Parenteral injections of d-lysergic acid diethylamide (LSD), a serotonin 5-HT2A receptor agonist, enhance eyeblink conditioning. Another hallucinogen, (±)-1(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), was shown to elicit a 5-HT2A-mediated behavior (head bobs) after injection into the hippocampus, a structure known to mediate trace eyeblink conditioning.
This study aims to determine if parenteral injections of the hallucinogens LSD, d,l-2,5-dimethoxy-4-methylamphetamine, and 5-methoxy-dimethyltryptamine elicit the 5-HT2A-mediated behavior of head bobs and whether intrahippocampal injections of LSD would produce head bobs and enhance trace eyeblink conditioning.
Materials and methods
LSD was infused into the dorsal hippocampus just prior to each of eight conditioning sessions. One day after the last infusion of LSD, DOI was infused into the hippocampus to determine whether there had been a desensitization of the 5-HT2A receptor as measured by a decrease in DOI-elicited head bobs.
Acute parenteral or intrahippocampal LSD elicited a 5-HT2A but not a 5-HT2C-mediated behavior, and chronic administration enhanced conditioned responding relative to vehicle controls. Rabbits that had been chronically infused with 3 or 10 nmol per side of LSD during Pavlovian conditioning and then infused with DOI demonstrated a smaller increase in head bobs relative to controls.
LSD produced its enhancement of Pavlovian conditioning through an effect on 5-HT2A receptors located in the dorsal hippocampus. The slight, short-lived enhancement of learning produced by LSD appears to be due to the development of desensitization of the 5-HT2A receptor within the hippocampus as a result of repeated administration of its agonist (LSD).
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Abramson HA, Jarvik ME, Kaufman MR, Kornetsky C, Levine A, Wagner M (1955) Lysergic acid diethylamide (LSD-25). I. Physiological and perceptual responses. J Psychol 39:3–60
Aloyo VJ, Harvey JA (2000) Antagonist binding at 5-HT2A and 5-HT2C receptors in the rabbit: high correlation with the profile for the human receptors. Eur J Pharmacol 406:163–169
Aloyo VJ, Dave KD, Rahman T, Harvey JA (2001) Selective and divergent regulation of cortical 5-HT2A receptors in the rabbit. J Pharmacol Exp Ther 299:1066–1072
Aloyo VJ, Berg KA, Spampinato U, Clarke WP, Harvey JA (2009) Current status of inverse agonism at serotonin2A (5-HT2A) and 5-HT2C receptors. Pharmacol Ther 121:160–173
Braun U, Shulgin AT, Braun G (1980) Centrally active n-substituted analogs of 3, 4-methylenedioxyphenylisopropylamine (3, 4-methylenedioxyamphetamine). J Pharm Sci 69:192–195
Brawley P, Duffield JC (1972) The pharmacology of hallucinogens. Pharmacol Rev 24:31–66
Clarke RE, Squire LR (1998) Classical conditioning and brain systems: the role of awareness. Science 280:77–81
Cole JC, Sumnall HR (2003) Altered states: the clinical effects of ecstasy. Pharmacol Ther 98:35–58
Dave KD, Harvey JA, Aloyo VJ (2002) A novel behavioral model that discriminates between 5-HT2A and 5-HT2C receptor activation. Pharmacol Biochem Behav 72:371–378
Dave KD, Quinn JL, Harvey JA, Aloyo VJ (2004a) Role of central 5-HT2 receptors in mediating head bobs and body shakes in the rabbit. Pharmacol Biochem Behav 77:623–629
Dave KD, Fernando GS, Quinn JL, Harvey JA, Aloyo VJ (2004b) Serotonin 5-HT2A receptors in the CA1 field of the hippocampus mediate head movements in the rabbit. Psychopharmacology 176:287–295
Dave KD, Harvey JA, Aloyo VJ (2007) The time-course for up- and down-regulation of the cortical 5-hydroxytryptamine (5-HT)2A receptor density predicts 5-HT2A receptor-mediated behavior in the rabbit. J Pharmacol Exp Ther 323:327–335
Gimpl MP, Gormezano I, Harvey JA (1978) Effects of LSD on learning as measured by classical conditioning of the rabbit nictitating membrane response. J Pharmacol Exp Ther 208:330–334
Harvey JA (1996) Serotonergic regulation of associative learning. Behav Brain Res 73:47–50
Harvey JA (2003) Role of the serotonin 5-HT2A receptor in learning. Learn Mem 10:355–362
Harvey JA, Gormezano I, Cool VA (1982) Effects of d-lysergic acid diethylamide, d-bromolysergic acid diethylamide, dl-2, 5-dimethoxy-4-methlyamphetamine and d-amphetamine on classical conditioning of the rabbit nictitating membrane response. J Pharmacol Exp Ther 221:289–294
Harvey JA, Quinn JL, Liu R, Aloyo VJ, Romano AG (2004) Selective remodeling of frontal cortex: relationship between 5-HT2A receptor density and associative learning. Psychopharmacology 172:435–442
Jakab RL, Goldman-Rakic PS (1998) 5-Hydroxytryptamine2A serotonin receptors in the primate cerebral cortex: possible site of action of hallucinogens and antipsychotic drugs in pyramidal cell apical dendrites. Proc Natl Acad Sci 95:735–740
LaBar KS, Disterhoft JF (1998) Conditioning, awareness, and the hippocampus. Hippocampus 8:620–626
Marquardt GM, DiStefano V, Ling LL (1978) Pharmacological effects of (+/−)-, (S)-, and (R)-MDA. In: Stillman RC, Willette RE (eds) Psychopharmacology of hallucinogens. Pergamon, New York, pp 84–104
McBride RL, Klemm WR (1968) Stereotaxic atlas of rabbit brain, based on the rapid method of photography of frozen unstained sections. Commun Behav Biol 2:179–215
Meneses A (2002) Tianeptine: 5-HT uptake sites and 5-HT(1–7) receptors modulate memory formation in an autoshaping Pavlovian/instrumental task. Neurosci Biobehav Rev 26:309–319
Moyer JR Jr, Deyo RA, Disterhoft JF (1990) Hippocampectomy disrupts trace eye-blink conditioning in rabbits. Behav Neurosci 104:243–252
Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181
Pranzatelli MR (1990) Evidence for involvement of 5-HT2 and 5-HT1C receptors in the behavioral effects of the 5-HT agonist l-(2, 4-dimethoxy-4-iodo-phenylaminopropane)-2 (DOI). Neurosci Lett 115:74–80
Romano AG, Harvey JA (1994) MDMA enhances associative and nonassociative learning in the rabbit. Pharmacol Biochem Behav 47:289–293
Romano AG, Bormann NM, Harvey JA (1991) A unique enhancement of associative learning produced by methylenedioxyamphetamine. Behav Pharmacol 2:225–231
Romano AG, Quinn JL, Liu R, Dave KD, Schwab D, Alexander G, Aloyo VJ, Harvey JA (2005) Effect of serotonin depletion on 5-HT2A mediated learning: evidence for constitutive activity of the 5-HT2A receptor in vivo. Psychopharmacology 184:173–181
Rothlin E (1957) Pharmacology of lysergic acid diethylamide and some of its related compounds. J Pharm Pharmacol 9:569–587
Schreiber R, Brocco M, Audinot V, Gobert A, Veiga S, Millan MJ (1995) (l-[2,5-Dimethoxy-4-iodophenyl]-2-aminopropane)-induced head twitches in the rat are mediated by 5-hydroxytryptamine (5-HT)2A receptors: modulation by novel 5-HT2A/2C antagonists, D1 antagonists, and 5-HT1A agonists. J Pharmacol Exp Ther 273:101–112
Shulgin AT (1978) Psychotomimetic drugs: structure–activity relationships. In: Iversen LL, Iverson SD, Snyder SH (eds) Handbook of psychopharmacology. Stimulants, vol 11. Plenum, New York, pp 243–333
Snyder SH, Faillace L, Hollister L (1967) 2,5-Dimethoxy-4-methylamphetamine (STP): a new hallucinogenic drug. Science 158:669–670
Solomon PR, Vander Schaaf ER, Norbe AC, Weisz DJ, Thompson RF (1986) Hippocampus and trace conditioning of the rabbit’s nictitating membrane response. Behav Neurosci 100:729–744
Weiner DM, Burstein ES, Nash N, Croston GE, Currier EA, Vanover KE, Harvey SC, Donohue E, Hansen HC, Andersson CM, Spalding TA, Gibson DF, Krebs-Thomson K, Powell SB, Geyer MA, Hacksell U, Brann MR (2001) 5-Hydroxytryptamine2A receptor inverse agonists as antipsychotics. J Pharmacol Exp Ther 299:268–276
Welsh JP, Harvey JA (1991) Pavlovian conditioning in the rabbit during inactivation of the interpositus nucleus. J Physiol 444:459–480
Welsh SE, Romano AG, Harvey JA (1998) Effects of serotonin 5-HT2A/C antagonists on associative learning in the rabbit. Psychopharmacology 137:157–163
Williams GV, Rao SG, Goldman-Rakic PS (2002) The physiological role of 5-HT2A receptors in working memory. J Neurosci 22:2843–2854
This work was supported by NIMH grant MH16841-40 (JAH).
All experiments comply with current laws governing animal experimentation in the USA.
About this article
Cite this article
Romano, A.G., Quinn, J.L., Li, L. et al. Intrahippocampal LSD accelerates learning and desensitizes the 5-HT2A receptor in the rabbit, Romano et al.. Psychopharmacology 212, 441–448 (2010). https://doi.org/10.1007/s00213-010-2004-7
- Eyeblink conditioning
- Serotonin 5-HT2A receptor
- Serotonin 5-HT2C receptor