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 is 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 over-expression in adults leads to stronger drug-cue associations and 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.
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Abbreviations
- NAc:
-
Nucleus accumbens
- plPFC:
-
Prelimbic PFC
- CamKII:
-
Calmodulin kinase II
- GFP:
-
Green fluorescent protein
- D1:
-
Dopamine receptor type I
- D2:
-
Dopamine receptor type II
- FR:
-
Fixed ratio
- PR:
-
Progressive ratio
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Acknowledgments
The authors acknowledge the support of DA-10543 and DA-026485 (to SLA), the Leopoldina Fellowship Program LPDS 2009–40 (to NF), and NS067335 (to KCS). We also would like to thank Dr. Joris van Arensbergen, Yenare Lee, and Noah McKenna for the technical help, Dr. David Sibley (NIH) for providing the pSFD1 receptor plasmid, Dr. Karl Deisseroth (Stanford University) for the CamKII promotor, Dr. Atsushi Miyanohara (UCSD) for the synapsin promoter, and Dr. Didier Trono (EPFL, Lausanne, CH) for providing the original lentivirus vector system.
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The authors declare that they have no competing financial interests.
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Sonntag, K.C., Brenhouse, H.C., Freund, N. et al. Viral over-expression of D1 dopamine receptors in the prefrontal cortex increase high-risk behaviors in adults: Comparison with adolescents. Psychopharmacology 231, 1615–1626 (2014). https://doi.org/10.1007/s00213-013-3399-8
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DOI: https://doi.org/10.1007/s00213-013-3399-8