Electrophysiological comparison of 5-hydroxytryptamine(1A) receptor antagonists on dorsal raphe cell firing

Single-unit recording studies were undertaken in chloral hydrate anesthetiz ed rats to compare the effects on dorsal raphe cell firing of several putat ive 5-hydroxytryptamine (HT)(1A) receptor antagonists, including WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl) cyclohexa necarboxamide), p-MPPI (4-(2-methoxyphenyl)1-[2'-[N-(2 " -pyridinyl)-p-iodo benzamido]ethyl]piperazine), and two newly described 5-HT1A receptor antago nists, NDL-249 [(R)-3-(N-propylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran- 5-carboxamide] and NAD-299 [(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydr o-2H-1 -benzopyran-5-carboxamide]. Consistent with a 5-HT1A receptor antago nist profile, pretreatment with an approximately equimolar (0.02-0.03 mu mo l/kg) i.v. dose of each compound caused a significant rightward shift in th e dose-response curve for 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin ]. Antagonist potency was clearly highest for NAD-299 and WAY 100635, which caused shifts roughly 3 times greater than those for either p-MPPI or NDL- 249 (ED50 for 8-OH-DPAT, 1.3 +/- 0.3 mu g/kg; after NAD-299, 18.2 +/- 1.0 m u g/kg; after WAY 100635, 16.9 +/-: 2.9 mu g/kg; after NDL-249, 6.0 +/- 1.2 mu g/kg; after p-MPPI, 4.7 +/- 1.1 mu g/kg). In separate studies, each of the antagonists was administered alone in increasing cumulative doses to ev aluate whether they possessed intrinsic agonist activity in this system. At doses below 0.01 mu mol/kg, none of the drugs altered firing by more than +/-20% basal rates. At higher doses (>0.1 mu mol/kg), WAY 100635, NDL-249, and NAD-299 caused a dose-dependent suppression of dorsal raphe cell firing (ED50 = 0.6 +/- 0.2, 0.7 +/- 0.3, and 0.9 +/- 0.4 mu mol/kg, respectively) . However, the ED50 values for inhibition by these drugs were roughly 30 ti mes higher than the doses that antagonized effects of 8-OH-DPAT. Moreover, the inhibition by ail three antagonists (but not 8-OH-DPAT) was readily rev ersed by d-amphetamine (3.2 mg/kg i.v.), a releaser of norepinephrine, sugg esting that these effects were likely due to alpha adrenergic receptor bloc kade rather than to 5-HT1A receptor agonism. Thus, it was concluded that WA Y 100635, NAD-299, NDL-249, and p-MPPI all fulfill criteria as 5-HT1A recep tor antagonists lacking intrinsic efficacy in the dorsal raphe system. The newly described compound NAD-299 exhibits antagonist potency comparable to that of WAY 100635 in this electrophysiological assay.