Training dose as a factor in LSD-saline discrimination.

To assess the effects of training dose on the discriminative stimulus properties of LSD, groups of rats (eight/group) were trained to discriminate each of three doses of LSD (0.02, 0.08 or 0.32 mg/kg) from saline. This was accomplished by using a method of progressively altering dose ("fading"). Dose-response tests revealed that the three LSD cues were specific to the dose used during training and that, as the training dose declined, the slope of the LSD dose-response curve became less steep. Substitution tests with direct serotonin (5-HT) agonists (quipazine, MK-212, 5-methoxy-N,N-dimethyltryptamine) and antagonism tests with central 5-HT antagonists (methiothepin and cyproheptadine) indicated that 5-HT is involved in mediating the in vivo effects of LSD and that training dose co-determines (along with the dose of the test compound) the extent of substitution or antagonism. In addition, substitution tests with the peripherally-active 5-HT agonist 5-methoxytryptamine and 5-HT antagonist xylamidine suggested that the peripheral serotonergic actions of LSD may be involved (in part) in the low dose (0.02 mg/kg) LSD cue. In contrast to 5-HT, dopamine (DA) did not appear to be involved in the discriminative stimulus properties of LSD, because no significant dose or group effects were seen during tests with the DA agonists apomorphine and d-amphetamine or the DA antagonist haloperidol.