Exposure to adversity during development is an identified risk factor for depression later in life. In humans, early adversity accelerates the onset of depressive symptoms, which manifest during adolescence. Animal studies have used maternal separation as a model of early adversity to produce adult depressive-like behaviors, but have yet to examine these behaviors during adolescence. Moreover, the nature of depressive-like behaviors has not been well characterized in this model. Here, we used the triadic model of learned helplessness to understand controllability, helplessness, and motivational factors following maternal separation in male and female adolescent rats. We found sex-dependent changes in the effects of separation, with males demonstrating loss of controllability in an escapable shock condition, whereas females demonstrated motivational impairment in a no-shock condition. The effect, however, did not endure as adult females were no longer helpless. Reductions in parvalbumin, a GABAergic marker, in the prefrontal cortex of separated subjects relative to age-matched controls were evident and paralleled depressive-like behavior. Understanding the risk factors for depression, the nature of depressive-like behaviors, and their unique sex dependency may ultimately provide insight into improved treatments.

Rationale Adolescents are often described as “lacking brakes” resulting in an increase in several behaviors associated with risk for addiction. Prefrontal cortex dopamine and cortico-limbic interaction play an important role in addiction, and we have previously shown that the dopamine D1 receptor is elevated on prelimbic prefrontal output neurons in adolescent rats. We hypothesized that a constellation of risk-related behaviors are mediated by prefrontal output neuron expression of D1. Objectives We aimed to determine the role of the dopamine D1 receptor in behavioral and neural correlates of risk for addiction that are often observed in adolescents. Therefore high-risk behaviors as well as subcortical D2 receptor expression were investigated in adult animals with experimentally elevated D1 on prefrontal glutamatergic neurons. Methods A lentiviral vector that selectively expressed the D1 receptor within glutamate neurons was injected in the prelimbic prefrontal cortex of adult male rats. Place conditioning to cocaine, alcohol, and nicotine, as well as delay discounting, novelty preferences, anxiety, cocaine self-administration, and sucrose preferences were assessed. Results Virally-mediated D1 overexpression in adults leads to stronger drug-cue associations, greater consumption of sweet solutions, elevates bias towards immediate satisfaction rather than delaying gratification, decreases anxiety and causes rats to work harder for and take more cocaine. Furthermore elevated cortical D1 reduces D2 receptors in the accumbens (a putative risk marker). Conclusions Together, these data suggest a common mechanism for increased motivational drive to seek and consume substances with hedonic value, consistent with adolescent addictive processes.

Rationale Increased activity of prefrontal D1 dopamine receptors (D1R) is involved in reward-related behavior found in bipolar disorder and drug addiction. While the effects of elevated D1R are known, depressive-like behaviors also occur in these disorders after reward-seeking ends. Objectives The goal is to characterize how termination of D1R over-expression influences depressive-like behaviors. Methods An inducible (Tet.On), lentiviral vector was used to manipulate the expression of the DRD1 gene in glutamate neurons within the prefrontal cortex in male, adult rats. Sexual activity and sucrose preference were studied in both D1R elevated ‘ON’ and relatively reduced ‘OFF’ states. Following termination of the D1R ‘ON’ state, depressive-like behavior was determined in the ‘OFF’ state. Expression of the transcriptional regulator, cyclic AMP-responsive element binding protein (CREB), was used as an indication of down-stream effects in the NA. Results ‘ON’ D1R expression increased sexual activity that returned to baseline in the ‘OFF’ state. Sucrose preferences increased ∼ 6% in ‘ON’ state but fell 11% below control levels when ‘OFF’. Consistent with a depressive-like phenotype, D1R ‘OFF’ decreased activity by 40%, impaired the ability to control (43%) and motivation to escape shock (27% more impaired) relative to dsRed ‘OFF’. CREB increased 29% in the NA in the D1R ‘OFF’ state relative to the ‘ON’ state. Conclusions This novel approach demonstrates that elevated D1R expression increased hedonic behavior, whereas the termination of D1R over-expression often resulted in depressive-like behavior. These observations support a role for D1R expression cycling in bipolar-associated behaviors and addiction.