Complex stimulus properties of LSD: a drug discrimination study with alpha 2-adrenoceptor agonists and antagonists

The influence of several alpha 2-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 mumol/kg). Yohimbine's 5-HT1A agonist properties may be responsible for this substitution. Other alpha 2-adrenoceptor antagonists, idazoxan with an agonist/antagonist profile at 5-HT1A receptors and RS 26026-197, a highly selective alpha 2-adrenoceptor antagonist, failed to produce substitution. Clonidine, an alpha 2-adrenoceptor agonist, did not substitute for LSD but the response rate was dose-dependently reduced. None of the alpha 2-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 alpha 2-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.