piperidines and 1-ethyl-2-pyrrolidinylmethyl-alpha-phenylcyclopentylglycolate--1-ethyl-3-piperidyl-alpha-phenylcyclopentylglycolate-drug-combination

In the first part of this paper, a classification was proposed which divided dysleptic drugs into two categories. Further evidence in support of this classification is drawn from the variability of the clinical picture in schizophrenics elicited by mescaline or allied substances, whereas dysleptics with potent anticholinergic properties always induce the same symptomatology. If the therapeutic usefulness of LSD-25 for instance still may be argued, dysleptics belonging to the second group seem to have no therapeutic usefulness. The dysleptics of the first group include in their chemical formula an aromatic or an indole nucleus; the second group is characterized by a phenylglycolate group. The classification proposed here may be compared with Henri Ey's ideas: in this Jacksonian perspective, dysleptics like LSD would impair the superior strata of the psycho-organic structure whereas Ditran (in the second group) would act at a lower level.

Topics: Cerebral Cortex; Chemical Phenomena; Chemistry; Classification; Dosage Forms; Drug Combinations; Electroencephalography; Glycolates; Hallucinogens; Humans; Indoles; Lysergic Acid Diethylamide; Mescaline; Phencyclidine; Piperidines; Psychopharmacology; Pyrrolidines; Schizophrenia; Toxicology

Previous research has indicated that low voltage fast activity (LVFA) in the neocortex and rhythmical slow activity (RSA) in the hippocampus can result from activity in either (or both) the cholinergic corticipetal projections from the basal forebrain and the serotonergic corticipetal projections from the brainstem raphe. These inputs appear to give rise, respectively, to atropine-sensitive LVFA and RSA and atropine-resistant LVFA and RSA. The atropine-sensitive and atropine-resistant waveforms have been shown to have distinctive behavioral correlates. The present experiments extend these findings by providing dose-response data on the effects of scopolamine and Ditran on neocortical activity in relation to behavior in the rat. In addition, new evidence is presented which indicates that neuroleptic drugs reduce activity in the atropine-resistant (presumably serotonergic) inputs to the hippocampus and neocortex by an indirect action involving dopamine receptors. A single dose of d-amphetamine or apomorphine appears to increase activity in the same pathway by a similar indirect action. These findings may be relevant to the psychiatric effects of neuroleptic drugs.

Topics: Acetylcholine; Animals; Behavior, Animal; Cerebral Cortex; Dextroamphetamine; Drug Combinations; Glycolates; Hippocampus; Male; Membrane Potentials; Piperidines; Pyrrolidines; Rats; Scopolamine; Serotonin; Trifluoperazine

Alterations by ketamine (10-100 microM) and ditran (50-100 microM) of end-plate currents were studied using transected cutaneous pectoris muscles. Both drugs reduced peak current and shortened the time constant for end-plate current decay (tau). Ketamine was more effective at pH 5.3 than at 7.4 or 9.1. Recovery from blockade was asymmetrical in that tau recovered more quickly than did peak current when the drugs were removed from the bath. By contrast, 4-aminopyridine antagonized the depression of peak current by ketamine, but not the reduction of tau. Both ketamine and ditran disrupted the voltage dependence of tau. The binding to microsacs prepared from electric organs of [3H]phencyclidine ([3H]PCP) was blocked by ketamine and ditran. In microsacs treated with carbachol, the IC50 for ketamine block of [3H]PCP binding was 6.6 X 10(-6) M. For ditran, the IC50 for block of [3H]PCP binding in the presence of carbachol was 1.7 X 10(-6) M. The binding of [alpha-125I]bungarotoxin to the microsacs or to the cultured chick myotubes was reduced only slightly by ketamine. Because ketamine has no effect on transmitter release and little effect on [alpha-125I]bungarotoxin binding, it is concluded that, like PCP, ketamine and ditran block open channels in the end-plate. In addition, the asymmetrical recovery of end-plate current parameters suggests that ketamine may block closed channels. The recovery from block of closed channels (caused by either a direct action on closed channels or a very slow channel unblocking rate) proceeds more slowly than does the block of open channels.

Topics: Animals; Drug Combinations; Electric Organ; Glycolates; Hydrogen-Ion Concentration; In Vitro Techniques; Ion Channels; Ketamine; Neurotransmitter Agents; Phencyclidine; Piperidines; Pyrrolidines; Rana pipiens; Receptors, Cholinergic; Torpedo

Groups of rats were trained in a T-shaped maze to discriminate the effects produced by IP injections of ditran (1.60 mg/kg), either when given singly, or when combined with the acetylcholinesterase inhibitors neostigmine (0.25 mg/kg) or physostigmine (0.50 and 1.00 mg/kg), from the nondrug condition (saline). The results from this state-dependency (StD) model indicated that acquisition of the drug discrimination was similar for the 4 groups of rats. After drug discrimination was established the rats were tested with various drug combinations. Physostigmine (0.50 and 1.00 mg/kg) challenge reversed drug discrimination among rats trained with ditran solely or the ditran plus neostigmine combination. There was no antagonism among the ditran plus physostigmine trained rats. Involvement of the C.N.S. is implicated since tests with neostigmine did not upset ditran discrimination. In addition, survival rate of physostigmine treated mice is increased with ditran. In conclusion, this study indicates the usefulness of employing both training and transfer test procedures when evaluating antagonism in this StD model.

Topics: Animals; Drug Combinations; Glycolates; Learning; Male; Neostigmine; Physostigmine; Piperidines; Probability; Pyrrolidines; Rats

Rats, trained to respond differentially in a T-maze contingent upon the presence or absence of physostigmine (0.50 mg/kg), showed a reversal of drug responding when physostigmine (0.50 mg/kg) was given simultaneously with the anticholinergic ditran (dose range: 0.80-3.20 mg/kg). Testing the quaternary anticholinesterase neostigmine (0.50 mg/kg) resulted in no drug responding which indicates a central site of action for the physostigmine discrimination.

Topics: Acetylcholine; Animals; Avoidance Learning; Discrimination, Psychological; Drug Combinations; Glycolates; Male; Neostigmine; Physostigmine; Piperidines; Pyrrolidines; Rats; Time Factors

Topics: Acridines; Animals; Behavior, Animal; Biphenyl Compounds; Dogs; Drug Combinations; Fluorenes; Glycolates; Hallucinogens; Mandelic Acids; Pharmacology; Piperidines; Pyridines; Pyrrolidines; Research

Topics: Antisocial Personality Disorder; Bipolar Disorder; Depression; Drug Combinations; Glycolates; Hallucinogens; Mental Disorders; Piperidines; Psychotic Disorders; Pyrrolidines; Schizophrenia; Toxicology

Topics: Adolescent; Bender-Gestalt Test; Central Nervous System Stimulants; Drug Combinations; Glycolates; Hallucinogens; Humans; Lysergic Acid Diethylamide; Mental Disorders; Piperidines; Projective Techniques; Psychological Tests; Psychopharmacology; Pyrrolidines; Succinates; Toxicology

Topics: Biomedical Research; Drug Combinations; Glycolates; Hallucinogens; Humans; Piperidines; Psychopharmacology; Psychotic Disorders; Pyrrolidines

Topics: Antisocial Personality Disorder; Anxiety; Anxiety Disorders; Atropine; Bipolar Disorder; Depression; Drug Combinations; Drug Therapy; Electroencephalography; Glycolates; Hallucinogens; Mental Disorders; Piperidines; Psychoses, Alcoholic; Psychotic Disorders; Pyrrolidines; Schizophrenia; Toxicology

Topics: Delusions; Drug Combinations; Glycolates; Hallucinogens; Humans; Object Attachment; Piperidines; Pyrrolidines; Syndrome

Topics: Atropine; Coma; Depression; Depressive Disorder; Drug Combinations; Glycolates; Hallucinogens; Humans; Piperidines; Pyrrolidines

Topics: Drug Combinations; Glycolates; Hallucinations; Humans; Mental Disorders; Mentally Ill Persons; Piperidines; Pyrrolidines

Topics: Drug Combinations; Glycolates; Hallucinogens; Humans; Piperidines; Psilocybin; Psychotropic Drugs; Pyrrolidines; Volunteers

Topics: Convulsive Therapy; Drug Combinations; Glycolates; Hallucinogens; Humans; Piperidines; Pyrrolidines