An animal model of genetic vulnerability to behavioral disinhibition and responsiveness to reward-related cues: implications for addiction.
Rats selectively bred based on high or low reactivity to a novel environment were characterized for other behavioral and neurobiological traits thought to be relevant to addiction vulnerability. The two lines of animals, which differ in their propensity to self-administer drugs, also differ in the value they attribute to cues associated with reward, in impulsive behavior, and in their dopamine system. When a cue was paired with food or cocaine reward bred high-responder rats (bHRs) learned to approach the cue, whereas bred low-responder rats (bLRs) learned to approach the location of food delivery, suggesting that bHRs but not bLRs attributed incentive value to the cue. Moreover, although less impulsive on a measure of 'impulsive choice', bHRs were more impulsive on a measure of 'impulsive action'- ie, they had difficulty withholding an action to receive a reward, indicative of 'behavioral disinhibition'. The dopamine agonist quinpirole caused greater psychomotor activation in bHRs relative to bLRs, suggesting dopamine supersensitivity. Indeed, relative to bLRs, bHRs also had a greater proportion of dopamine D2(high) receptors, the functionally active form of the receptor, in the striatum, in spite of lower D2 mRNA levels and comparable total D2 binding. In addition, fast-scan cyclic voltammetry revealed that bHRs had more spontaneous dopamine 'release events' in the core of the nucleus accumbens than bLRs. Thus, bHRs exhibit parallels to 'externalizing disorders' in humans, representing a genetic animal model of addiction vulnerability associated with a propensity to attribute incentive salience to reward-related cues, behavioral disinhibition, and increased dopaminergic 'tone.'
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA. sflagel@umich.edu
Shelly B
SB
Flagel
Terry E
TE
Robinson
Jeremy J
JJ
Clark
Sarah M
SM
Clinton
Stanley J
SJ
Watson
Phillip
P
Seeman
Paul E M
PE
Phillips
Huda
H
Akil
D000818:Animals; D016739:Behavior, Addictive / Q000523:psychology*; D003214:Conditioning, Classical / Q000502:physiology; D003463:Cues; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology*; D005824:Genetics, Behavioral; D007175:Impulsive Behavior / Q000235:genetics*; D008297:Male; D010641:Phenotype; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D019257:Quinpirole / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D012201:Reward
D018491:Dopamine Agonists; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D019257:Quinpirole