The overall aim is to explore mechanisms by which hallucinogenic drug, actiong through 5-HT2A receptors, enhance glutamatergic synaptic transmission in the prefrontal cortex. The proposed experiments focus upon how 5-HT2A receptor activation induces two distinct types glutamateric excitatory postsynaptic potentials/currents (EPSPs/EPSCs) at apical dendrites of layer V pyramidal cells of medial prefrontal cortex. The first is a 5-HT-induced increase in spontaneous (non-electrically-evoked) EPSCs that directly or indirectly involves thalamocortical terminals in the midline/intralaminar ascending arousal pathway. The second is a late component of corticocortical electrically-evoked EPSCs, a signature effect of both indoleamine (e.g., LSD) and phenethylamine (e.g., mescaline, DOI) psychedelic hallucingenic drugs. The studies will be conducted with a combination of whole cell patch-clamp recording and 2-photon laser scanning to identify events at a single synapse level; this will be done in conjunction with localized molecular manipulations of 5-HT2 receptor expression.
Specific aims are: 1) To determine how 5-HT-induced spontaneous EPSCs (spEPSCs) are generated in layer V pyramidal cells of medial prefrontal cortex and 2) To determine the mechanisms underlying hallucinogen-induced late electrically-evoked EPSCs (evEPSCs) in mPFC layer V pyramidal cells and its modulation by non-5-HT2A and NMDA receptors. Significance: Hyperglutamatergic states have been suggested to underlie both drug-induced psychoses and prodromal stages of naturally occurring psychoses as schizophrenia. The concept that a downstream dysfunction of glutamatergic transmission could be involved in the early pathogenesis of schizophrenia prompts a search for novel therapies that are prophylactic rather than symptomatic as are the traditional monoamine receptor-targeted typical or atypical antipsychotic drugs.
|Abdallah, Chadi G; Sanacora, Gerard; Duman, Ronald S et al. (2015) Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics. Annu Rev Med 66:509-23|
|Krystal, John H; Sanacora, Gerard; Duman, Ronald S (2013) Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry 73:1133-41|
|Liu, Rong-Jian; Lee, Francis S; Li, Xiao-Yuan et al. (2012) Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry 71:996-1005|
|Liu, Rong-Jian; Aghajanian, George K (2008) Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy. Proc Natl Acad Sci U S A 105:359-64|
|Lambe, E K; Aghajanian, G K (2007) Prefrontal cortical network activity: Opposite effects of psychedelic hallucinogens and D1/D5 dopamine receptor activation. Neuroscience 145:900-10|
|Aghajanian, G K (1994) Electrophysiological studies on the actions of hallucinogenic drugs at 5-HT2 receptors in rat brain. NIDA Res Monogr 146:183-202|
|Gellman, R L; Aghajanian, G K (1994) Serotonin2 receptor-mediated excitation of interneurons in piriform cortex: antagonism by atypical antipsychotic drugs. Neuroscience 58:515-25|
|Marek, G J; Aghajanian, G K (1994) Excitation of interneurons in piriform cortex by 5-hydroxytryptamine: blockade by MDL 100,907, a highly selective 5-HT2A receptor antagonist. Eur J Pharmacol 259:137-41|
|Gellman, R L; Aghajanian, G K (1993) Pyramidal cells in piriform cortex receive a convergence of inputs from monoamine activated GABAergic interneurons. Brain Res 600:63-73|
|Rasmussen, K; Krystal, J H; Aghajanian, G K (1991) Excitatory amino acids and morphine withdrawal: differential effects of central and peripheral kynurenic acid administration. Psychopharmacology (Berl) 105:508-12|
Showing the most recent 10 out of 40 publications