Abstract
Alpha7 nicotinic acetylcholine receptors (nAChRs) are promising novel targets for the treatment of neurocognitive disorders. Although the cognitive enhancer potential of alpha7 nAChR agonists and positive allosteric modulators (PAMs) has been confirmed in several preclinical animal models, there are only sparse in vivo electrophysiological data on their effects on the firing activity and excitability of neurons. The present study investigated and compared local effects of alpha7 nAChR agonist PHA-543613 and PAMs PNU-120596 and NS-1738 on the spontaneous and N-methyl-D-aspartate-evoked (NMDA-evoked) firing rate of rat CA1 hippocampal pyramidal cells, in vivo. Furthermore, effects of alpha7 nAChR antagonist methyllycaconitine (MLA) and GABA were also tested. Results showed substantially different effects of the alpha7 nAChR agonist and PAMs. While PNU-120596 and NS-1738 predominantly and significantly increased both spontaneous and NMDA-evoked firing rate of the neurons, application of PHA-543613 resulted in almost equal distribution of facilitatory and inhibitory effects. The increase of the NMDA-evoked firing rate exerted by NS-1738 was superadditive over the sum of the single effects of NMDA and NS-1738. The simultaneous application of alpha7 nAChR agonist PHA-543613 and PAM NS-1738 resulted in additive increase of both spontaneous and NMDA-evoked firing rate. However, NS-1738 counteracted inhibitory effects of PHA-543613 in 5 out of 6 neurons, resulting in a synergistic potentiation of their firing responses to NMDA. Our results suggest that alpha7 nAChR PAMs increase neuronal excitability more potently than agonists, while the remarkable occurrence of inhibitory effects of PHA-543613 (possibly originating from receptor desensitization) implies that agonists may exert neuroprotective effects.
Highlights
Direct stimulation of the alpha[7] nicotinic acetylcholine receptor has become a promising target to attenuate cognitive decline in dementia as they are highly expressed in brain areas essential for cognition, attention and working memory, including the hippocampus, cerebral cortex and limbic structures[3,4]
The effects of local microiontophoretic application of alpha[7] nicotinic acetylcholine receptors (nAChRs) agonist PHA-543613, positive allosteric modulators (PAMs) NS-1738 and PNU-120596, and antagonist MLA were tested on the spontaneous and NMDA-evoked firing rate (NMDA)-evoked firing activity of altogether 111 hippocampal pyramidal neurons in rats anesthetized with chloral hydrate
The great majority of the neurons were clearly responsive to iontophoretically applied NMDA suggesting that the relevant dose of chloral hydrate for anesthesia did not markedly affect neurotransmission via NMDARs
Summary
Direct stimulation of the alpha[7] nicotinic acetylcholine receptor (nAChR) has become a promising target to attenuate cognitive decline in dementia as they are highly expressed in brain areas essential for cognition, attention and working memory, including the hippocampus, cerebral cortex and limbic structures[3,4]. We found that the synergistic effect of ACh and NMDA on the firing activity of the neurons was robustly decreased by the systemic administration of alpha[7] nAChR antagonist methyllycaconitine (MLA) but not by muscarinic antagonist scopolamine This prior work provided an in vivo evidence that alpha[7] nAChRs may contribute to pyramidal cell activation through the potentiation of glutamatergic neurotransmission. Our aim was to examine whether exogenous alpha[7] nAChR agonists and PAMs exert the same or similar effects as ACh on the firing activity of hippocampal CA1 neurons, and whether and how exogenous alpha[7] nAChR ligands may potentiate firing rate responses to glutamatergic receptor stimulation. The present experiments provide new insights into the actions of alpha[7] nAChR ligands on the neuronal level in vivo, and into the differences between the modulation of alpha[7] nAChR by agonists and PAMs with implications on their potential therapeutic use in the future
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