title: Involvement of nNOS/NO/sGC/cGMP signaling pathway in cocaine sensitization and in the associated hippocampal alterations: does phosphodiesterase 5 inhibition help to drug vulnerability?
abstract: BACKGROUND
  Repeated cocaine administration induces behavioral sensitization in about 50 % of treated animals. Nitric oxide could be involved in the acquisition and maintenance of behavioral cocaine effects, probably by activation of neuronal nitric oxide synthase (nNOS)/NO/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) signaling pathway, since inhibition of the nNOS enzyme attenuates development of sensitization in rats. On the other hand, increased cGMP availability by phosphodiesterase 5 inhibitors has been correlated to the misuse and recreational use of these agents and also to the concomitant use with illicit drugs in humans. Hippocampus is an important brain region for conditioning to general context previously associated to drug availability, influencing drug-seeking behavior and sensitization. Moreover, cocaine and other drugs of abuse can affect the strength of glutamate synapses in this structure, lastly modifying neuronal activity in main regions of the reward circuitry.
  
  
  OBJECTIVE
  The objective of this study is to determine whether the pharmacological manipulation of nNOS/NO/sGC/cGMP signaling pathway altered changes induced by repeated cocaine exposure.
  
  
  RESULTS
  The present investigation showed a relationship between behavioral cocaine sensitization, reduced threshold to generate long-term potentiation (LTP) in hippocampal dentate gyrus, and increased nNOS activity in this structure. However, when nNOS or sGC were inhibited, the number of sensitized animals was reduced, and the threshold to generate LTP was increased. The opposite occurred when cGMP availability was increased.
  
  
  CONCLUSIONS
  We demonstrate a key role of the nNOS activity and NO/sGC/cGMP signaling pathway in the development of cocaine sensitization and in the associated enhancement of hippocampal synaptic transmission.
authors.affiliation: IFEC-CONICET, Departamento de Farmacología, Facultad de Ciencias Químicas, UNC, Haya de la Torre y Medina Allende 5000, Córdoba, Argentina.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Gabach
authors.forename: Valeria P
authors.initials: VP
authors.lastname: Carlini
authors.forename: María C
authors.initials: MC
authors.lastname: Monti
authors.forename: Laura E
authors.initials: LE
authors.lastname: Maglio
authors.forename: Susana Rubiales
authors.initials: SR
authors.lastname: De Barioglio
authors.forename: Mariela F
authors.initials: MF
authors.lastname: Perez
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism / Q000503:physiopathology; D003042:Cocaine / Q000008:administration & dosage*; D006152:Cyclic GMP / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D003042:Cocaine