Neonatal maternal separation exacerbates the reward-enhancing effect of acute amphetamine administration and the anhedonic effect of repeated social defeat in adult rats

Abstract

Early life adversity or parental neglect is linked to the development of a number of psychiatric illnesses, including major depression and substance use disorder. These two disorders are often comorbid and characterized by anhedonia, defined as the reduced ability to experience pleasure or reward. The aim of the present study was to determine the effects of neonatal maternal separation in Long Evans rats, a model of early life stress, on anhedonia under baseline conditions and in response to drug and stress exposure during adulthood. Three hours of daily maternal separation from postnatal day 1 to 14 led to marked decreases in arched-back nursing, licking, and grooming of pups by their dams. In adulthood, brain reward function was assessed using intracranial self-stimulation of the lateral hypothalamus. Lowered current thresholds derived from this procedure are interpreted as reward-enhancing effects, whereas elevations in thresholds are an operational measure of anhedonia. Maternally separated rats did not exhibit anhedonia under baseline conditions compared with non-handled controls but exhibited a greater reward-enhancing effect of acute amphetamine administration. Acute social defeat produced anhedonia in non-handled controls, but not in maternally separated rats. Conversely, control rats habituated to 7 days of repeated social defeat, whereas maternally separated rats developed an increased anhedonic response to the repeated stressor. One week after termination of stress exposure, maternally separated rats still exhibited an increased reward-enhancing effect of acute amphetamine administration compared with non-handled controls, regardless of prior social defeat experience. These data indicate that early life stress increases the reward-enhancing properties of amphetamine, protects against the anhedonic effects of acute stress exposure, and exacerbates the anhedonic response to repeated stress. Thus, early life stress may increase an individual's vulnerability to depressive or addictive disorders when confronted with stress or drug challenge in adulthood.

Figure 1

Diagram depicting maternal separation groups and experimental design.

Figure 2

Mean (± SEM) frequency of maternal behaviors scored daily prior to maternal separation during the (A) first and (B) second postnatal weeks. NC, no contact; LG, licking and grooming; ABN, arched-back nursing; BN, blanket nursing; PN, passive nursing. *p < 0.05, significantly different from non-handled controls.

Figure 3

(A) Daily ICSS current threshold values (mean ± SEM) during 14 days of baseline assessment in maternally separated and non-handled rats. (B) Average ICSS current threshold values (mean ± SEM) under baseline conditions in maternally separated and non-handled rats.

Figure 4

Mean (± SEM) change in ICSS current thresholds, expressed as a percentage of baseline threshold values, in response to amphetamine (0.5 mg/kg, i.p.) in maternally separated and non-handled rats. **p < 0.01, significantly different from non-handled controls.

Figure 5

Mean (± SEM) change in ICSS current thresholds, expressed as a percentage of baseline threshold values, in response to the (A) first and (B) seventh repeated social defeat sessions. *p < 0.05, significantly different from non-handled/no stress rats and from maternal separation/social defeat rats. **p < 0.01, significantly different from maternal separation/no stress rats.

Figure 6

Mean (± SEM) change in ICSS current thresholds, expressed as a percentage of baseline values, in response to amphetamine (0.5 mg/kg, i.p.) in maternally separated and non-handled control rats 1 week after repeated social defeat. *p < 0.05, significantly different from non-handled controls.