Viral over-expression of D1 dopamine receptors in the prefrontal cortex increase high-risk behaviors in adults: Comparison with adolescents

Abstract

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.

Extinction and reinstatement to cocaine-associated cues in male and female juvenile rats and the role of D1 dopamine receptor

“…Expression was stable throughout all experiments and placement and D1 over-expression confirmed by immunohistochemistry for D1 receptors. We have previously confirmed that this virus is specific for glutamatergic neurons (Sonntag et al, 2014). Subjects who did not demonstrate D1 overexpression within the plPFC were not used in the analyses.…”

“…The system expressed the rat D1R or green fluorescent protein; GFP) and was driven by a CamKIIα promoter, with full methods found in Sonntag et al (2014). The resulting viruses are CK.GFP and CK.D1.…”

“…Animals began behavioral assessments 5 days after surgery (at P90 and P24) to allow for viral expression (Sonntag et al, 2014). Expression was stable throughout all experiments and placement and D1 over-expression confirmed by immunohistochemistry for D1 receptors.…”

“…Specifically, we determined whether immature (juvenile) rats would show the same prolonged extinction as we have shown in adolescent rats (Brenhouse and Andersen, 2008) relative to adult rats and how this relates to D1 dopamine expression (Experiment 1). We genetically increased D1 dopamine receptors via a lentiviral vector with a CamKIIα (CK) promotor specifically within glutamatergic neurons in the plPFC (Sonntag et al, 2014). We have previously shown that increased D1 by viral transduction increases cocaine place preferences.…”

Mesocorticolimbic dopamine functioning in primary psychopathy: A source of within-group heterogeneity

“…For example, adolescence, which is a period associated with stronger DA-driven risk-taking, impulsivity, and novelty-seeking (Luciana et al, 2012), is marked by a transient increase of specifically the D1-receptors on PFC output neurons to the striatum and administering D1-antagonists directly in the PFC of adolescent rats dampened their impulsivity to immediate rewards (Brenhouse et al, 2008). This also holds true for adulthood since D1 over-expression on PFC output neurons in adult rats has been found to increase effort to obtain and boosts consumption of cocaine, biases towards a need for immediate satisfaction, and decreases anxiety (Sonntag et al, 2014). In other words, a low PFC DA activity and non-optimally high D1-to-D2-receptor ratio in the PFC boosts attention and motivation towards short-term rewards and reduces the D2-triggered anxiety since network dynamics are not labile enough to become aware about all sorts of possible outcomes, whereas a non-optimally low ratio increases D2-mediated labilization of PFC neural membranes and leads to distractibility, rumination, and impulsive responding to environmental stimuli.…”