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


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.


CONCLUSIONS
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.
Marona-Lewicka
Danuta
D
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences-RHPH, Purdue University, 575 Stadium Mall Dr., West Lafayette, IN 47907-2091, USA.
Chemel
Benjamin R
BR
Nichols
David E
DE
D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001667:Binding, Competitive; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000494:pharmacology*; D006801:Humans; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology*; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D050638:Receptors, Dopamine D4 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
C487766:ABT724; D000662:Amphetamines; D001562:Benzimidazoles; D006213:Hallucinogens; D010879:Piperazines; D011725:Pyridines; D050638:Receptors, Dopamine D4; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D008238:Lysergic Acid Diethylamide; D000242:Cyclic AMP; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine