Antagonism of a PCP drug discrimination by hallucinogens and related drugs.

Drugs such as PCP and MK-801 can cause psychotic reactions in humans by antagonizing NMDA receptors. This action is ultimately toxic to certain cortical neurons and may be one mechanism underlying neurodegenerative diseases, including schizophrenia. It has been reported that hallucinogens such as LSD, DOM, and DOI can block the neurotoxic effects of NMDA antagonists, possibly by activating inhibitory 5-HT2A receptors on GABAergic interneurons that normally inhibit glutamatergic projections to the retrosplenial and cingulate cortexes. The purpose of this experiment was to determine the extent to which similar drugs might also alter the behavioral effects of one NMDA antagonist, PCP. Rats were trained to discriminate this compound (2.5 mg/kg) from saline and were then given a series of antagonist tests. It was found that LSD (0.32 mg/kg) and DOM (4.0 mg/kg) blocked the PCP cue completely; DMT (8.0 mg/kg) and a structural congener of LSD, lisuride (LHM; 0.4 mg/kg), blocked the effects of PCP partially. The 5-HT/DA antagonists spiperone and ritanserin had no effect on the PCP cue. These data suggest that LSD, DOM, and, less effectively, DMT and LHM can block the behavioral as well as the neurotoxic effects of NMDA antagonists most likely through agonist actions at 5-HT2 receptors.

Increasing the selectivity of drug discrimination procedures.

In an attempt to increase the selectivity of drug discrimination, rats were trained to discriminate LSD (0.08 mg/kg) from a group of "other" compounds consisting of cocaine (10 mg/kg), pentobarbital (5 mg/kg), and saline. Acquisition of this LSD-other discrimination was rapid (31 days) in chambers equipped with retractable levers and did not differ significantly from that of a group of animals trained to discriminate LSD from saline (26 days). In substitution (generalization) tests, hallucinogens such as LSD, DMT, and DOM mimicked LSD in a dose-dependent manner in both groups. The designer drug (+/-)MDMA substituted for LSD in the LSD-other group (ED50 = 1.38) but did not substitute for the training drug in the LSD-ND group; neither (+) MDMA nor PCP mimicked LSD in either group. Most importantly, lisuride, quipazine, and yohimbine, drugs that have been described as "false positives," substituted for LSD in animals trained to discriminate LSD from saline (ED50s = 0.012, 1.662, 2.344, respectively), but not in animals trained to discriminate LSD from other drugs. Thus, the LSD-other training procedure can be described as more selective than the standard drug-ND procedure.

Stimulus effects of d-amphetamine II: DA, NE, and 5-HT mechanisms.

Activation of dopaminergic (DA) systems is a necessary component of the behavior effects of d-amphetamine, but other neurotransmitters such as norepinephrine (NE) and serotonin (5-HT) appear to modulate DA input; thus, they might have an important role in the stimulus (subjective) effects of this drug. Therefore, rats were trained to discriminate d-amphetamine (1 mg/kg) from saline and given combination (antagonism, potentiation) or substitution (generalization) tests with drugs that act through DA, noradrenergic, or serotonergic (5-HT) mechanisms. In the first of two experiments, the D1 antagonist SCH 39166 blocked the effects of d-amphetamine (1 mg/kg) at doses of 0.05, 0.1, and 0.2 mg/kg. NE and 5-HT antagonists including prazosin (0.5-2 mg/kg), idazoxan (1.25-5 mg/kg), ketanserin (0.06-0.15 mg/kg), and metergoline (5-20 mg/kg) had no significant effects on the d-amphetamine cue. In the second experiment, neither the alpha 2-NE agonist clonidine (0.0025-0.1 mg/kg), the beta-NE agonist salbutamol (0.05-0.25 mg/kg), nor the NE uptake inhibitor nisoxetine (5-15 mg/kg) had d-amphetamine-like effects. The alpha 2-NE antagonist yohimbine (0.5-2 mg/kg) and the beta-NE antagonist propranolol (0.5-3 mg/kg) failed to alter the d-amphetamine cue. ICS 205-930 (10 mg/kg) neither mimicked nor blocked the effects of 1 mg/kg of d-amphetamine. Indeed, this 5-HT3 antagonist potentiated the actions of lower doses of d-amphetamine (0.25-0.4 mg/kg); the potentiation of the 0.25-mg/kg dose was blocked significantly by the alpha 1-NE antagonist prazosin (1 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of the discriminative stimulus effects of the optical isomers of ecstasy (3,4-methylenedioxymethamphetamine; MDMA).

The discriminative stimulus effects of the stereoisomers of 3,4-methylenedioxymethamphetamine (MDMA) were studied in rats trained to discriminate 1.25mg/kg of (+)-MDMA or 3.5mg/kg of (-)-MDMA from saline, in a two lever, water-reinforced, drug discrimination situation. The isomers of MDMA and 3,4-methylenedioxyamphetamine (MDA) substituted completely for both training drugs. The stimulants amphetamine and cocaine did not substitute for either MDMA isomer. The hallucinogens (+/-)-2,5-dimethoxy-4-methylamphetamine (DOM), (+)-lysergic acid diethylamide (LSD), and mescaline failed to substitute completely for (+)-MDMA. Similarly, DOM and mescaline did not substitute for (-)-MDMA; however, LSD did substitute for this isomer at a dose of 0.06mg/kg but not at higher doses. Substitution tests with 5-HT-releasing agents revealed that fenfluramine substituted partially for (+)-MDMA and completely for (-)-MDMA, while p-chloroamphetamine substituted completely for both isomers of MDMA. When given in combination with (+)-or (-)-MDMA, neither the 5-HT(2) antagonist pirenpirone nor the less selective 5-HT antagonist metergoline consistently blocked drug-appropriate responding. These results indicate that the stereoisomers of MDMA and MDA have similar discriminative stimulus properties. More importantly, the present findings suggest that 5-HT release may be important for the discriminative stimulus effects of (+)-and (-)-MDMA. Actions at 5-HT(2) receptors, however, do not appear to be critical.

Meditation as an adjunct to a happiness enhancement program.

This study investigated the impact that meditation has on Fordyce's (1977, 1983) Personal Happiness Enhancement Program (PHEP). Experimental subjects were divided into two groups, both of which received instruction on the PHEP. Subjects in one experimental group were taught a meditation exercise in addition to the PHEP. A control group received no instruction. The Happiness Measure, Psychap Inventory, Beck Depression Inventory, and State-Trait Anxiety Scale were dependent measures. The three (groups) x two (pre-post) mixed ANOVAs with Student Newman-Keuls found that the meditation plus PHEP group significantly improved on all dependent measures over both the PHEP only group and the control group. The PHEP only group improved significantly over the control group on all measures except state anxiety.