Faculty Bibliography

Reports of ephedrine-induced psychoses resembling amphetamine psychosis prompted studies of this classic sympathomimetic agent in systems that indicate central dopaminergic actions. Ephedrine induced dose-related stereotyped behavior in rats. This behavior was antagonized by haloperidol, but not by alpha- or beta-adrenergic blockers. Pretreatment with AMPT, but not reserpine, attenuated the stereotypy induced by ephedrine under one of two sets of conditions. Consistent prolactin suppression in humans was not seen. These findings are discussed in the context of clinical and pharmacologic data regarding other dopamine agonist drugs (the central nervous system stimulants, apomorphine, ET 495). These data suggest the possibility that synergistic noradrenergic and dopaminergic facilitation may be important in the induction of the stimulant psychoses

Growth hormone (hGH) responses to centrally acting dopamine agonists were used as indices of CNS dopaminergic function in order to test hypotheses implicating dopaminergic alteration in the etiopathology of schizophrenia. Apomorphine, a direct acting dopamine receptor agonist, and L-Dopa, an indirect agonist dependent upon presynaptic conversion to dopamine for its action, both elicited elevations in plasma hGH in most young male schizophrenic- and control-subjects. A highly significant difference was seen between the distribution of hGH responses to apomorphine for schizophrenics and that for controls. Unusually high hGH response to apomorphine was seen in schizophrenics who subsequently failed to respond to neuroleptic therapy; intermediate hGH response was seen in controls; and low hGH response was seen in subsequent neuroleptic responders; differences in hGH response were statistically significant for all intergroup comparisons. No such differences were seen between responses of individuals to L-Dopa and to apomorphine. The findings suggest that the variability of hGH response to apomorphine is a reflection of dopamine receptor sensitivity, and that this variability may be an index of non-endocrine related dopaminergic sensitivity. They are consistent with hypotheses relating schizophrenia to alteration in dopamine receptors, although the type of receptor and the direction of alteration may be complex

1. The effects of cocaine (20 mg/kg s.c.) on 5-hydroxytryptamine (5-HT) turnover were examined in rats. 2. In vivo cocaine administration resulted in decreased turnover of 5-HT, as indicated by the decreased accumulation of 5-HT after pargyline administration and the decreased accumulation of 5-hydroxyindoleacetic acid (5-HIAA) following probenecid injection. 3. A time-related decrease in 5-HIAA concentrations and a small fall in 5-HT concentrations in the whole brain were observed following the acute administration of cocaine hydrochloride (20 mg/kg). Tryptophan levels were found to be slightly decreased in the brain. 4. Enhanced reactivity, but neither stereotypy nor hyperthermia, was observed following cocaine injection (20 mg/kg). 5. It is concluded that cocaine inhibits the turnover of brain 5-HT and that this action of cocaine may be responsible for the differences in a number of pharmacological effects between cocaine and amphetamine

In an attempt to identify specific binding to dopamine receptors the binding of 3H-pimozide to preparations of brain and to an artificial cellulose membrane was examined. Binding occurred rapidly, was pH and temperature dependent, and was displaceable by other neuroleptics. Displaceable binding was saturable at 5 X 10(-8) M pimozide. A weak correlation between IC50's for displacement of binding by drugs and their clinical potencies was observed. Displaceable binding of 3H-pimozide in different brain areas did not correlate with dopamine levels. The similarity of binding properties to brain and to artificial membrane suggests that these effects are a function of the physical-chemical properties of these drugs, and that these properties may be related to their clinical effect