Phosphodiesterase 4 inhibition impairs cocaine-induced inhibitory synaptic plasticity and conditioned place preference.
Endocannabinoid-mediated long-term depression of inhibitory synaptic transmission (I-LTD) in the ventral tegmental area (VTA) is implicated in cocaine-induced inhibitory synaptic plasticity and behavioral effects. It remains poorly understood, however, how this I-LTD is regulated and whether this regulation affects cocaine-seeking behavior. I-LTD requires cyclic adenosine 3', 5'-monophosphate (cAMP)-dependent protein kinase A (PKA) signaling, raising the possibility that modulators of cAMP/PKA signaling may regulate I-LTD and the reinforcement behavior. Phosphodiesterase (PDE) 4 hydrolyses cAMP and terminates cAMP/PKA signaling. Here, we report that selective PDE4 inhibitors rolipram and Ro 20-1724 blocked I-LTD and acute depression of inhibitory postsynaptic currents (IPSCs) induced by D₂ dopamine receptor and cannabinoid CB₁ receptor agonists in VTA dopamine neurons. We also show that intra-VTA microinjections of PDE4 inhibitor rolipram impaired the acquisition, but not the expression, of conditioned place preference (CPP) to cocaine. Systemic administration of rolipram also increased cAMP response element-binding protein (CREB) phosphorylation and activation in the VTA. Together, our results suggest that blockade of cocaine-induced inhibitory synaptic plasticity (I-LTD) and enhancement of CREB activation are two putative cellular mechanisms by which PDE4 inhibition impairs the acquisition of cocaine CPP.
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
Peng
P
Zhong
Wei
W
Wang
Fei
F
Yu
Maressa
M
Nazari
Xiaojie
X
Liu
Qing-Song
QS
Liu
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004333:Drug Administration Routes; D004347:Drug Interactions; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D008845:Microinjections; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects
D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; D014446:Tyrosine 3-Monooxygenase; D050882:CREB-Binding Protein; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D014633:Valine; D003042:Cocaine; D004298:Dopamine