Psychedelic Research

Danuta Marona-Lewicka and colleagues have been studying the complex pharmacology of LSD and have previously shown it has an early serotonergic (5-HT2A receptor) phase that lasts about an hour in rats (unclear how to translate the timing to humans) and a later dopaminergic (D2-like receptor) phase. This dopaminergic aspect to LSD may help explain why LSD is more potent than you’d expect based on its interactions with the 5-HT2A receptor.

Marona-Lewicka D, Chemel BR, Nichols DE.
Dopamine D(4) receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI.
Psychopharmacology (Berl). 2008 Jul 6. [Epub ahead of print]

RATIONALE: Lysergic acid diethylamide (LSD) differs from other types of hallucinogens in that it possesses direct dopaminergic effects. The exact nature of this component has not been elucidated. OBJECTIVE: The present study sought to characterize the effects of several dopamine D(4) agonists and antagonists on the discriminative stimulus effect of LSD at two pretreatment times and 2,5-dimethoxy-4-iodoamphetamine (DOI), a selective 5-HT(2A/2C) agonist. MATERIALS AND METHODS: Male Sprague-Dawley rats were trained in a two-lever, fixed ratio (FR) 50, food-reinforced task with LSD-30 (0.08 mg/kg, i.p., 30-min pretreatment time), LSD-90 (0.16 mg/kg, i.p., 90-min pretreatment time), and DOI (0.4 mg/kg, i.p., 30-min pretreatment time) as discriminative stimuli. Substitution and combination tests with the dopamine D(4) agonists, ABT-724 and WAY 100635, were performed in all groups. Combination tests were run using the dopamine D(4) antagonists A-381393 and L-745,870 and two antipsychotic drugs, clozapine and olanzapine. RESULTS: WAY 100635 produced full substitution in LSD-90 rats, partial substitution in LSD-30 rats, and saline appropriate responding in DOI-trained rats. ABT-724 partially mimicked the LSD-90 and LSD-30 cues, but produced no substitution in DOI-trained rats. In combination tests, both agonists shifted the dose-response curve of LSD leftward, most potently for the LSD-90 cue. The D(4) antagonists significantly attenuated both the LSD-90 and LSD-30 cue, but had no effect on the DOI cue. CONCLUSION: Dopamine D(4) receptor activation plays a significant modulatory role in the discriminative stimulus effects in LSD-90-trained rats, most markedly for the later temporal phase of LSD, but has no effect on the cue produced by DOI.

This paper found the hallucinogen DOI reduced the power of low-frequency oscillations (0.3–4 Hz) and altered (that is, desynchronized) the relationship between pyramidal cell firing and slow oscillations in anesthetized rats. Presumably other classical serotonergic hallucinogens would do the same. This is particularly intriguing because oscillations are a potential mechanism of ‘binding’ the activity of neurons that are processing the same information. In other words, it is possible that these lower frequency oscillations serve to connect neural activity in distant neurons. The changes induced by DOI might be important for the fundamental effects of hallucinogens on consciousness. One caveat is that the animals were anesthetized. Still, the finding is consistent with what Jordi Riba and colleagues (2004) reported in humans given ayahuasca, although the low frequency changes (1.5-6 Hz, they didn’t report lower) that Riba et al. measured with EEG were more occipital. The reduced low-frequency oscillations may be the same phenomenon previously reported by Lambe and Aghajanian.

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