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

Abstract

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.

Extensive Rigid Analogue Design Maps the Binding Conformation of Potent N-Benzylphenethylamine 5-HT2A Serotonin Receptor Agonist Ligands

“…Racemic 9b had an EC50 of 74 nM and 73% intrinsic activity, being close to a full agonist relative to 5-HT. Furthermore, in rats trained to discriminate between intraperitoneal LSD (0.08 mg/kg) and saline, with a 30 min pretreatment time (LSD-30), 19 the racemate showed full substitution at low doses, as did the positive control 1. We were encouraged by the fact that the dosage required for a 50% response when using the constrained analogue was about onehalf that required for the control, 1, which translates into close to a 3-fold increase in molar potency in vivo (Table 3).…”

Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes

“…As recently outlined in an excellent review on the pharmacology of hallucinogens (Nichols 2004), serotonin 2C receptor (5-HT 2C ) agonism, 5-HT 1A agonism, and SERT uptake inhibition have all been implicated in the activity of hallucinogens. Dopamine (DA) receptors (Marona-Lewicka et al 2009; Marona-Lewicka et al 2005; Seeman et al 2005), the trace amine receptor (Bunzow et al 2001) and the sigma-1 receptor (Fontanilla et al 2009; Su et al 2009) have also been suggested to modulate the effects of hallucinogenic compounds. The hallucinogen salvinorin A ( 10 ), a natural product derived from Salvia divinorum or “magic mint” was unexpectedly found to be a highly selective kappa opioid receptor agonist (Roth et al 2002), providing yet another possible neurochemical pathway for psychoactivity.…”

d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology

“…Later, the hypothesis that the dopaminergic system could be involved in the effects of LSD caught the attention of other researchers. LSD binds to the D 1 and D 2 receptors as a partial agonist [120], and the D 4 receptor as a full agonist [124]. In particular, LSD shows high affinity ( k i = 2 nM) for D 2 receptors in both pig brain [57] and in human cloned D 2 receptors [50,59].…”