title: Prefrontal dopamine is directly involved in the anxiogenic interoceptive cue of pentylenetetrazol but not in the interoceptive cue of chlordiazepoxide in the rat.
abstract: BACKGROUND
  The prefrontal cortical (PFC) dopamine (DA) system has been implicated in anxiety-related behavioral changes, but direct, unequivocal support for this idea is sparse.
  
  
  OBJECTIVE
  The present aim was to study the functional significance of prefrontal DA using the pentylenetetrazol (PTZ) discrimination model of anxiety. A comparison was made with its role in the cue of the anxiolytic drug chlordiazepoxide (CDP).
  
  
  METHODS
  Two groups of rats were trained to discriminate either PTZ (20 mg/kg, s.c.) or CDP (10 mg/kg, i.p.) from saline using an operant drug discrimination procedure. After prolonged training, half of each group was used to assess biochemical changes induced by both drugs in different sub areas of the PFC. For the remaining rats, discrimination training continued and generalization tests with PTZ and CDP were performed. Rats were then provided with bilateral guide cannulae aimed at the ventromedial (vm) PFC, and the effects of local infusions of DAergic drugs on discriminative performance were evaluated.
  
  
  RESULTS
  CDP did not affect PFC DA activity, but PTZ increased the DOPAC/DA ratio in the vmPFC selectively. Generalization tests showed that the cues of PTZ and CDP were dose dependent. In PTZ-trained rats, infusions of the DA receptor antagonist cis-flupenthixol into the vmPFC blocked the PTZ cue dose dependently, whereas the agonist apomorphine partially generalized to this cue. In CDP-trained rats, neither drug antagonized or generalized to the CDP cue, showing that PFC DA is not critically involved in the CDP cue and that local pharmacological manipulations of PFC DA do not affect discriminative abilities per se.
  
  
  CONCLUSIONS
  The DAergic innervation of the PFC is directly involved in the behavioral effects of PTZ suggesting a role for it in anxiety.
authors.affiliation: Department of Psychopharmacology, Faculty of Pharmacy, Utrecht, The Netherlands. L.M.Broersen@pharm.uu.nl
authors.forename: L M
authors.initials: LM
authors.lastname: Broersen
authors.forename: F
authors.initials: F
authors.lastname: Abbate
authors.forename: M G
authors.initials: MG
authors.lastname: Feenstra
authors.forename: J P
authors.initials: JP
authors.lastname: de Bruin
authors.forename: R P
authors.initials: RP
authors.lastname: Heinsbroek
authors.forename: B
authors.initials: B
authors.lastname: Olivier
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D001058:Apomorphine / Q000494:pharmacology; D002707:Chlordiazepoxide / Q000494:pharmacology; D003463:Cues; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D008297:Male; D010433:Pentylenetetrazole / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018491:Dopamine Agonists; D018756:GABA Antagonists; D018757:GABA Modulators; D002707:Chlordiazepoxide; D001058:Apomorphine; D004298:Dopamine; D010433:Pentylenetetrazole