Phosphodiesterase 4 inhibition impairs cocaine-induced inhibitory synaptic plasticity and conditioned place preference. Neuropsychopharmacology 2012 Oct;37(11):2377-87
Date
06/21/2012Pubmed ID
22713909Pubmed Central ID
PMC3442353DOI
10.1038/npp.2012.93Scopus ID
2-s2.0-84866412744 (requires institutional sign-in at Scopus site) 32 CitationsAbstract
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.
Author List
Zhong P, Wang W, Yu F, Nazari M, Liu X, Liu QSAuthor
Qing-song Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
6-Cyano-7-nitroquinoxaline-2,3-dioneAnimals
CREB-Binding Protein
Cocaine
Conditioning, Operant
Cyclic Nucleotide Phosphodiesterases, Type 4
Dopamine
Dopamine Uptake Inhibitors
Drug Administration Routes
Drug Interactions
Electric Stimulation
Enzyme Inhibitors
Excitatory Amino Acid Antagonists
In Vitro Techniques
Inhibitory Postsynaptic Potentials
Male
Microinjections
Neural Inhibition
Neuronal Plasticity
Patch-Clamp Techniques
Rats
Rats, Sprague-Dawley
Signal Transduction
Tyrosine 3-Monooxygenase
Valine
Ventral Tegmental Area
