LSD AND THE PHENETHYLAMINE HALLUCINOGEN DOI ARE POTENT PARTIAL AGONISTS AT 5-HT2A RECEPTORS ON INTERNEURONS IN RAT PIRIFORM CORTEX(1,2)

Correlations between 5-hydroxytryptamine (5-HT) receptor binding affin ities and human hallucinogenic potency have suggested that 5-HT2 recep tors mediate the hallucinogenic effects of lysergic acid diethylamide (LSD) and phenethylamine hallucinogens. Electrophysiological studies h ave suggested that a subpopulation of gamma-aminobutyric acid (GABA)er gic interneurons in layer III of the rat piriform cortex are excited b y serotonin (5-HT) via 5-HT2A receptors. These interneurons have inhib itory inputs on pyramidal cells in layer II. In the present study, we tested low concentrations of both LSD (3-100 nM) and the phenethylamin e hallucinogen 1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI; 0.3- 10 mu M) on rat piriform cortical interneurons that were excited by 5- HT. Both LSD (3-100 nM) and DOI (0.3-10 mu M) excited almost every cel l excited by 5-HT. The maximal excitation achieved with LSD and DOI wa s 39% and 55% of the effect of a near-maximal 5-HT concentration (100 mu M). Consistent with a partial agonist action, LSD and DOI blocked t he 5-HT excitation of piriform cortical interneurons only at the highe r hallucinogen concentrations tested. A specific 5-HT2A receptor antag onist, MDL 100,907, blocked excitation of these interneurons by 5-HT, LSD and DOI, but not by norepinephrine or ha-amino-3-hydroxy-5-methyl- 4-isoxazolepropionate. Again, consistent with a partial agonist action of the hallucinogens, intracellular experiments showed that a maximal concentration of DOI (10 mu M) induced fewer postsynaptic inhibitory currents than did 5-HT (100 mu M) 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.