α7 and non-α7 nicotinic acetylcholine receptors modulate dopamine release in vitro and in vivo in the rat prefrontal cortex

Nicotine enhances attentional and working memory aspects of executive function in the prefrontal cortex (PFC) where dopamine plays a major role. Here, we have determined the nicotinic acetylcholine receptor (nAChR) subtypes that can modulate dopamine release in rat PFC using subtype-selective drugs. Nicotine and 5-Iodo-A-85380 (β2* selective) elicited [³H]dopamine release from both PFC and striatal prisms in vitro and dopamine overflow from medial PFC in vivo . Blockade by dihydro-β-erythroidine supports the participation of β2* nAChRs. However, insensitivity of nicotine-evoked [³H]dopamine release to α-conotoxin-MII in PFC prisms suggests no involvement of α6β2* nAChRs, in contrast to the striatum, and this distinction is supported by immunoprecipitation of nAChR subunits from these tissues. The α7 nAChR-selective agonists choline and Compound A also promoted dopamine release from PFC in vitro and in vivo , and their effects were enhanced by the α7 nAChR-selective allosteric potentiator PNU-120596 and blocked by specific antagonists. DNQX and MK801 inhibited [³H]dopamine release evoked by choline and PNU-120596, suggesting crosstalk between α7 nAChRs, glutamate and dopamine in the PFC. In vivo, systemic (but not local) administration of PNU-120596, in the absence of agonist, facilitated dopamine overflow in the medial PFC, consistent with the activation of extracortical α7 nAChRs by endogenous acetylcholine or choline. These data establish that both β2* and α7 nAChRs can modulate dopamine release in the PFC in vitro and in vivo . Through their distinct actions on dopamine release, these nAChR subtypes could contribute to executive function, making them specific therapeutic targets for conditions such as schizophrenia and attention deficit hyperactivity disorder.