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Open Access item Control of serotonergic function in medial prefrontal cortex by serotonin-2A receptors through a glutamate-dependent mechanism

Authors:Martín-Ruiz, Raúl
Puig, M. Victoria
Celada, Pau
Shapiro, David A.
Roth, Bryan L.
Mengod Los Arcos, Guadalupe
Artigas, Francesc
Keywords:5-hydroxytryptamine, 5-HT1A receptors, 5-HT2A receptors, AMPA, DOI, dorsal raphe nucleus, GABA, glutamate, hallucinogens, medial prefrontal cortex, microdialysis, mGluR, NMDA, single-unit recordings, thalamus
Issue Date:15-Dec-2001
Publisher:Society for Neuroscience
Citation:Journal of Neuroscience 21 (24) : 9856–9866 (2001)
Abstract:We examined the in vivo effects of the hallucinogen 4-iodo-2,5-dimethoxyamphetamine (DOI). DOI suppressed the firing rate of 7 of 12 dorsal raphe (DR) serotonergic (5-HT) neurons and partially inhibited the rest (ED(50) = 20 microg/kg, i.v.), an effect reversed by M100907 (5-HT(2A) antagonist) and picrotoxinin (GABA(A) antagonist). DOI (1 mg/kg, s.c.) reduced the 5-HT release in medial prefrontal cortex (mPFC) to 33 +/- 8% of baseline, an effect also antagonized by M100907. However, the local application of DOI in the mPFC increased 5-HT release (164 +/- 6% at 100 microm), an effect antagonized by tetrodotoxin, M100907, and BAY x 3702 (5-HT(1A) agonist) but not by SB 242084 (5-HT(2C) antagonist). The 5-HT increase was also reversed by NBQX (AMPA-KA antagonist) and 1S,3S-ACPD (mGluR 2/3 agonist) but not by MK-801 (NMDA antagonist). AMPA mimicked the 5-HT elevation produced by DOI. Likewise, the electrical-chemical stimulation of thalamocortical afferents and the local inhibition of glutamate uptake increased the 5-HT release through AMPA receptors. DOI application in mPFC increased the firing rate of a subgroup of 5-HT neurons (5 of 10), indicating an enhanced output of pyramidal neurons. Dual-label fluorescence confocal microscopic studies demonstrated colocalization of 5-HT(1A) and 5-HT(2A) receptors on individual cortical pyramidal neurons. Thus, DOI reduces the activity of ascending 5-HT neurons through a DR-based action and enhances serotonergic and glutamatergic transmission in mPFC through 5-HT(2A) and AMPA receptors. Because pyramidal neurons coexpress 5-HT(1A) and 5-HT(2A) receptors, DOI disrupts the balance between excitatory and inhibitory inputs and leads to an increased activity that may mediate its hallucinogenic action.
Publisher version (URL):http://www.jneurosci.org/content/21/24/9856.full
URI:http://hdl.handle.net/10261/33137
ISSN:0270-6474
E-ISSNmetadata.dc.identifier.doi = DOI:1529-2401
Appears in Collections:(IIBB) Artículos

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