TY - JOUR
T1 - Lack of abuse potential in a highly selective dopamine D3 agonist, PF-592,379, in drug self-administration and drug discrimination in rats
AU - Collins, Gregory T.
AU - Butler, Paul
AU - Wayman, Chris
AU - Ratcliffe, Sian
AU - Gupta, Paul
AU - Oberhofer, Geoffrey
AU - Caine, S. Barak
PY - 2012/6
Y1 - 2012/6
N2 - Dopamine D3-preferring agonists are commonly used to treat Parkinson's disease and restless leg syndrome; however, laboratory animal studies suggest that they may possess a moderate abuse potential. These studies aimed to compare the highly selective, full D 3 agonist PF-592,379 to the less selective D 3 agonist 7-OH-DPAT, and the indirect dopamine agonist cocaine in drug self-administration and discrimination assays. Although rats readily acquired high rates of fixed ratio (FR)1 responding for cocaine, experimentally naive rats failed to acquire responding when 7-OH-DPAT or PF-592,379 was made available during an 18-session acquisition period. Cocaine also maintained dose-dependent levels of responding when available under a FR5 or a progressive ratio (PR) schedule of reinforcement. Although 7-OH-DPAT maintained modest levels of responding when substituted under a FR5, it failed to maintain significant levels of PR responding. PF-592,379 maintained saline-like rates of responding when substituted under FR5 or PR schedules of reinforcement. Similar behavioral profiles were observed in cocaine discrimination assays, with 7-OH-DPAT partially substituting for cocaine, and PF-592,379 producing saline-like effects over a wide range of doses. Together, the results of these studies predict that highly selective D 3 agonists, such as PF-592,379, will have low abuse potential in humans.
AB - Dopamine D3-preferring agonists are commonly used to treat Parkinson's disease and restless leg syndrome; however, laboratory animal studies suggest that they may possess a moderate abuse potential. These studies aimed to compare the highly selective, full D 3 agonist PF-592,379 to the less selective D 3 agonist 7-OH-DPAT, and the indirect dopamine agonist cocaine in drug self-administration and discrimination assays. Although rats readily acquired high rates of fixed ratio (FR)1 responding for cocaine, experimentally naive rats failed to acquire responding when 7-OH-DPAT or PF-592,379 was made available during an 18-session acquisition period. Cocaine also maintained dose-dependent levels of responding when available under a FR5 or a progressive ratio (PR) schedule of reinforcement. Although 7-OH-DPAT maintained modest levels of responding when substituted under a FR5, it failed to maintain significant levels of PR responding. PF-592,379 maintained saline-like rates of responding when substituted under FR5 or PR schedules of reinforcement. Similar behavioral profiles were observed in cocaine discrimination assays, with 7-OH-DPAT partially substituting for cocaine, and PF-592,379 producing saline-like effects over a wide range of doses. Together, the results of these studies predict that highly selective D 3 agonists, such as PF-592,379, will have low abuse potential in humans.
KW - Cocaine
KW - Dopamine D2
KW - Dopamine D3
KW - Drug discrimination
KW - Drug self-administration
KW - PF-592,379
KW - Rat
UR - http://www.scopus.com/inward/record.url?scp=84860759962&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84860759962&partnerID=8YFLogxK
U2 - 10.1097/FBP.0b013e3283536d21
DO - 10.1097/FBP.0b013e3283536d21
M3 - Article
C2 - 22470105
AN - SCOPUS:84860759962
SN - 0955-8810
VL - 23
SP - 280
EP - 291
JO - Behavioural pharmacology
JF - Behavioural pharmacology
IS - 3
ER -