A drug discrimination analysis of the actions of novel serotonin1A receptor ligands in the rat using the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin

Abstract

In the present study, using a two-lever drug discrimination procedure, we characterized the effects of a series of chemically-diverse, novel 5-HT1A receptor agonists and antagonists in rats trained to discriminate the serotonin (5-HT)1A receptor agonist, 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT) (0.31 mg/kg, i.p.) from saline. In analogy to the 5-HT1A receptor agonists, ipsapirone (a pyrimidinylpiperazine) and flesinoxan (a benzodioxane), the arylpiperazine derivatives, WY-48,723 and WY-50,324, as well as the methoxynaphtylpiperazines, S 14506 and S 14671, substituted 100% for the discriminative stimulus (DS) effects of 8-OH-DPAT, with the latter two displaying remarkable potency [50 effective doses (ED50s): 1.25, 0.34, 0.05, 0.69, 0.009 and 0.006 mg/kg, s.c., respectively]. In contrast, an additional pyrimidinylpiperazine, zalospirone, failed to fully mimick the training drug (maximal effect: 40%) even at a dose markedly disrupting response rates (2.5 mg/kg, s.c.). The potency of agonists in generalizing to 8-OH-DPAT correlated significantly (P < .05) with their affinity at rat hippocampal 5-HT1A receptors in vitro (r = .78), and with their potency to induce hypothermia in the rat (r = .96). S 15535 and S 15931, novel benzodioxopiperazines possessing mixed 5-HT1A autoreceptor agonist/postsynaptic 5-HT1A receptor antagonist properties, antagonized (approximately 75%) the discriminative stimulus (DS) properties of 8-OH-DPAT (ED50s: 6.9 and 0.97 mg/kg, s.c., respectively), although their structural analogue, S 14489, reduced by only 50% the action of 8-OH-DPAT. The 5-HT1A receptor antagonists, (+/-)-pindolol (-70%; ED50: 0.65 mg/kg, s.c.), (-)-alprenolol (-67%; ED50: 7.1) and NAN-190 (-80%; ED50: 1.5), all blocked the 8-OH-DPAT DS. Likewise, several novel antagonists at 5-HT1A autoreceptors and postsynaptic 5-HT1A receptors; the benzoisothiazolpiperazine, SDZ 216-525 (-83%; ED50: 0.64), the aryloxyalkylamine, (-)-tertatolol (-83%; ED50: 7.7) and the methoxyphenylpiperazine, (+)-WAY 100,135 (-80%; ED50: 17.0), antagonized the 8-OH-DPAT cue. Antagonist potency correlated significantly with affinity at 5-HT1A receptors (r = .83) and potency for antagonism of 8-OH-DPAT-induced hypothermia (r = .83). Antagonists showed only variable and not significant (P > .05) generalization rates (13-50%) when tested alone.(ABSTRACT TRUNCATED AT 400 WORDS)