Effect of diazepam on cerebral monoamine synthesis during hypoxia and hypercapnia in the rat.
In view of the fact that diazepam has been shown to prevent an increase in catecholamine synthesis and/or turnover rates in stressful situations, and to modify the cerebral metabolic (and circulatory) response to hypoxia and hypercapnia, the influence of the drug on synthesis rates of DOPA and 5-HTP in three regions of the rat brain were studied under normoxic-normocapnic conditions, as well as in hypoxia and hypercapnia. In order to exclude a modifying influence of variations in tissue pO2 during hypercapnia, cerebral venous pO2 was kept at control values by moderate arterial hypoxia. When compared to the control state (paralyzed animals maintained on 70% N2O) normoxic and normocapnic animals given diazepam (in the absence of N2O) showed a slightly enhanced DOPA synthesis in limbic structures and reduced 5-HTP synthesis in limbic structures and striatum. In hypoxia, the drug considerably curtailed DOPA synthesis in limbic structures and striatum but had no effect on synthesis rate in cortex. The drug also appeared to exaggerate the generalized reduction in 5-HTP synthesis observed under 70% N2O. In hypercapnia, diazepam reduced the enhanced rate of DOPA synthesis (observed under 70% N2O) in striatum but left that in the cortex unchanged. The drug prevented the hypercapnia-induced increase in 5-HTP synthesis, observed under 70% N2O. It is concluded that diazepam significantly alters dopamine and serotonin synthesis in hypoxia and hypercapnia. Probably an indirect action, perhaps related to the stress-alleviating effect of diazepam, is involved. The results suggest that the effect of the drug on cerebral metabolic rate and blood flow in hypoxia and hypercapnia is unrelated to changes in noradrenaline synthesis or turnover. Furthermore, although the results demonstrate that diazepam modulates dopamine metabolism in hypoxia and hypercapnia it seems questionable that this influence can explain the metabolic and circulatory effects of diazepam in these conditions.
D006916:5-Hydroxytryptophan / Q000096:biosynthesis; D000596:Amino Acids / Q000096:biosynthesis*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology*; D004295:Dihydroxyphenylalanine / Q000096:biosynthesis; D006935:Hypercapnia; D000860:Hypoxia; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D014364:Tryptophan / Q000096:biosynthesis; D014443:Tyrosine / Q000096:biosynthesis
D000596:Amino Acids; D014443:Tyrosine; D004295:Dihydroxyphenylalanine; D014364:Tryptophan; D006916:5-Hydroxytryptophan; D003975:Diazepam