Presynaptic α7- and β2-Containing Nicotinic Acetylcholine Receptors Modulate Excitatory Amino Acid Release from Rat Prefrontal Cortex Nerve Terminals via Distinct Cellular Mechanisms

Abstract

Nicotine can enhance working memory and attention. Activation of both ␣7 and ␤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 ␣7 and ␤2* nAChR-mediated ]D-aspartate release was also blocked by mitogen-activated protein kinase kinase 1 inhibitors, implicating extracellular signal-regulated kinase (ERK)1/2 in ␣7 nAChRevoked 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, ␤2* and ␣7 nAChR subtypes in the PFC mediate [3 H]D-aspartate release via distinct mechanisms as a result of their differential coupling to VOCCs and Ca 2ϩ -induced Ca 2ϩ release (CICR), respectively. The ability of ␣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.

Nicotinic receptor-evoked hippocampal norepinephrine release is highly sensitive to inhibition by isoflurane

“…This suggests that nAChR activation can trigger downstream Na þ channel activation to produce further depolarization and Ca 2þ -dependent NE release. Presynaptic nAChR effects are region-specific, as nicotinic receptor agonists evoke excitatory amino acid release from rat prefrontal cortex 28 and GABA release from mouse whole-brain 29 synaptosomes. In addition to differences in nAChR-subtype distribution between brain regions, 30 31 differences in nAChR-subtypes exist between the same brain region of different species.…”

Nicotinic α7 and α4β2 agonists enhance the formation and retrieval of recognition memory: Potential mechanisms for cognitive performance enhancement in neurological and psychiatric disorders

“…Activation of these receptors may improve cognitive function by several mechanisms; α4β2 agonists have been shown to stimulate the release of dopamine, noradrenaline, and acetylcholine in the hippocampus and frontal cortex in rats (Bontempi et al, 2001). In addition, activation of α7 nAChRs has been shown to modulate the release of glutamate (Dickinson et al, 2008), GABA (Arnaiz-Cot et al, 2008), and dopamine (Quarta et al, 2009) in the PFC, hippocampus and striatum. Our data, together with previous preclinical and clinical results, strongly supports the role of α7 and α4β2 nAChRs in improving cognitive performance.…”

Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors

“…This subtype of nAChR has major pre-synaptic roles in the brain [4], which include regulating the release of dopamine from nerve terminals in the dopaminergic reward pathway [5,6]. The activation of α7 nAChRs is neuroprotective against toxicity resulting from exposure to the neurotoxic β-amyloid peptide, Aβ1-42, important in Alzheimer's disease and other toxins [7].…”