title: LSD and the phenethylamine hallucinogen DOI are potent partial agonists at 5-HT2A receptors on interneurons in rat piriform cortex.
abstract: Correlations between 5-hydroxytryptamine (5-HT) receptor binding affinities and human hallucinogenic potency have suggested that 5-HT2 receptors mediate the hallucinogenic effects of lysergic acid diethylamide (LSD) and phenethylamine hallucinogens. Electrophysiological studies have suggested that a subpopulation of gamma-aminobutyric acid (GABA)ergic interneurons in layer III of the rat piriform cortex are excited by serotonin (5-HT) via 5-HT2A receptors. These interneurons have inhibitory inputs on pyramidal cells in layer II. In the present study, we tested low concentrations of both LSD (3-100 nM) and the phenethylamine hallucinogen 1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI; 0.3-10 microM) on rat piriform cortical interneurons that were excited by 5-HT. Both LSD (3-100 nM) and DOI (0.3-10 microM) excited almost every cell excited by 5-HT. The maximal excitation achieved with LSD and DOI was 39% and 55% of the effect of a near-maximal 5-HT concentration (100 microM). Consistent with a partial agonist action, LSD and DOI blocked the 5-HT excitation of piriform cortical interneurons only at the higher hallucinogen concentrations tested. A specific 5-HT2A receptor antagonist, MDL 100,907, blocked excitation of these interneurons by 5-HT, LSD and DOI, but not by norepinephrine or alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate. Again, consistent with a partial agonist action of the hallucinogens, intracellular experiments showed that a maximal concentration of DOI (10 microM) induced fewer postsynaptic inhibitory currents than did 5-HT (100 microM) in pyramidal neurons in layer II of the piriform cortex. Based on the present electrophysiological studies, we conclude that LSD and DOI, a phenethylamine hallucinogen, act as highly potent partial agonists at cortical 5-HT2A receptors.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, Ribicoff Research Facilities of the Connecticut Mental Health Center, New Haven, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Marek
authors.forename: G K
authors.initials: GK
authors.lastname: Aghajanian
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000494:pharmacology; D006213:Hallucinogens / Q000494:pharmacology*; D066298:In Vitro Techniques; D007395:Interneurons / Q000502:physiology; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D000662:Amphetamines; D005464:Fluorobenzenes; D006213:Hallucinogens; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D008238:Lysergic Acid Diethylamide; C079049:volinanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D009638:Norepinephrine