Low expression of D2R and Wntless correlates with high motivation for heroin.
Drug overdose now exceeds car accidents as the leading cause of accidental death in the United States. Of those drug overdoses, a large percentage of the deaths are due to heroin and/or pharmaceutical overdose, specifically misuse of prescription opioid analgesics. It is imperative, then, that we understand the mechanisms that lead to opioid abuse and addiction. The rewarding actions of opioids are mediated largely by the mu-opioid receptor (MOR), and signaling by this receptor is modulated by various interacting proteins. The neurotransmitter dopamine also contributes to opioid reward, and opioid addiction has been linked to reduced expression of dopamine D2 receptors (D2R) in the brain. That said, it is not known if alterations in the expression of these proteins relate to drug exposure and/or to the "addiction-like" behavior exhibited for the drug. Here, we held total drug self-administration constant across acquisition and showed that reduced expression of the D2R and the MOR interacting protein, Wntless, in the medial prefrontal cortex was associated with greater addiction-like behavior for heroin in general and with a greater willingness to work for the drug in particular. In contrast, reduced expression of the D2R in the nucleus accumbens and hippocampus was correlated with greater seeking during signaled nonavailability of the drug. Taken together, these data link reduced expression of both the D2R and Wntless to the explicit motivation for the drug rather than to differences in total drug intake per se.
Department of Pharmacology, College of Medicine, Pennsylvania State University.
Diana M
DM
Tacelosky
Department of Neural and Behavioral Sciences, College of Medicine, Pennsylvania State University.
Danielle N
DN
Alexander
Department of Pharmacology, College of Medicine, Pennsylvania State University.
Megan
M
Morse
Department of Neural and Behavioral Sciences, College of Medicine, Pennsylvania State University.
Andras
A
Hajnal
Division of Biostatistics and Bioinformatics, Department of Public Health Sciences, College of Medicine, Pennsylvania State University.
Arthur
A
Berg
Department of Pharmacology, College of Medicine, Pennsylvania State University.
Robert
R
Levenson
Department of Neural and Behavioral Sciences, College of Medicine, Pennsylvania State University.
Patricia S
PS
Grigson
D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism; D058999:Drug-Seeking Behavior / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D003932:Heroin / Q000008:administration & dosage*; D006556:Heroin Dependence / Q000378:metabolism / Q000523:psychology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D009042:Motivation / Q000187:drug effects* / Q000502:physiology; D009294:Narcotics / Q000008:administration & dosage*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012201:Reward; D012646:Self Administration
C000607792:DRD2 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D009294:Narcotics; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; C549112:Wls protein, rat; D003932:Heroin