Early preclinical studies of discriminable sedative and hallucinogenic drug effects.

RATIONALE: One important technique in behavioral pharmacology is to train laboratory animals to discriminate between a psychoactive drug effect and a nondrug condition. Tests with different drugs have identified several categories of drugs that have different discriminable effects. OBJECTIVES: The two authors describe and discuss the early research on discriminable effects of sedative and hallucinogenic drugs and their acquaintance with each other at Yale University prior to their early and frequent publications on discriminable drug effects. Herb Barry studied sedative drugs primarily and Jim Appel studied hallucinogenic drugs. RESULTS: Sedative drugs include ethyl alcohol, barbiturates, and benzodiazepines. Their discriminable effects are largely attributable to the activation of an inhibitory neurotransmitter, gamma-amino butyric acid. Alcohol has the most pervasive effect in accordance with the high dose required to alter behavior. Hallucinogenic drugs include lysergic acid diethylamide and mescaline. They increase the activity of the neurotransmitter 5-hydroxytryptamine and, perhaps, dopamine in the central nervous system (CNS). In spite of their relatively low concentrations in the brain, both of these neurotransmitters have many important behavioral effects. CONCLUSIONS: Various sedative drugs cause a discriminable decrease in the function of the CNS. Different types of sedatives can be discriminated from each other. Indole and phenylethylamine hallucinogens have potent discriminative stimulus properties, which are related to the actions of biogenic amine neurotransmitters in the CNS.

Increasing the selectivity of the discriminative stimulus effects of delta 9-tetrahydrocannabinol: complete substitution with methanandamide.

In an attempt to increase the selectivity of the discriminative stimulus effects of Delta9-tetrahydrocannabinol (THC), rats were trained to discriminate 3.2 mg/kg of this compound from a group of "other" drugs consisting of morphine (3.2 mg/kg), PCP (2.5 mg/kg), and vehicle. Acquisition of the Delta9-THC-other discrimination was rapid (38 days) and did not differ significantly from that of a group of "control" animals trained to discriminate Delta9-THC (3.2 mg/kg) from its vehicle (33 days). In substitution (generalization) tests, a high dose of anandamide, which also severely decreased response rate, substituted partially in both the control and the Delta9-THC-other group; (R)-methanandamide, an analog of anandamide which is metabolized more slowly, substituted completely for Delta9-THC in the control, and partially in the Delta9-THC-other group; neither pentobarbital nor diazepam substituted completely for Delta9-THC under any experimental condition. Regardless of the level of Delta9-THC lever responding, all drugs except diazepam substituted less in the Delta9-THC-other than in the control group. For this reason, the Delta9-THC-other training procedure might be described as being more selective than the commonly used drug-no drug procedure.

LSD, 5-HT (serotonin), and the evolution of a behavioral assay.

Research in our laboratory, supported by NIDA and facilitated by Roger Brown, has indicated that serotonergic neuronal systems are involved in the discriminative stimulus effects of LSD. However, the only compounds that fully antagonize the LSD cue act at both serotonin (5-HT) and dopamine (DA) receptors. In addition, substitution for LSD in standard drug vs. no-drug (DND) discriminations does not necessarily predict either similar mechanisms of action or hallucinogenic potency because 'false positives' occur when animals are given drugs such as lisuride (LHM), quipazine, or, possibly, yohimbine. These effects can be greatly reduced by using drug vs. drug (D-D), drug vs. drug vs. no drug (D-ND), or drug vs. ' other' drug (saline, cocaine, pentobarbital) training procedures. Additional studies, in which drugs were administered directly into the cerebral ventricles or specific brain areas, suggest that structures containing terminal fields of serotonergic neurons might be involved in the stimulus effects of LSD.