Behavioral changes induced through adenosine A2A receptor ligands in a rat depression model induced by olfactory bulbectomy

Abstract

Background: Major depressive disorders are characterized by their severity and long-lasting symptoms, which make such disorders highly disabling illnesses. Unfortunately, 50% of major depressive patients experience relapses, perhaps partly because drug research has been performed only in animal models that screen for antidepressant drugs that appear to only ameliorate acute depression symptoms. The bilateral olfactory bulbectomy (OBX) animal model presents the advantage of mimicking the symptoms of chronic depression by means of brain surgery. Adenosine purinergic receptors A2A (A2AR) have been the target of interest in the field of psychiatric diseases. This study aimed to show which A2A receptor ligands exert antidepressive-like effects in the OBX rat model.

Methods: Forty Sprague-Dawley male rats were divided into four groups: control, OBX + vehicle, OBX + ZM 241385, and OBX + adenosine groups. Pharmacological treatment was administered for 14 days, and the rats were examined via the forced swim test (FST), open field test (OFT), and sucrose preference test (SPT).

Results: The OBX + ZM 241385 group exhibited decreased immobility time in the FST, decreased isolation time in the OFT, and reversed anhedonia behavior in the SPT compared to the vehicle group. However, no significant differences for adenosine treatment were found.

Conclusions: ZM 241385 administration (2 mg/kg i.p.) restored behavioral changes associated with OBX-induced depression.

Keywords: A2A receptors; ZM 241385; adenosine; behavioral tests; major depressive disorder.

Figure 1

Experimental schedule. Rats were first acclimated to the laboratory conditions for 2 weeks (0–2). At the end of week 2, all animals underwent behavioral tests (BTs). At week 3, the animals were divided into sham surgery bulbectomy (sham) and olfactory bulbectomy (OBX) groups, and the surgeries were performed. OBX group was subdivided into OBX + DMSO (vehicle), OBX + ZM241385 (ZM), OBX + NaCl 0.9%) (Vehicle), and OBX + adenosine (ADO) groups. At week 5, the groups underwent a second round of BTs, and pharmacological treatments were begun (from week 5 to week 10). At weeks 7 and 10, the groups again underwent BTs, and the animals were sacrificed at the end of week 10

Figure 2

Effects of ZM 241385 and adenosine on body weight. All treatments began 2 weeks after the OBX surgery and were continued for 2 weeks. Each point represents the mean ± SD. Two‐way ANOVA and post hoc Bonferroni's test were used to evaluate differences between groups each week (*p < .05, **p < .01, ***p < .001 indicate significant differences compared to the sham group) (#p < .01 indicates significant differences compared to the vehicle group)

Figure 3

Effects of ZM 241385 and adenosine on the FST. Immobility time in the FST increased significantly after the OBX surgery. (a) The immobility time decreased after administration of ZM 241385 (2 mg/kg, i.p.), and (b) the struggling time increased. (c) Immobility time and (d) struggling time did not recover after adenosine administration. The bars represent the mean ± SD (n = 10) Two‐way ANOVA and post hoc Bonferroni's test were used to evaluate differences between groups (*p < .05, **p < .01, ***p < .001 indicate significant differences compared to the sham group)

Figure 4

Effects of ZM241385 and adenosine on the OFT in (a) isolation latency, (b) number of sniffs, (c) frequency of grooming and (d) crosses. Frequency of behaviors during 10 min of the OFT. The bars represent the means ± SD (n = 10⁻²), Two‐way ANOVA was used to evaluate differences between groups (*p < .05, **p < .01, ***p < .001 indicate significant differences compared to the sham group). The different letters (a and b) represent significant differences

Figure 5

Effects of A2AR ligands on sucrose intake. Sucrose preference significantly decreased after OBX surgery. (a) The A2AR antagonist (2 mg/kg i.p.) restored sucrose preference, whereas (b) A2AR agonist (5 mg/kg i.p.) induced partial recovery, but sucrose preference was not completely restored. The vehicles had no effects on sucrose preference. Each bar represents the mean ± SD, and different letters represent significant differences (ANOVA, post hoc Tukey's test)