Biomedical subjects
Publications and source records attributed to Z W Brown.
In a double-blind study, subjects were treated with either disulfiram or calcium carbimide, inhibitors of acetaldehyde elimination, prior to consumption of low doses of alcohol. Self-rating scales, individual interviews, and observations by independent judges revealed that experimental subjects manifested enhanced changes in mood and euphoria compared to placebo control subjects.
Naive laboratory rats, without pre-exposure to operant training procedures or to opioids, were shown to self-administer directly into their cerebral ventricles the endogenous opiate peptide, leucine-enkephalin. They were shown to self-administer the peptide consistently for six consecutive days with no indication of the development of tolerance. The results indicate that leucine-enkephalin may possess potent reinforcing properties and suggests that it may play a role as an endogenous reward transmitter.
The effect of blockage of 5-hydroxytryptamine and norepinephrine uptake on voluntary ethanol consumption in rats was investigated. It was demonstrated that attenuation of ethanol intake occurred only as a result of treatment with specific 5-hydroxytryptamine uptake inhibitors. These results suggested that increasing the availability of central 5-hydroxytryptamine may in some way interfere with the positive reinforcing properties of ethanol. The second phase was designed to determine whether the attenuation of ethanol intake following blockade of 5-hydroxytryptamine uptake may be due to increased post-synaptic activity. Ethanol-preferring animals were pretreated with methergoline, a post-synaptic receptor blocker, followed by treatment with zimelidine, a 5-hydroxytryptamine uptake inhibitor. The results indicate that treatment with methergoline did not alter the zimelidine-induced attenuation of ethanol intake. Based on these results it is suggested that blockade of 5-hydroxytryptamine uptake produces an attenuation of ethanol intake but not as a result of increased post-synaptic activity.
Research in the areas of intracranial self-stimulation and drug self-administration has provided a substantial data base that has contributed to our understanding of brain reward mechanisms. In a recent article, Wise [83] argued that dopamine is the catecholamine critically involved in the central mediation of reward. The present paper attempts to examine the available data with particular reference to alcohol, but also with reference to opiates, and argues that the reinforcing effects of at least these drugs are primarily and directly mediated by noradrenergic rather than dopaminergic systems in the brain. It also argues, in direct contrast to Wise, that in the context of these drugs, dopamine seems to play a minor if not negligible role.
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Non-alcoholic male subjects were given either a placebo or zimelidine (100, 200 or 300 mg, p.o.) 2 h prior to consumption of alcohol (1 g/kg) or a non-alcoholic mixer. Slight increases in heart rate and diastolic blood pressure induced by alcohol were unaffected by pretreatment with zimelidine. Alcohol, zimelidine, and the combination of the two, did not affect any of the hematologic measures except for serum potassium levels. The latter were reduced slightly but not in any discernible pattern. Blood alcohol concentrations were not changed by zimelidine pretreatment. Conversely, blood concentrations of zimelidine and its metabolite norzimelidine were also relatively unaffected by alcohol consumption. In general, the results indicate that the simultaneous administration of zimelidine and alcohol to human subjects does not produce any observable adverse effects.
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Subcutaneous injections of adrenocorticotropin (ACTH) or of the opiate antagonist naltrexone produced a one (2.0 mg/kg) dpressed, whereas smaller doses of ACTH (50 micrograms/kg) and of naltrexone (0.125 and 0.25 mg/kg) stimulated motor activity in the open field test. Furthermore, naltrexone at a dose level that had no effect on motor activity blocked the suppressive effect of the high doses of ACTH but had no effect on the stimulating effect of the intermediate dose of ACTH. Finally, chronic naltrexone administration resulted in enhanced sensitivity to the suppressive but not to the stimulating effect of ACTH on motor activity. It is argued that opiate receptors may play a selective role in the effect of ACTH on motor activity. Such receptors may mediate the supressive effect of high doses of ACTH whereas other, naltrexone insensitive receptor systems may mediate the stimulating effect of ACTH on activity functions.
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Several lines of evidence suggest that the endogenous opioid peptides endorphins may play a role in the defensive response of the organism to stress. The present paper summarizes these findings as well as evidence linking endorphins to the anterior pituitary polypeptide hormone adrenocorticotropin (ACTH). Evidence is presented that endorphins may function as trophic hormones in peripheral target organs such as the adrenal medulla and the pancreas. As such they may be part of the physiological mechanisms that mediate adrenaline and glucagon release in response to stress. Endorphins (enkephalins) are also suggested to play a role in the control of the pituitary gland during stress. In such capacity they may act as hormone-releasing or inhibiting factors. Finally, endorphins appear to play a role in the behavioral concomitants of stress. In such capacity endorphins are suggested to function as modulators of neural systems that mediate the elaboration and expression of the reactive/affective components of stress. Speculations on the mode of interaction between endorphins and ACTH in the global response to stress are discussed.
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Male Wistar rats were presented with an everyday free choice between water and a morphine-sucrose solution. Following a 5-day baseline period animals were injected with either zimelidine (10 or 20 mg/kg, i.p.), a neuronal serotonin uptake inhibitor, or Ringer's solution (2 ml/kg, i.p.) for 5 consecutive days. Treatment with zimelidine was shown to significantly attenuate morphine drinking suggesting that an increased availability of serotonin may interfere with the positive reinforcing properties of morphine. The results are also discussed in terms of a possible interaction with brain norepinephrine. The possibility that the reinforcing effects of both morphine and ethanol are subserved by common mechanisms is suggested.
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