Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 receptor-mediated effects in the rat and implications for psychosis

Psychopharmacology (Berl). 2005 Jul;180(3):427-35. doi: 10.1007/s00213-005-2183-9. Epub 2005 Feb 19.


Rationale: The effect of LSD in humans has been described as occurring in two temporal phases. The behavioral effects in rats also occur in two temporal phases: an initial suppression of exploration followed by increased locomotor activity.

Objectives: We decided to investigate this phenomenon from the perspective that the pharmacology might have relevance to the neurochemical mechanisms underlying psychosis.

Methods: Twenty-five male Sprague-Dawley rats were trained to discriminate LSD (186 nmol/kg, 0.08 mg/kg, i.p.) with a 30-min preinjection time (LSD-30, N=12) and LSD (372 nmol/kg, 0.16 mg/kg, i.p.) with a 90-min preinjection time (LSD-90, N=13) from saline, using a two-lever, food-reinforced operant conditioning task.

Results: LSD (186 or 372 nmol/kg, 0.08 or 0.16 mg/kg) given 30 min prior to training produced a cue that was completely antagonized by 5-HT2A antagonists and lasted no longer than 1 h. LSD (372 nmol/kg, 0.16 mg/kg) injected 90 min before training produced a cue that was not fully blocked by 5-HT2A antagonists, but instead was significantly inhibited by haloperidol. In these rats, substitution no longer occurred with the 5-HT2 agonists DOI or LSD (30 min preinjection), but full substitution was obtained with the D2 agonists apomorphine, N-propyldihydrexidine, and quinelorane.

Conclusion: The discriminative stimulus effect of LSD in rats occurs in two phases, and these studies provide evidence that the later temporal phase is mediated by D2 dopamine receptor stimulation. A second temporal phase that involves dopaminergic pathways would be consistent with the widespread belief that excessive dopaminergic activity may be an underlying cause of paranoid psychosis.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amphetamine / pharmacology
  • Amphetamines / pharmacology
  • Animals
  • Apomorphine / pharmacology
  • Behavior, Animal / drug effects*
  • Cues
  • Discrimination Learning / drug effects
  • Dopamine Agonists / pharmacology
  • Dopamine Antagonists / pharmacology
  • Dopamine D2 Receptor Antagonists
  • Dopamine Uptake Inhibitors / pharmacology
  • Dose-Response Relationship, Drug
  • Fluorobenzenes / pharmacology
  • Hallucinogens / administration & dosage
  • Hallucinogens / pharmacology
  • Haloperidol / pharmacology
  • Indans / pharmacology
  • Injections, Intraperitoneal
  • Lysergic Acid Diethylamide / administration & dosage
  • Lysergic Acid Diethylamide / pharmacology*
  • Male
  • Piperidines / pharmacology
  • Psychotic Disorders / physiopathology
  • Quinolines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / physiology*
  • Serotonin Antagonists / pharmacology
  • Serotonin Receptor Agonists / pharmacology
  • Time Factors


  • Amphetamines
  • Dopamine Agonists
  • Dopamine Antagonists
  • Dopamine D2 Receptor Antagonists
  • Dopamine Uptake Inhibitors
  • Fluorobenzenes
  • Hallucinogens
  • Indans
  • Piperidines
  • Quinolines
  • Receptors, Dopamine D2
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • 5-methoxy-6-methyl-2-aminoindan
  • Lysergic Acid Diethylamide
  • Amphetamine
  • volinanserin
  • Haloperidol
  • Apomorphine
  • 4-iodo-2,5-dimethoxyphenylisopropylamine
  • quinelorane