Effectiveness of morphine and ineffectiveness of diazepam and phenobarbital on the motivational properties of hypothalamic self-stimulation behaviour

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The actions of diazepam, phenobarbital, and morphine on self-stimulation were investigated to find out whether the site of action of these drugs is in the reward pathway when facilitation or suppression of responding for brain stimulation is observed. The range of doses tested was 1·25–120 mg/kg for diazepam, 1·25–200 mg/kg for phenobarbital and 1·25–5 mg/kg for morphine. A self-stimulation test at a given intensity of stimulation was always initiated with priming stimuli. Diazepam and phenobarbital at doses of 1·25–10 mg/kg increased the rate of self-stimulation; at doses between 10 and 60 mg/kg the drugs increased the rates in some subjects and decreased the rates in others. Very high doses, 120 mg/kg for diazepam and 200 mg/kg for phenobarbital, were needed to produce suppression of self-stimulation behaviour. Sedation was observed at doses of 10 mg/kg or more in the intervals between testing for self-stimulation at the different intensities. Thus, responding for brain reward was maintained with only minor reductions in rates when the tests were initiated with priming stimuli. Morphine did not increase the rate of responding at low doses, and it suppressed the rate of responding at doses that caused depression or sedation. Tests to determine the time-course of the drugs showed that the time of peak action was between 30–45 min after injection, the time when brain stimulation counteracted the sedation produced by diazepam and phenobarbital. The minor effects of diazepam and phenobarbital at high doses were not due to the development of tolerance because similar effects were obtained in subjects not previously treated with the drugs. The main finding was the absence of a strong depressant effect on the rate of self-stimulation after large doses of diazepam and phenobarbital, but the presence of depressant effects on the rate of responding after small doses of morphine. These results indicate the possibility that the first two compounds, at doses that sedate, have minor effects on the motivational properties of hypothalamic stimulation while morphine, at doses that sedate, has major effects on these properties.