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Nootropic agents enhance the recruitment of fast GABAA inhibition in rat neocortex.
Cereb Cortex. 2005 Jul; 15(7):921-8.CC

Abstract

It is widely believed that nootropic (cognition-enhancing) agents produce their therapeutic effects by augmenting excitatory synaptic transmission in cortical circuits, primarily through positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors (AMPARs). However, GABA-mediated inhibition is also critical for cognition, and enhanced GABA function may be likewise therapeutic for cognitive disorders. Could nootropics act through such a mechanism as well? To address this question, we examined the effects of nootropic agents on excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) recorded from layer V pyramidal cells in acute slices of somatosensory cortex. Aniracetam, a positive modulator of AMPA/kainate receptors, increased the peak amplitude of evoked EPSCs and the amplitude and duration of polysynaptic fast IPSCs, manifested as a greater total charge carried by IPSCs. As a result, the EPSC/IPSC ratio of total charge was decreased, representing a shift in the excitation-inhibition balance that favors inhibition. Aniracetam did not affect the magnitude of either monosynaptic IPSCs (mono-IPSCs) recorded in the presence of excitatory amino acid receptor antagonists, or miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin. However, the duration of both mono-IPSCs and mIPSCs was prolonged, suggesting that aniracetam also directly modulates GABAergic transmission. Cyclothiazide, a preferential modulator of AMPAR function, enhanced the magnitude and duration of polysynaptic IPSCs, similar to aniracetam, but did not affect mono-IPSCs. Concanavalin A, a kainate receptor modulator, had little effect on EPSCs or IPSCs, suggesting there was no contribution from kainate receptor activity. These findings indicate that AMPAR modulators strengthen inhibition in neocortical pyramidal cells, most likely by altering the kinetics of AMPARs on synaptically connected interneurons and possibly by modulating GABA(A) receptor responses in pyramidal cells. This suggests that the therapeutic actions of nootropic agents may be partly mediated through enhanced cortical GABAergic inhibition, and not solely through the direct modification of excitation, as previously thought.

Authors+Show Affiliations

Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA.dling@downstate.eduNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15459084

Citation

Ling, Douglas S F., and Larry S. Benardo. "Nootropic Agents Enhance the Recruitment of Fast GABAA Inhibition in Rat Neocortex." Cerebral Cortex (New York, N.Y. : 1991), vol. 15, no. 7, 2005, pp. 921-8.
Ling DS, Benardo LS. Nootropic agents enhance the recruitment of fast GABAA inhibition in rat neocortex. Cereb Cortex. 2005;15(7):921-8.
Ling, D. S., & Benardo, L. S. (2005). Nootropic agents enhance the recruitment of fast GABAA inhibition in rat neocortex. Cerebral Cortex (New York, N.Y. : 1991), 15(7), 921-8.
Ling DS, Benardo LS. Nootropic Agents Enhance the Recruitment of Fast GABAA Inhibition in Rat Neocortex. Cereb Cortex. 2005;15(7):921-8. PubMed PMID: 15459084.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nootropic agents enhance the recruitment of fast GABAA inhibition in rat neocortex. AU - Ling,Douglas S F, AU - Benardo,Larry S, Y1 - 2004/09/30/ PY - 2004/10/2/pubmed PY - 2005/7/26/medline PY - 2004/10/2/entrez SP - 921 EP - 8 JF - Cerebral cortex (New York, N.Y. : 1991) JO - Cereb Cortex VL - 15 IS - 7 N2 - It is widely believed that nootropic (cognition-enhancing) agents produce their therapeutic effects by augmenting excitatory synaptic transmission in cortical circuits, primarily through positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors (AMPARs). However, GABA-mediated inhibition is also critical for cognition, and enhanced GABA function may be likewise therapeutic for cognitive disorders. Could nootropics act through such a mechanism as well? To address this question, we examined the effects of nootropic agents on excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) recorded from layer V pyramidal cells in acute slices of somatosensory cortex. Aniracetam, a positive modulator of AMPA/kainate receptors, increased the peak amplitude of evoked EPSCs and the amplitude and duration of polysynaptic fast IPSCs, manifested as a greater total charge carried by IPSCs. As a result, the EPSC/IPSC ratio of total charge was decreased, representing a shift in the excitation-inhibition balance that favors inhibition. Aniracetam did not affect the magnitude of either monosynaptic IPSCs (mono-IPSCs) recorded in the presence of excitatory amino acid receptor antagonists, or miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin. However, the duration of both mono-IPSCs and mIPSCs was prolonged, suggesting that aniracetam also directly modulates GABAergic transmission. Cyclothiazide, a preferential modulator of AMPAR function, enhanced the magnitude and duration of polysynaptic IPSCs, similar to aniracetam, but did not affect mono-IPSCs. Concanavalin A, a kainate receptor modulator, had little effect on EPSCs or IPSCs, suggesting there was no contribution from kainate receptor activity. These findings indicate that AMPAR modulators strengthen inhibition in neocortical pyramidal cells, most likely by altering the kinetics of AMPARs on synaptically connected interneurons and possibly by modulating GABA(A) receptor responses in pyramidal cells. This suggests that the therapeutic actions of nootropic agents may be partly mediated through enhanced cortical GABAergic inhibition, and not solely through the direct modification of excitation, as previously thought. SN - 1047-3211 UR - https://www.unboundmedicine.com/medline/citation/15459084/Nootropic_agents_enhance_the_recruitment_of_fast_GABAA_inhibition_in_rat_neocortex_ L2 - https://academic.oup.com/cercor/article-lookup/doi/10.1093/cercor/bhh191 DB - PRIME DP - Unbound Medicine ER -