Presynaptic α7- and β2-containing nicotinic acetylcholine receptors modulate excitatory amino acid release from rat prefrontal cortex nerve terminals via distinct cellular mechanisms

Nicotine can enhance working memory and attention. Activation of both alpha 7 and beta 2* nicotinic acetylcholine receptors (nAChRs) in the prefrontal cortex (PFC) has been implicated in these processes. The ability of presynaptic nAChRs to modulate neurotransmitter release, notably glutamate release, is postulated to contribute to nicotine's effects. We have examined the cellular mechanisms underlying alpha 7 and beta 2* nAChR-mediated [H-3]D-aspartate release from the PFC in vitro. Using the alpha 7 and beta 2* nAChR-selective agonists (R)-N-(1-azabicyclo[2.2.2]oct- 3-yl)(5-(2-pyridyl)thiophene-2-carboxamide) (compound A) and 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-iodo-A-85380), respectively, in conjunction with inhibitors of voltage-operated Ca2+ channels (VOCCs) and intracellular Ca2+ stores, we show that [H-3] D-aspartate release evoked by activation of beta 2* nAChRs occurs via VOCCs. In contrast, alpha 7 nAChR-evoked release was unaffected by VOCC blockers but was abolished by modulators of Ca2+ stores, including ryanodine. The alpha 7 nAChR ligand alpha-bungarotoxin and ryanodine receptors were colocalized to a subpopulation of PFC synaptosomes. Compound A-evoked [H-3] D-aspartate release was also blocked by mitogen-activated protein kinase kinase 1 inhibitors, implicating extracellular signal-regulated kinase (ERK)1/2 in alpha 7 nAChR-evoked exocytosis. Western blotting confirmed that compound A, but not 5-iodo-A-85380, application increased ERK2 phosphorylation in PFC synaptosomes, and this was dependent on ryanodine-sensitive stores. Compound A also promoted synapsin-1 phosphorylation at ERK1/2-dependent sites, in a ryanodine-sensitive manner. Thus, beta 2* and alpha 7 nAChR subtypes in the PFC mediate [H-3] D-aspartate release via distinct mechanisms as a result of their differential coupling to VOCCs and Ca2+-induced Ca2+ release (CICR), respectively. The ability of alpha 7 nAChRs to promote the phosphorylation of presynaptic ERK2 and synapsin-1, downstream of CICR, provides a potential mechanism for presynaptic facilitation in the PFC.