The general purpose of this project continues to be the investigation of the electrophysiological actions of the indoleamine/phenethethylamine class of psychedelic hallucinogens on identified neurons of the rat brain.
Specific aims are: 1. To investigate the pathways by which hallucinogenic drugs alter the activity and reactivity of locus coeruleus neurons in vivo: The role of major afferent inputs will be examined since the effect of psychedelic hallucinogens on locus coeruleus neurons does not appear to be due to a direct action on these cells. 2. To analyze cellular subtypes and membrane mechanisms underlying 5-HT2- receptor-mediated excitatory actions of serotonin and hallucinogenic drugs on identified neurons in brain slices. The membrane mechanisms underlying the excitatory/facilitatory effects of serotonin and hallucinogenic drugs will be studied on identified neurons in brain slices from facial nucleus and cerebral cortex. 3. To evaluate the role of G proteins and protein kinase C in modulating neuronal responses to serotonin and hallucinogenic drugs. The involvement of G proteins and protein kinase C in the mediation of 5-HT2 responses will be examined in brain slices from cerebral cortex and facial nucleus. 4. To study the cellular mechanisms of tolerance and sensitization to hallucinogenic drugs. Chronic studies will be conducted in terms of known changes in receptor and effector mechanisms (e.g., 5-HT2 receptor downregulation by hallucinogenic drugs). The value of the proposed research would be to advance knowledge about the mechanism of action of a major class of drugs, the psychedelic hallucinogens. In addition to any implications for the treatment of drug overdose (or other untoward reactions), this information could aid the rational development of more efficacious antipsychotic drugs, which, for example, might act upon convergent effector mechanisms and second messenger systems rather than the initial receptor site as is the case with currently available treatments.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Asanuma, Chiiko
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Yale University
Schools of Medicine
New Haven
United States
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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
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
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
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
Sheldon, P W; Aghajanian, G K (1991) Excitatory responses to serotonin (5-HT) in neurons of the rat piriform cortex: evidence for mediation by 5-HT1C receptors in pyramidal cells and 5-HT2 receptors in interneurons. Synapse 9:208-18

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