knockout rats; Maternal deprivation; PTSD; Reward; Roman; Wistar Kyoto (WKY) rat; mGluR2.

Figure 1:. Reward Deficiency Syndrome: The Behavioral Octopus.

Schematic shows many arms of individual disorders with unique characteristics that share a common foundation of low dopamine signaling tone (hypodopaminergia); a foundational cause/consequence of reward deficiency.

Figure 2:. Behaviors categorized as symptomatology of reward deficiency syndrome in the WKY and HL rats.

Rodent behaviors reported in various studies which this paper proposes are RDS characteristics.

Figure 3:. Shared RDS behaviors for animal models of ELS and PTSD.

A-C are modified from Gondré-Lewis et al., Stress 2016, March; 19 (2):235–247 with permission. (A) Responding for alcohol is increased in maternally deprived (MD) (B) Blood alcohol content of MD rats were elevated to >80mg%/dL following 2 hours of 10% EtOH drinking. (C) Adjusted amount is decreased (impulsivity is increased) in delay discounting task. (D) shows the different RDS behaviors that have been test in PTSD and MD. * represents traits also shown for PTSD animal models. The absence of a shared behavior may indicate that it is not yet reported or tested.

FIgure 4:. Possible Neurocircuitry in Alcohol-Preferring (P) compared to Non-Preferring (NP) rat.

Dopaminergic signaling is likely blunted in P rats, possibly due to low levels of dopamine or dopamine receptors. P rats also exhibit reduced serotonin, CRF, and NPY compared to the NP rat line. 5-HT, 5-hydroxytryptamine; AMG, amygdala; CRF, Corticotropin Releasing Factor; DA, Dopamine; PFC, prefrontal cortex; NAc, nucleus accumbens; NPY, Neuropeptide Y; VTA, ventral tegmental area; NAc, Nucleus Accumbens; PFC, prefrontal cortex; VTA, ventral tegmental area; VP, ventral pallidum.

Figure 5.. Animal Models of RDS and Core Behavioral Traits.

Behavioral traits associated with low dopamine (blue pie slices), and the animal models reviewed here (Clear rectangles) in which they have been detected (black). The animal models in red shows those for which no data about the behavioral trait is available as of the writing of this review.