LSD and the phenethylamine hallucinogen DOI are potent partial agonists at 5-HT2A receptors on interneurons in rat piriform cortex.
Gerard J. Marek, George K. Aghajanian
Journal of Pharmacology and Experimental Therapeutics September 1, 1996 DOI: 10.1016/s0022-3565(25)20792-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Electrophysiological study (in vitro) Peer reviewed |
|---|---|
| Population | Rat piriform cortical interneurons and layer II pyramidal neurons |
| Interventions | LSD DOI |
| Dose | LSD 3-100 nM; DOI 0.3-10 microM |
| Topics | LSD Serotonin |
| Keywords | Cerebral cortex Interneurons Animals Rats, sprague-dawley Norepinephrine Amphetamines Fluorobenzenes Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid Piperidines Receptors, serotonin Receptor, serotonin, 5-ht2a Serotonin antagonists Hallucinogens Action potentials Dose-response relationship, drug Male Serotonin receptor agonists In vitro techniques |
| Key points | LSD and DOI excited nearly all piriform cortical interneurons that serotonin excited, but with lower maximal efficacy (39% and 55% of a near-maximal serotonin response), and blocked serotonin excitation only at higher concentrations. The authors conclude that LSD and DOI act as highly potent partial agonists at cortical 5-HT2A receptors. |
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.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
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