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Control of Serotonergic Function in Medial Prefrontal Cortex by Serotonin-2A Receptors through a Glutamate-Dependent Mechanism

Raúl Martín‐Ruiz, M. Victoria Puig, Pau Celada, А. О. Шпаков, Bryan L. Roth, Guadalupe Mengod, Francesc Artigas

Journal of Neuroscience December 15, 2001 DOI: 10.1523/jneurosci.21-24-09856.2001 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Experimental study Peer reviewed
Population Rat dorsal raphe serotonergic neurons and medial prefrontal cortex
Interventions 4-iodo-2 5-dimethoxyamphetamine (DOI)
Dose 20 microg/kg, i.v. (ED50); 1 mg/kg, s.c.; 100 microm (local)
Topics Serotonin
Keywords Nbqx Ampa receptor Agonist Nmda receptor Dorsal raphe nucleus Glutamate receptor Biochemistry
Citations 335
Key findings DOI reduces ascending serotonergic neuron activity through a dorsal raphe-based action and enhances serotonergic and glutamatergic transmission in medial prefrontal cortex through 5-HT2A and AMPA receptors, disrupting excitatory-inhibitory balance in pyramidal neurons coexpressing 5-HT1A and 5-HT2A receptors.

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.

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The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... 1992 Laboratory study
5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain 1997 Experimental study

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