Intrahippocampal LSD accelerates learning and desensitizes the 5-HT2A receptor in the rabbit, Romano et al.

Abstract

Rationale

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.

Objective

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.

Results

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.

Conclusions

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).

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Corresponding authors

Correspondence to Anthony G. Romano or John A. Harvey.

Additional information

This work was supported by NIMH grant MH16841-40 (JAH).

All experiments comply with current laws governing animal experimentation in the USA.

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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

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Keywords

  • Hallucinogens
  • LSD
  • DOI
  • DOM
  • 5-MeO-DHT
  • Learning
  • Eyeblink conditioning
  • Rabbit
  • Serotonin 5-HT2A receptor
  • Serotonin 5-HT2C receptor
  • Hippocampus