Dopamine modulates individual differences in avoidance behavior: A pharmacological, immunohistochemical, neurochemical and volumetric investigation

Geiza Fernanda Antunes,Flavia Venetucci Gouveia,Fabiana Strambio Rezende,Midiã Dias De Jesus Seno,Milene Cristina De Carvalho,Caroline Cruz De Oliveira,Lennon Cardoso Tosati Dos Santos,Marina Correia De Castro,Mayra Akemi Kuroki,Manoel Jacobsen Teixeira,José Pinhata Otoch,Marcus Lira Brandao,Erich Talamoni Fonoff,Raquel Chacon Ruiz Martinez

doi:10.1016/j.ynstr.2020.100219

Geiza Fernanda Antunes, Flavia Venetucci Gouveia + Show 12 more

Open Access

https://doi.org/10.1016/j.ynstr.2020.100219

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Abstract

Avoidance behavior is a hallmark in pathological anxiety disorders and results in impairment of daily activities. Individual differences in avoidance responses are critical in determining vulnerability or resistance to anxiety disorders. Dopaminergic activation is implicated in the processing of avoidance responses; however, the mechanisms underlying these responses are unknown. In this sense, we used a preclinical model of avoidance behavior to investigate the possibility of an intrinsic differential dopaminergic pattern between good and poor performers. The specific goal was to assess the participation of dopamine (DA) through pharmacological manipulation, and we further evaluated the effects of systemic injections of the dopaminergic receptor type 1 (D1 antagonist - SCH23390) and dopaminergic receptor type 2 (D2 antagonist - sulpiride) antagonists in the good performers. Additionally, we evaluated the effects of intra-amygdala microinjection of a D1 antagonist (SCH23390) and a D2 antagonist (sulpiride) in good performers as well as intra-amygdala microinjection of a D1 agonist (SKF38393) and D2 agonist (quinpirole) in poor performers. Furthermore, we quantified the contents of dopamine and metabolites (3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)) in the amygdala, evaluated the basal levels of tyrosine hydroxylase expression (catecholamine synthesis enzyme) and measured the volume of the substantia nigra, ventral tegmental area and locus coeruleus. Our results showed that it could be possible to convert animals from good to poor performers, and vice versa, by intra-amygdala (basolateral and central nucleus) injections of D1 receptor antagonists in good performers or D2 receptor agonists in poor performers. Additionally, the good performers had lower levels of DOPAC and HVA in the amygdala, an increase in the total volume of the amygdala (AMG), substantia nigra (SN), ventral tegmental area (VTA) and locus coeruleus (LC), and an increase in the number of tyrosine hydroxylase-positive cells in SN, VTA and LC, which positively correlates with the avoidance behavior. Taken together, our data show evidence for a dopaminergic signature of avoidance performers, emphasizing the role of distinct dopaminergic receptors in individual differences in avoidance behavior based on pharmacological, immunohistochemical, neurochemical and volumetric analyses. Our findings provide a better understanding of the role of the dopaminergic system in the execution of avoidance behavior.

Highlights

Avoidance behavior consists of the transition from fear reactions to motor actions to avoid a harmful or unpleasant stimulus, increasing the animal's chance of survival in the face of potential damage (Skinner, 1969; Lang et al, 1998)
The two-way active avoidance task is performed in a shuttle box that is divided into two compartments by a door, and the rats are trained to exhibit the avoidance behavior by moving from one compartment to another in order to avoid the delivery of the footshocks (Martinez et al, 2013)
Along the seven daily training sessions, the animals were divided into good and poor performance groups based on the number of avoidance responses

Summary

Introduction

Avoidance behavior consists of the transition from fear reactions to motor actions to avoid a harmful or unpleasant stimulus, increasing the animal's chance of survival in the face of potential damage (Skinner, 1969; Lang et al, 1998). The two-way active avoidance task is performed in a shuttle box that is divided into two compartments by a door, and the rats are trained to exhibit the avoidance behavior by moving from one compartment to another in order to avoid the delivery of the footshocks (Martinez et al, 2013) This is a interesting model because two different subpopulations are distinguished based on the avoidance response, the good (high avoiders) and poor (low avoiders) performers, with higher levels of anxiety displayed by the poor performers (Martinez et al, 2013). In the context of post-traumatic stress disorder (PTSD) and other anxiety disorders, the distinction between good and poor performers could be helpful to study the persistent and maladaptive threat responses (Mahan and Ressler, 2012; GalatzerLevy et al, 2014)

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