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

Abstract

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.

Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI

“…We have previously demonstrated, however, that the discriminative stimulus effect of LSD in rats proceeds through two temporal phases (Marona-Lewicka et al 2005). The first phase is mediated by stimulation of 5-HT 2A receptors, reaches a maximum 15-30 min after drug administration, and lasts about 1 h, a finding that has been replicated in numerous laboratories (e.g., Colpaert et al 1982;Glennon et al 1984;Winter et al 1999).…”

“…Combination of 10 μmol/kg of WAY 100635 with LSD or DOI resulted in leftward shifts of the dose-response curves quite markedly in LSD-90 rats and less so in LSD-30-and DOI-trained rats. We believe that the high degree of potentiation observed in LSD-90-trained rats occurs because the primary mechanism responsible for the discriminative stimulus effects in these rats occurs through stimulation of D 2 -like receptors (Marona-Lewicka et al 2005), the dopamine D 4 receptor being a member of the D 2 receptor family.…”

“…Full, partial, and no substitution were statistically determined using a binomial test (Zar 1999). This test is very conservative, and additional details for the use of the binomial test to analyze quantal drug discrimination data are provided in our earlier publication (Marona-Lewicka et al 2005). If the drug was one that completely substituted for the training drug, the method of Litchfield and Wilcoxon (1949) was used to determine the ED 50 and 95% confidence interval (95% CI).…”

“…The first phase is mediated by stimulation of 5-HT 2A receptors, reaches a maximum 15-30 min after drug administration, and lasts about 1 h, a finding that has been replicated in numerous laboratories (e.g., Colpaert et al 1982;Glennon et al 1984;Winter et al 1999). The second phase of action for LSD appears to be mediated by activation of dopamine D 2 -like receptors (Marona-Lewicka et al 2005) and reaches a maximum at times from 60 to 90 min after LSD administration. That is, when LSD (0.16 mg/kg) is administered 90 min prior to discrimination training, it produces a robust interoceptive cue that is mediated primarily by dopamine D 2 -like receptor activation.…”

“…Although a larger dose of LSD is necessary to maintain the salience of a cue out to 90 min, when the higher dose of LSD is administered 30 min prior to discrimination training, the cue is still mediated by 5-HT 2A receptor activation (Marona-Lewicka et al 2005). Thus, the length of time between LSD administration and discrimination training is the key factor that determines the nature of the discriminative cue.…”