The overall goal of the present proposed project studying glutamate-serotonin interactions in the prefrontal cortex is to bridge cellular and behavioral levels of analysis for 5-HT2A receptor-mediated responses that will lead to the development of novel treatments for mood and psychotic disorders. The serotonin2A (5-HT2A) receptor has been implicated in the pathophysiology of depression, suicide and schizophrenia. Regulation of the 5-HT2A receptor by many antidepressant and atypical antipsychotic drugs. may conthbute to their therapeutic effects. Clinical studies have found functional and structural abnormalities in the prefrontal cortex in depressed patients. 5-HT2A receptors are known to be strongly expressed in the apical dendritic region of layer V pyramidal cells throughout the neocortex. This localization may underly the most prominent effect of 5-HT2A receptor activation throughout the cortex: the 5-HT-induced increase in the frequency of excitatory postsynaptic currents/potentials (EPSCs/EPSPs) that appear to be the result of an increase in glutamate release. These excitatory effects of 5-HT also lead to an activity-dependent increase in the expression of brain-derived neurotrophic factor (BDNF) mRNA throughout the neocortex, including the medial prefrontal cortex. Activation of prefrontal cortical 5-HT2A receptors by hallucinogenic drugs may also mediate behavioral effects in rodents such as head shakes and the disruption of operant behavior. Since blockade of 5-HT2A receptors appears may be related to the thymoleptic action of atypical antidepressant/antipsychotic drugs, the overall aim of the present proposal is to determine the inhibitory metabotropic glutamate (mGlu) and 5-HT receptor subtypes that suppress the effects of 5-HT,A receptor activation on a electrophysiological, biochemical, and behavioral level. Intracellular recording using in vitro medial prefrontal cortical slice preparation, in situ hybridization of BDNF mRNA expression, and study of the effects of both systemic and local (medial prefrontal cortex) administration of the hallucinogen and 5-HT2 agonist DOl on head shakes and operant behavior will be used to study interactions of glutamate and 5-HT in the medial prefrontal cortex. MGlu autoreceptors and 5-HT heteroceptors that suppress glutamate release in response to 5-HT2A receptor activation might also suppress glutamate release in response to a variety of deleterious agents. As such, this multi-disciplinarian study may provide new strategies to develop novel antidepressant treatments that would be more efficacious than simply blocking 5-HT2A receptors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH062186-01A1
Application #
6325240
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Winsky, Lois M
Project Start
2001-05-01
Project End
2001-12-31
Budget Start
2001-05-01
Budget End
2001-12-31
Support Year
1
Fiscal Year
2001
Total Cost
$136,195
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Marek, Gerard J (2012) Activation of adenosine? receptors induces antidepressant-like, anti-impulsive effects on differential reinforcement of low-rate 72-s behavior in rats. J Pharmacol Exp Ther 341:564-70
Marek, Gerard J (2009) Activation of adenosine(1) (A(1)) receptors suppresses head shakes induced by a serotonergic hallucinogen in rats. Neuropharmacology 56:1082-7
Marek, Gerard J (2008) Cortical 5-hydroxytryptamine2A-receptor mediated excitatory synaptic currents in the rat following repeated daily fluoxetine administration. Neurosci Lett 438:312-6
Marek, Gerard J; Zhang, Ce (2008) Activation of metabotropic glutamate 5 (mGlu5) receptors induces spontaneous excitatory synaptic currents in layer V pyramidal cells of the rat prefrontal cortex. Neurosci Lett 442:239-43
Zhang, Ce; Marek, Gerard J (2008) AMPA receptor involvement in 5-hydroxytryptamine2A receptor-mediated pre-frontal cortical excitatory synaptic currents and DOI-induced head shakes. Prog Neuropsychopharmacol Biol Psychiatry 32:62-71
Zhang, Ce; Marek, Gerard J (2007) Group III metabotropic glutamate receptor agonists selectively suppress excitatory synaptic currents in the rat prefrontal cortex induced by 5-hydroxytryptamine2A receptor activation. J Pharmacol Exp Ther 320:437-47
Lee, Younglim; Duman, Ronald S; Marek, Gerard J (2006) The mGlu2/3 receptor agonist LY354740 suppresses immobilization stress-induced increase in rat prefrontal cortical BDNF mRNA expression. Neurosci Lett 398:328-32
Marek, Gerard J; Wright, Rebecca A; Schoepp, Darryle D (2006) 5-Hydroxytryptamine2A (5-HT2A) receptor regulation in rat prefrontal cortex: interaction of a phenethylamine hallucinogen and the metabotropic glutamate2/3 receptor agonist LY354740. Neurosci Lett 403:256-60
Marek, Gerard J; Martin-Ruiz, Raul; Abo, Allyson et al. (2005) The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology 30:2205-15
Marek, Gerard J (2003) Behavioral evidence for mu-opioid and 5-HT2A receptor interactions. Eur J Pharmacol 474:77-83

Showing the most recent 10 out of 11 publications