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

168

The mechanism(s) by which serotonin modulates dopamine release in the medial prefrontal cortex is not known, although studies suggest an involvement of 5-HT2 family receptors. We employed in vivo microdialysis and putatively selective 5-HT2A antagonists (M100907, MDL 11,939, SR46349B) to determine if 5-HT2A receptors are responsible for both drug-and stress-induced DA release in the medial prefrontal cortex. MDL 11,939 and SR46349B receptor-binding studies indicated, for the first time, that only MDL 11,939 had greater selectivity for the 5-HT2A vs the 5-HT2C receptor subtypes similar to M100907, and that both showed low or no affinity for non-5-HT2 receptors. Reverse dialysis with 5-HT2A antagonists had little or no effect on basal dopamine efflux. However, intracortical administration of MDL 11,939 or M100907 attenuated dopamine release induced by systemic administration of the 5-HT2 agonist DOI. Dual-probe microdialysis demonstrated that systemic DOI also increased glutamate concentrations in the ventral tegmental area (VTA). This was blocked by intracortical M100907. Cortical perfusion with M100907, or the atypical antipsychotic drug risperidone, but not the 5-HT2B/C ligand SB 206553, also decreased dopamine release induced physiologically by stress. These results indicate that stimulation of cortical 5-HT2A receptors increases the release of dopamine from the mesocortical system. They suggest that this effect may be mediated by increases in glutamate release from corticotegmental projections to the VTA. Additionally, they indicate that cortical 5-HT2A receptors modulate evoked dopamine release, such as that observed physiologically following mild stress. These findings may have implications for the pharmacological treatment of disorders resulting from or exacerbated by stress.

Section: Discussionmentioning

confidence: 96%

“…5-HT2A and 5-HT1A receptors locally modulate 5-HT in the mPFC (Martin-Ruiz et al, 2001). However, risperidone is a 5-HT2A antagonist and cortical 5-HT2A antagonist treatment does not increase 5-HT locally (Martin-Ruiz et al, 2001). Also, risperidone has low affinity for the 5-HT1A receptor (K i ¼ 250 nM; http://kidb.case.edu/ pdsp.php).…”

Section: Discussionmentioning

confidence: 99%

Evidence for the Preferential Involvement of 5-HT2A Serotonin Receptors in Stress- and Drug-Induced Dopamine Release in the Rat Medial Prefrontal Cortex

Pehek

Nocjar

Roth

et al. 2005

168

“…As cortical 5-HT 2A receptors are excitatory, and cortical 5-HT 1A receptors are inhibitory, it has been suggested recently that blockade of cortical 5-HT 2A receptors and/or functional 5-HT 1A receptor agonism may mediate the physiological balance between excitatory and inhibitory inputs onto prefrontal pyramidal neurons (Martin-Ruiz et al, 2001). In preclinical trials, 5-HT 1A selective agonists were capable of antagonizing (attenuating) neuroleptic-induced EPS in animal models (Ellenbroek et al, 1994;Liebman et al, 1989).…”

Section: Discussion Receptor Profile and Mechanism Of Actionmentioning

confidence: 99%

Aripiprazole, A Novel Atypical Antipsychotic Drug with a Unique and Robust Pharmacology

Shapiro

Renock

Arrington

et al. 2003

844

693

Atypical antipsychotic drugs have revolutionized the treatment of schizophrenia and related disorders. The current clinically approved atypical antipsychotic drugs are characterized by having relatively low affinities for D 2 -dopamine receptors and relatively high affinities for 5-HT 2A serotonin receptors (5-HT, 5-hydroxytryptamine (serotonin)). Aripiprazole (OPC-14597) is a novel atypical antipsychotic drug that is reported to be a high-affinity D 2 -dopamine receptor partial agonist. We now provide a comprehensive pharmacological profile of aripiprazole at a large number of cloned G protein-coupled receptors, transporters, and ion channels. These data reveal a number of interesting and potentially important molecular targets for which aripiprazole has affinity. Aripiprazole has highest affinity for h5-HT 2B -, hD 2L -, and hD 3 -dopamine receptors, but also has significant affinity

“…Thus, in line with previous reports (Moghaddam et al, 1997;Adams and Moghadam, 2001;Lorrain et al, 2003), MK-801 increases glutamate release onto AMPA/kainate receptors, which, in turn, elicit an enhanced glutamatergic output from mPFC neurons, including those projecting to the dorsal raphe nucleus, thereby increasing serotonergic cell firing and cortical 5-HT efflux. Although this functional interplay between the mPFC and the dorsal raphe nucleus is well documented (Hajós et al, 1998;Celada et al, 2001;Martín-Ruiz et al, 2001;Amargós-Bosch et al, 2003;Lucas et al, 2005), we presently cannot rule out the possibility of a direct effect of MK-801 on serotonergic neurons of the dorsal raphe nucleus (Callado et al, 2000;Tao and Auerbach, 2000) and its blockade downstream by NBQX acting on AMPA receptors putatively located in serotonergic terminals Effect of clozapine and haloperidol X Ló pez-Gil et al (Maione et al, 1997). With regard to glutamate, however, although presynaptic AMPA receptors have been described in striatal glutamatergic axon terminals (Patel et al, 2001;Fujiyama et al, 2004), they do not seem to be present in the cortical counterparts (Fujiyama et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Clozapine and Haloperidol Differently Suppress the MK-801-Increased Glutamatergic and Serotonergic Transmission in the Medial Prefrontal Cortex of the Rat

López-Gil

Babot

Amargós-Bosch

et al. 2007

Self Cite

166

161

The administration of noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine and ketamine has been shown to increase the extracellular concentration of glutamate and serotonin (5-HT) in the medial prefrontal cortex (mPFC). In the present work, we used in vivo microdialysis to examine the effects of the more potent noncompetitive NMDA receptor antagonist, MK-801, on the efflux of glutamate and 5-HT in the mPFC, and whether the MK-801-induced changes in the cortical efflux of both transmitters could be blocked by clozapine and haloperidol given systemically or intra-mPFC. The systemic, but not the local administration of MK-801, induced an increased efflux of 5-HT and glutamate, which suggests that the NMDA receptors responsible for these effects are located outside the mPFC, possibly in GABAergic neurons that tonically inhibit glutamatergic inputs to the mPFC. The MK-801-induced increases of extracellular glutamate and 5-HT were dependent on nerve impulse and the activation of mPFC AMPA/ kainate receptors as they were blocked by tetrodotoxin and NBQX, respectively. Clozapine and haloperidol blocked the MK-801-induced increase in glutamate, whereas only clozapine was able to block the increased efflux of 5-HT. The local effects of clozapine and haloperidol paralleled those observed after systemic administration, which emphasizes the relevance of the mPFC as a site of action of these antipsychotic drugs in offsetting the neurochemical effects of MK-801. The ability of clozapine to block excessive cortical 5-HT efflux elicited by MK-801 might be related to the superior efficacy of this drug in treating negative/cognitive symptoms of schizophrenia.