Alcohol-induced euphoria enhanced by disulfiram and calcium carbimide.

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.

Intraventricular self-administration of leucine-enkephalin by laboratory rats.

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.

Actions of drugs of abuse on brain reward systems: a reconsideration with specific attention to alcohol.

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.

An investigation of the mechanisms of action of 5-hydroxytryptamine in the suppression of ethanol intake.

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.

An examination of possible interactions between zimelidine, a serotonin uptake inhibitor, and ethanol ingested conjointly in human subjects.

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.

Opiate receptors may mediate the suppressive but not the excitatory action of ACTH on motor activity in rats.

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.

Reduction of voluntary morphine consumption following treatment with zimelidine.

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.

The role of endorphins in stress: evidence and speculations.

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.

Attenuation of ethanol intake by 5-hydroxytryptamine uptake blockade in laboratory rats. I. Involvement of brain 5-hydroxytryptamine in the mediation of the positive reinforcing properties of ethanol.

The role of 5-hydroxytryptamine (5-HT) uptake blockade in the mediation of the positive reinforcing peroperties of ethanol in male wistar rats was investigated. It was demonstrated that treatment with zimelidine (H102/09) a 5-HT uptake inhibitor, specifically attenuated ethanol consumption. In an attempt to extinguish the ethanol drinking response, ethanol preferring animals in a second experiment, were provided with ethanol as the only source of fluid in combination with zimelidine treatment. Animals treated in such a manner subsequently reduced their ethanol consumption when presented with a free-choice between ethanol and water. These results were attributed to an increased availability of central 5-HT, suggesting that central 5-HT mechanisms may in some way be involved in the mediation of the positive reinforcing properties of ethanol.

Intraventricular self-administration of acetaldehyde, but not ethanol, in naive laboratory rats.

For 11 consecutive days, naive rats were maintained in operant chambers where they were given the opportunity to self-administer acetaldehyde (1,2, or 5% v/v), ethanol (2 or 10% v/v), or pH control solutions directly into the cerebral ventricles. Only the animals that had access to the 2 and 5% acetaldehyde solutions showed rates of lever pressing significantly higher than controls. It is suggested that acetaldehyde rather than ethanol itself may mediate the positive reinforcing effects of ethanol in the brain.