title: Peroxisome proliferator-activated receptors-alpha modulate dopamine cell activity through nicotinic receptors.
abstract: BACKGROUND
  Modulation of midbrain dopamine neurons by nicotinic acetylcholine receptors (nAChRs) plays an important role in behavior, cognition, motivation, and reward. Specifically, nAChRs containing beta2 subunits (beta2-nAChRs) switch dopamine cells from a resting to an excited state. However, how beta2-nAChRs can be modulated and thereby how dopamine firing activity is affected remains elusive. Because changes in dopamine cell activity are reflected in the dynamics of microcircuits generating altered responses to stimuli and inputs, factors regulating their state are fundamental. Among these, endogenous ligands to the nuclear receptor-transcription factor peroxisome proliferator-activated receptors type-alpha (PPARalpha) have been recently found to suppress nicotine-induced responses of dopamine neurons.
  
  
  METHODS
  We used both in vitro and in vivo electrophysiological techniques together with behavioral analysis to investigate on the effects of modulation of PPARalpha in Sprague-Dawley rat and C57BLJ/6 mouse dopamine neurons and their interactions with beta2-nAChRs. To this aim, we took advantage of a selective reexpression of beta2-nAChR exclusively in dopamine cells by stereotaxically injecting a lentiviral vector in the mouse ventral tegmental area.
  
  
  RESULTS
  We found that activation of PPARalpha decreases in vitro both dopamine cell activity and ventral tegmental area net output through negative modulation of beta2-nAChRs. Additionally, PPARalpha activation in vivo reduces both the number of spontaneously active dopamine neurons and nicotine-induced increased locomotion.
  
  
  CONCLUSIONS
  Our combined findings suggest PPARalpha ligands as important negative modulators of beta2-nAChRs on dopamine neurons. Thus, PPARalpha ligands might prove beneficial in treating disorders in which dopamine dysfunction plays a prominent role, such as schizophrenia and nicotine addiction.
authors.affiliation: B.B. Brodie Department of Neuroscience, University of Cagliari, Monserrato, Italy. myriam@unica.it
authors.forename: Miriam
authors.initials: M
authors.lastname: Melis
authors.forename: Stefano
authors.initials: S
authors.lastname: Carta
authors.forename: Liana
authors.initials: L
authors.lastname: Fattore
authors.forename: Stefania
authors.initials: S
authors.lastname: Tolu
authors.forename: Sevil
authors.initials: S
authors.lastname: Yasar
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
authors.forename: Walter
authors.initials: W
authors.lastname: Fratta
authors.forename: Uwe
authors.initials: U
authors.lastname: Maskos
authors.forename: Marco
authors.initials: M
authors.lastname: Pistis
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000378:metabolism
chemical_list: D004298:Dopamine; D047493:PPAR alpha; D011978:Receptors, Nicotinic