Elsevier

Biological Psychiatry

Volume 76, Issue 3, 1 August 2014, Pages 223-230
Biological Psychiatry

Archival Report
Amygdala-Ventral Pallidum Pathway Decreases Dopamine Activity After Chronic Mild Stress in Rats

https://doi.org/10.1016/j.biopsych.2013.09.020Get rights and content

Background

Major depressive disorder affects more than 15% of the population across their lifespan. In this study, we used the well-characterized unpredictable chronic mild stress (CMS) model of depression to examine this condition.

Methods

Sprague-Dawley rats were presented randomly with mild stressors for 4 weeks, with body weight and sucrose intake monitored weekly. Locomotor activity and elevated plus maze test/forced swim test were conducted on Week 5; ventral tegmental area dopamine (DA) neuron activity was assessed within 1 week after the behavioral test with three indices: DA neuron population activity (defined as the number of spontaneously firing DA neurons); mean firing rate; and percent burst firing (i.e., the proportion of action potentials occurring in bursts).

Results

Consistent with previous studies, we found that, compared with control subjects, rats that underwent the CMS procedure were slower in gaining body weight and developed anxiety- and despair-like behavior. We now report a significant decrease in DA neuron population activity of CMS rats, and this decrease is restored by pharmacologically attenuating the activity of either the basolateral nucleus of the amygdala (BLA) or the ventral pallidum (VP). Moreover, pharmacological activation of the amygdala in nonstressed rats decreases DA neuron population activity similar to that with CMS, which is reversed by blocking the BLA-VP pathway.

Conclusions

The CMS rat depression model is associated with a BLA-VP-ventral tegmental area inhibition of DA neuron activity. This information can provide insight into the circuitry underlying major depressive disorder and serve as a template for refining therapeutic approaches to this disorder.

Section snippets

Subjects and Materials

Male Sprague-Dawley rats (300–400g; Harlan Laboratories, Hayward, California) were housed for at least 5 days in pairs in a temperature (22°C)- and humidity (47%)-controlled facility upon arrival on a 12-hour light/dark cycle (lights on at 7:00 am) with food and water available ad libitum. Animals were handled in accordance with the guidelines outlined in the United States Public Health Service Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care

Exp 1: CMS-Treated Rats Exhibited Slower Weight Gain, Anxiety-Like Behavior, and Attenuation of VTA DA Neuron Population Activity

Rats were exposed to the CMS procedure (n = 14) or controls (n = 14), with sucrose preference measured in a subgroup of rats (n = 8; CON and CMS, respectively) (Figure 1).

The CMS rats were slower in gaining body weight over the 4 weeks of the CMS procedure (Figure 3A) (ANOVA significant main effect of “week” [F4,104 = 790.86, p < .001], and a significant interaction between “group” and “week” [F4,104 = 3.63, p = .008]). We did not find an alteration in sucrose preference (index of anhedonia) in

Discussion

In this study, we found that the CMS model of depression resulted in a slower body weight gain and development of anxiety- and despair-like behaviors. There was a significant decrease in VTA DA neuron population activity, which was mediated through the BLA-VP pathway. Such decreases in the number of spontaneously firing DA neurons would be expected to greatly lessen the amplitude of the DA response to stimuli (34), which is proposed to decrease the rewarding value of external stimuli.

The CMS

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