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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.
J Pharmacol Exp Ther. 1995 Nov; 275(2):822-31.JP

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)

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Authors+Show Affiliations

Schreiber R
Centre de Recherches de Croissy, Department of Psychopharmacology, Croissy-sur-Seine, France.
Brocco M
No affiliation info available
Lefèbvre de Ladonchamps B
No affiliation info available
Monneyron S
No affiliation info available
Millan MJ
No affiliation info available

MeSH

8-Hydroxy-2-(di-n-propylamino)tetralinAnimalsDiscrimination LearningMaleRatsRats, WistarReceptors, SerotoninSerotonin AntagonistsSerotonin Receptor Agonists

Pub Type(s)

Journal Article

Language

eng

PubMed ID

7473172

Citation

Schreiber, R, et al. "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." The Journal of Pharmacology and Experimental Therapeutics, vol. 275, no. 2, 1995, pp. 822-31.
Schreiber R, Brocco M, Lefèbvre de Ladonchamps B, et al. 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. J Pharmacol Exp Ther. 1995;275(2):822-31.
Schreiber, R., Brocco, M., Lefèbvre de Ladonchamps, B., Monneyron, S., & Millan, M. J. (1995). 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. The Journal of Pharmacology and Experimental Therapeutics, 275(2), 822-31.
Schreiber R, et al. 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. J Pharmacol Exp Ther. 1995;275(2):822-31. PubMed PMID: 7473172.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Schreiber,R, AU - Brocco,M, AU - Lefèbvre de Ladonchamps,B, AU - Monneyron,S, AU - Millan,M J, PY - 1995/11/1/pubmed PY - 1995/11/1/medline PY - 1995/11/1/entrez SP - 822 EP - 31 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 275 IS - 2 N2 - 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) SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/7473172/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_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&amp;pmid=7473172 DB - PRIME DP - Unbound Medicine ER -
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