Abstract
Behavioral profiles composed of both locomotor activity and investigatory behavior were established for the 5HT-1A agonists 8OHDPAT, buspirone, gepirone, and ipsapirone using rats tested in a Behavioral Pattern Monitor. Typically these compounds dose-relatedly decreased horizontal locomotion and investigatory activity during the first half of the 1-h test session. Time-course studies revealed that the time interval between injection and placement of the animal in the testing chamber made no difference in the temporal distribution of locomotor activity following most 5HT-1A agonists. These results were compared and contrasted to the behavioral profiles previously established for hallucinogenic compounds such as LSD and DOM, the psychoactive properties of which have been suggested to be mediated by 5HT-2 binding sites. Examination of ipsapirone and 8OHDPAT in a familiar environment paradigm revealed that both drugs decreased behavioral responding independently of the animals' familiarity with the test environment, in contrast to the behaviorally suppressive effects of hallucinogenic 5HT-2 antagonists which disappear in a familiar environment. Additionally, d,l-propranolol was used as a 5HT-1 antagonist and was found to block the behavioral effects of the 5HT-1A agonists ipsapirone and buspirone without having significant effects by itself. Propranolol was also used to identify the contribution of the 5HT-1 binding site to the behavioral effects of LSD. Even at relatively high doses, propranolol only partially antagonized the effects of LSD, supporting the hypothesis that the behavioral effects of LSD reflect the activation of both 5HT-1 and 5HT-2 receptors. Together, these findings demonstrate that 5HT-1A agonists have a different profile of behavioral effects than 5HT-2 agonists and that the two classes of drugs can be differentiated using the same test paradigm. The results provide further support for the hypothesis that the previously described potentiation of neophobia induced by hallucinogens is due to the activation of 5HT-2 receptors.
Similar content being viewed by others
References
Adams LM, Geyer MA (1982) LSD-induced alterations of locomotor patterns and exploration in rats. Psychopharmacologia 77:179–185
Adams LM, Geyer MA (1985a) A proposed animal model for hallucinogens based on patterns of exploration in rats. Behav Neurosci 5:881–900
Adams LM, Geyer MA (1895b) Effects of DOM and DMT in a proposed animal model of hallucinogenic activity. Prog Neuropsychopharmacol Biol Psychiatry 9:121–132
Arvidsson L-E, Hacksell U, Nilsson JLG, Hjorth S, Carlsson A, Lindberg P, Sanchez D, Wikstrom H (1981) 8-Hydroxy-2-(di-n-propylamino)tetraline, a new centrally acting 5-hydroxytrptamine receptor agonist. J Med Chem 24:921–923
Dixon A (1968) Evidence of catecholamine mediation in the “aberrant” behaviour induced by lysergic acid diethylamine (LSD) in the rat. Experientia 24:743–747
Dixon WJ (1985) BMDP Biomedical Computer Programs. University of California Press, Los Angeles
Gately PF, Poon SL, Segal DS, Geyer MA (1985) Depletion of brain serotonin by 5,7-dihydroxytryptamine alters the response to amphetamine and the habituation of locomotor activity in rats. Psychopharmacology 87:400–405
Geyer MA, Light RK (1979) LSD-induced alterations of investigatory responding in rats. Psychopharmacology 65:41–47
Geyer MA, Light RK, Rose GJ, Petersen LR, Horwitt DD, Adams LM, Hawkins RL (1979) A characteristic effect of hallucinogens on investigatory responding of rats. Psychopharmacology 65:35–40
Geyer MA, Tapson GS (1988) Habituation of tactile startle is altered by drugs acting on serotonin-2 receptors. Neuropsychopharmacology 1:135–147
Geyer MA, Russo PV, Masten VL (1986) Multivariate assessment of locomotor behavior: pharmacological and behavioral analyses. Pharmacol Biochem Behav 25:277–288
Glennon RA, Titeler M, McKenney JD (1984) Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci 35:2505–2511
Gozlan S, El Mestikawy S, Pichat L, Glowinski J, Hamon M (1983) Identification of presynaptic serotonin autoreceptors using a new ligand: [3H]-PAT. Nature 350:140
Izquierdo I (1975) Relations between orienting, pseudoconditioned and conditioned responses in the shuttle-box: a pharmacological analysis by means of LSD and dibenamine. Behav Biol 15:193–205
Janssen PA (1982) The pharmacology of specific, pure and potent serotonin 5HT2 or S2 antagonists. In: Yoshida H, Hagihara Y, Ebashi S (eds) Advances in pharmacology and therapeutics III, vol 4. Pergamon, Oxford, pp 21–33
Key BJ, Bradley PB (1960) The effects of drugs on conditioning and habituation to arousal stimuli in animals. Psychopharmacologia 1:450–462
Lyon RA, Titeler M, Seggel MR, Glennon RA (1988) Indolealkylamine analogs share 5-HT2 binding characteristics with phenylalkylamine hallucinogens. Eur J Pharmacol 145:291–297
McMillen BA, Scott SM, Williams HL, Sanghera MK (1987) Effects of gepirone, an aryl-piperazine anxiolytic drug, on aggressive behavior and brain monoaminergic neurotransmission. Naunyn-Schmiedeberg's Arch Pharmacol 335:454–464
Middlemiss DN (1984) Stereoselective blockade at [3H]5-HT binding sites and at the 5-HT autoreceptor by propranolol. Eur J Pharmacol 101:289–293
Middlemiss DN, Blakeborough L, Leather SR (1977) Direct evidence for an interaction of β-adrenergic blockers with the 5-HT receptor. Nature 267:289–290
Middlemiss DN, Fozard JR (1983) 8-hydroxy-2-(di-n-propylamino)-tetralin discriminates between subtypes of the 5-HT recognition site. Eur J Pharmacol 90:151–153
Nahorski SR, Williams AL (1983) Interactions of β-adrenoceptor antagonists with 5-hydroxytryptamine receptor subtypes in rat cerebral cortex. Br J Pharmacol 80:107P
Pedigo NW, Yamamura HI, Nelson DL (1981) Discrimination of multiple [3H]5-hydroxytryptamine binding sites by the neuroleptic spiperone in rats. J Neurochem 36:220–226
Peroutka S (1985) Selective interaction of novel anxiolytics with 5-hydroxytryptamine 1A receptors. Biol Psychiatry 20:971–979
Peroutka SJ, Snyder SH (1979) Multiple serotonin receptors: differential binding of [3H]-lysergic acid diethylamide and [3H]-spiroperidol. Mol Pharmacol 16:687–699
Rickels K (1983) Nonbenzodiazepine anxiolytics: clinical usefulness. J Clin Psychiatry 44:38–43
Sanders-Bush E, Burris KD, Knoth K (1988) Lysergic acid diethylamide and 2,5-dimethoxy-4-methylamphetamine are partial agonists at serotonin receptors linked to phosphoinositide hydrolysis. J Pharmacol Exp Ther 246(3):924–928
Schnellmann RG, Waters SJ, Nelson DL (1984) [3H]5-hydroxytryptamine binding sites; species and tissue variation. J Neurochem 42:65–70
Sprouse JS, Aghajanian GK (1986) (−)-Propranolol blocks the inhibition of serotonergic dorsal raphe cell firing by 5-HT1A selective agonists. Eur J Pharmacol 128:295–298
Titeler M, Lyon RA, Glennon RA (1988) Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens. Psychopharmacology 94:213–216
Traber J, Glaser T (1987) 5-HT1A receptor-related anxiolytics. TIPS 8:432–437
Winter CA, Flataker L (1956) Effects of lysergic acid diethylamide upon performance of trained rats. Proc Soc Exp Biol Med 92:285–289
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Mittman, S.M., Geyer, M.A. Effects of 5HT-1A agonists on locomotor and investigatory behaviors in rats differ from those of hallucinogens. Psychopharmacology 98, 321–329 (1989). https://doi.org/10.1007/BF00451682
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00451682