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Complex stimulus properties of LSD: a drug discrimination study with α2-adrenoceptor agonists and antagonists

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Abstract

The influence of several α2-adrenergic agents on the discriminative stimulus (DS) properties of lysergic acid diethylamide (LSD) was studied in rats trained to discriminate 0.08 mg/kg (186 nmol/kg) of LSD from saline in a two-lever operant paradigm. Only yohimbine fully mimicked LSD with an ED50 of 2.05 mg/kg (5.24 µmol/kg). Yohimbine's 5-HT1A agonist properties may be responsible for this substitution. Other α2-adrenoceptor antagonists, idazoxan with an agonist/antagonist profile at 5-HT1A receptors and RS 26026-197, a highly selective α2-adrenoceptor antagonist, failed to produce substitution. Clonidine, an α2-adrenoceptor agonist, did not substitute for LSD but the response rate was dose-dependently reduced. None of the α2-adrenergic agents used for pretreatment before LSD inhibited the response to the LSD training dose. Coadministration of clonidine with LSD produced a leftward shift of the dose-response relationship of LSD without a significant change in the slope of the dose-response line. Simultaneous administration of α2-adrenergic agents with LSD shifted the dose-response curve to the left only when the adrenergic agent also possessed at least moderate affinity for the 5-HT1A receptor. In addition, radioligand competition experiments were performed that showed LSD to have relatively high affinity (Ki=37 nM) for [3H]clonidine-labeled sites in rat cortex with lower affinity for [3H]yohimbine labeled sites. While previous studies have suggested that the nature of the LSD cue may be essentially expressed by 5-HT2 receptor activation, the present data show that this cue can be modulated by effects of LSD at 5-HT1A and at other monoamine neurotransmitter receptors.

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  1. Departments of Pharmacology and Toxicology, and Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, 47907, West Lafayette, IN, USA

    D. Marona-Lewicka & D. E. Nichols

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  1. D. Marona-Lewicka
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  2. D. E. Nichols
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Marona-Lewicka, D., Nichols, D.E. Complex stimulus properties of LSD: a drug discrimination study with α2-adrenoceptor agonists and antagonists. Psychopharmacology 120, 384–391 (1995). https://doi.org/10.1007/BF02245809

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