Prefrontal dopamine is directly involved in the anxiogenic interoceptive cue of pentylenetetrazol but not in the interoceptive cue of chlordiazepoxide in the rat

Rationale: The prefrontal cortical (PFC) dopamine (DA) system has been impl icated in anxiety-related behavioral changes, but direct, unequivocal suppo rt for this idea is sparse. Objectives: The present aim was to study the fu nctional significance of prefrontal DA using the pentylenetetrazol (PTZ) di scrimination model of anxiety. A comparison was made with its role in the c ue of the anxiolytic drug chlordiazepoxide (CDP). Methods: Two groups of ra ts were trained to discriminate either PTZ (20 mg/kg, s.c.) or CDP (10 mg/k g, i.p.) from saline using an operant drug discrimination procedure. After prolonged training, half of each group was used to assess biochemical chang es induced by both drugs in different sub areas of the PFC. For the remaini ng rats, discrimination training continued and generalization tests with PT Z and CDP were performed. Rats were then provided with bilateral guide cann ulae aimed at the ventromedial (vm) PFC, and the effects of local infusions of DAergic drugs on discriminative performance were evaluated. Results: CD P did not affect PFC DA activity, but PTZ increased the DOPAC/DA ratio in t he 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 depende ntly whereas the agonist apomorphine partially generalized to this cue. In CDP-trained rats, neither drug antagonized or generalized to the CDP cue, s howing that PFC DA is not critically involved in the CDP cue and that local pharmacological manipulations of PFC DA do not affect discriminative abili ties per se. Conclusions: The DAergic innervation of the PFC is directly in volved in the behavioral effects of PTZ, suggesting a role for it in anxiet y.