Corticosterone Attenuates Reward-Seeking Behavior and Increases Anxiety via D2 Receptor Signaling in Ventral Tegmental Area Dopamine Neurons

Abstract

Corticosteroids (CORT) have been widely used in anti-inflammatory medication. Chronic CORT treatment can cause mesocorticolimbic system dysfunctions, which are known to play a key role for the development of psychiatric disorders. The VTA is a critical site in the mesocorticolimbic pathway and is responsible for motivation and reward-seeking behaviors. However, the mechanism by which chronic CORT alters VTA dopamine neuronal activity is largely unknown. We treated periadolescent male mice with vehicle, 1 d, or 7 d CORT in the drinking water, examined behavioral impacts with light/dark box, elevated plus maze, operant chamber, and open field tests, measured the effects of CORT on VTA dopamine neuronal activity using patch-clamp electrophysiology and dopamine concentration using fast-scan cyclic voltammetry, and tested the effects of dopamine D2 receptor (D2R) blockade by intra-VTA infusion of a D2R antagonist. CORT treatment induced anxiety-like behavior as well as decreased food-seeking behaviors. We show that chronic CORT treatment decreased excitability and excitatory synaptic transmission onto VTA dopamine neurons. Furthermore, chronic CORT increased somatodendritic dopamine concentration. The D2R antagonist sulpiride restored decreased excitatory transmission and excitability of VTA dopamine neurons. Furthermore, sulpiride decreased anxiety-like behavior and rescued food-seeking behavior in mice with chronic CORT exposure. Together, 7 d CORT treatment induces anxiety-like behavior and impairs food-seeking in a mildly aversive environment. D2R signaling in the VTA might be a potential target to ameliorate chronic CORT-induced anxiety and reward-seeking deficits. SIGNIFICANCE STATEMENT With widespread anti-inflammatory effects throughout the body, corticosteroids (CORT) have been used in a variety of therapeutic conditions. However, long-term CORT treatment causes cognitive impairments and neuropsychiatric disorders. The impact of chronic CORT on the mesolimbic system has not been elucidated. Here, we demonstrate that 7 d CORT treatment increases anxiety-like behavior and attenuates food-seeking behavior in a mildly aversive environment. By elevating local dopamine concentration in the VTA, a region important for driving motivated behavior, CORT treatment suppresses excitability and synaptic transmission onto VTA dopamine neurons. Intriguingly, blockade of D2 receptor signaling in the VTA restores neuronal excitability and food-seeking and alleviates anxiety-like behaviors. Our findings provide a potential therapeutic target for CORT-induced reward deficits.

Using intra-brain drug infusion to investigate neural mechanisms underlying reward-seeking behavior in mice

“…Chronic CORT treatment induces a variety of behavioral deficits, from anxiety-related phenotype ( David et al., 2009 ) to impaired positive valence behaviors ( Dieterich et al., 2019 ; Gourley et al., 2008 ; Moda-Sava et al., 2019 ). Consistently, we showed that 7-day CORT treatment decreased food-seeking behavior in a mildly risky environment, which is possibly be explained by elevated anxiety ( Peng et al., 2021 ). However, we did not observe any depressive-like phenotypes, which is reported in mice with 21-day CORT treatment ( Moda-Sava et al., 2019 ).…”

“…Although sulpiride reduced post reinforcement pause ( Figure 9 B), our analysis did not show that sulpiride normalized motivation in CORT mice ( Figures 9 A and 9C), except that it restored the reduced rear beam break rate ( Figure 9 E), which was constructive in interaction with the reward zone. Instead, Peng et al. (2021) found that intra-VTA sulpiride alleviated anxiety-like behavior using the elevated plus maze (data not shown here).…”

“…This protocol can be easily adapted to address various research questions related to behavioral pharmacology. For complete details on the use and execution of this protocol, please refer to Peng et al. (2021) .…”

“…For complete details on the use and execution of this protocol, please refer to Peng et al. (2021) .…”

Motivational disturbances in rodent models of neuropsychiatric disorders

“…In addition to producing motivation deficits, a 7-day corticosterone treatment has been found to also alter VTA DA-ergic activity, decreasing excitatory synaptic transmission ( Peng et al, 2021 ). Intra-VTA administration of the D2 receptor antagonist sulpiride was found to restore excitatory transmission in the VTA but failed to rescue operant performance in a PR test, delineating a complex relationship between DA-ergic VTA activity and effort-related behavior.…”