The phosphodiesterase-4 inhibitor rolipram attenuates heroin-seeking behavior induced by cues or heroin priming in rats.
Inhibition of phosphodiesterase-4 (PDE4), an enzyme that specifically hydrolyzes cyclic adenosine monophosphate (cAMP) increases intracellular cAMP/cAMP-response element binding protein (CREB) signaling. Activation of this signaling is considered as an important compensatory response that decreases motivational properties of drugs of abuse. However, it is not known whether PDE4 is involved in heroin seeking. Self-administration of heroin (50 μg/kg/infusion) was performed under the fixed ratio 1 (FR1) schedule for 14 d and then drug seeking was extinguished for 10 d. The progressive ratio schedule was used to evaluate the relative motivational value of heroin reinforcement. After training, the conditioned cue or heroin priming (250 μg/kg) was introduced for the reinstatement of heroin-seeking behavior. Pretreatment (i.p.) with rolipram (0.03-0.3 mg/kg), a prototypical, selective PDE4 inhibitor, failed to inhibit heroin self-administration under the FR1 schedule, but decreased the reward values under the progressive ratio schedule in a dose-dependent manner. In addition, rolipram decreased the reinstatement of heroin seeking induced by cues or heroin priming even at the lowest dose (0.03 mg/kg); in contrast, the highest dose (0.3 mg/kg) of rolipram was required to decrease sucrose reinforcement. Finally, the effects of rolipram on heroin-seeking behavior were correlated with the increases in expression of phosphorylated CREB in the nucleus accumbens. The study demonstrated that rolipram inhibited heroin reward and heroin-seeking behavior. The results suggest that PDE4 plays an essential role in mediating heroin seeking and that PDE4 inhibitors may be used as a potential pharmacotherapeutic approach for heroin addiction.
Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, School of Medicine,Ningbo University,Ningbo 315010,P. R. China.
Miaojun
M
Lai
Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, School of Medicine,Ningbo University,Ningbo 315010,P. R. China.
Huaqiang
H
Zhu
Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, School of Medicine,Ningbo University,Ningbo 315010,P. R. China.
Anna
A
Sun
Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, School of Medicine,Ningbo University,Ningbo 315010,P. R. China.
Dingding
D
Zhuang
Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, School of Medicine,Ningbo University,Ningbo 315010,P. R. China.
Dan
D
Fu
Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, School of Medicine,Ningbo University,Ningbo 315010,P. R. China.
Weisheng
W
Chen
Departments of Behavioral Medicine & Psychiatry and Physiology & Pharmacology,West Virginia University Health Sciences Center,Morgantown, WV 26506,USA.
Han-Ting
HT
Zhang
Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, School of Medicine,Ningbo University,Ningbo 315010,P. R. China.
Wenhua
W
Zhou
D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005108:Extinction, Psychological / Q000187:drug effects; D003932:Heroin / Q000008:administration & dosage*; D006556:Heroin Dependence / Q000188:drug therapy; D008297:Male; D009294:Narcotics / Q000008:administration & dosage*; D058988:Phosphodiesterase 4 Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule; D012201:Reward; D020889:Rolipram / Q000627:therapeutic use*; D012646:Self Administration
D009294:Narcotics; D058988:Phosphodiesterase 4 Inhibitors; D003932:Heroin; D050882:CREB-Binding Protein; D020889:Rolipram