Drugs Altering Insulin Secretion: Effects on Plasma and Brain Concentrations of Aromatic Amino Acids and on Brain 5‐hydroxytryptamine Turnover

Abstract

I An investigation was made into the effects of drugs which alter insulin secretion on the concentrations Of to hanWandacids in plasma and brain and on 5-hydroxv- streptozotocin, propranolol, tolbutamide and phentolamine. 2 Tolbutamide and phentolamine increased the plasma insulin concentrations by 100% and 300% respectively but with little effect on the brain/plasma ratios for the aromatic amino acids. Previously propranolol was found to decrease plasma insulin by 50% without altering the above ratios. The ratios were decreased by streptozotocin but only when plasma insulin fell by more than 50%. 3 Phentolamine and propranolol did not alter the brain/plasma ratios for the aromatic amino acids in streptozotocin-treated rats. 4 The results suggest that only large changes of insulin secretion e.g. those associated with food intake or aminophylline injection are likely to alter appreciably the brain/plasma ratios for the aromatic amino acids. STolbutamide displaced tryptophan from its binding to plasma albumin and increased brain 5-HIAA probably by inhibiting 5-HIAA efflux from brain. The other drugs did not alter brain 5-HT or 5-HIAA concentrations.

Facilitating Effect of Insulin on Brain 5-Hydroxytryptamine Metabolism

“…The reductions in brain TRP concentrations observed in streptozotocin-diabetic rats [3,5,12,19] were also observed in the present study (table I); these effects were seen at 3 days [5], 5-10 days [3], 7 or 14 days (table I), or 4-6 weeks [19] after the streptozotocin treatment. The doses of streptozotocin used in these earlier studies were 65-75 mg kg-1 and were injected intravenously [5], intraperitoneally [12,13,19], or intracardially [3, 4, present study].…”

“…These increases are probably due to increases in the ratio between serum TRP, p-tyrosine, phenylalamine, and the other larg neutral am ino acids (leucine, isoleucine, and valine) which share the same uptake system for the blood-brain barrier [14]. In con trast, diabetic rats show a marked decrease in brain TRP [5, 12] with no changes in the concentration of 5-hydroxytrypt amine (5-HT) or 5-hydroxyindole acetic acid (5-HIAA) [5, 12] or a reduction in 5-HIAA [3] and a consistent reduction in brain 5-HT metabolism [4. 19].…”

“…The administration of insulin to diabetic rats had a tendency to reverse the decreases in 5-hydroxytryptamine metabolism observed in these animals. Treatment with trypto phan (12-25 mg k g '1) markedly increased rat striatal tryptophan, but did not affect 5-hydroxytryptamine metabolism, an effect that was only observed after the administration of higher doses (50-100 mg kg ')■ This is in contrast to the effect of insulin that produces a lesser increase in striatal tryptophan accompanied by an increase in 5-hydroxytryptamine metabo lism, indicating that in addition to the inrease in tryptophan availability that it produces, it also possesses some other facilitatory effect on 5-hydroxytryptamine metabolism.The existence of a relationship between the concentra tion of peripheral insulin and the levels of the precursor amino acids of some neurotransmitters has been known for quite some time (5, 12, 18]. Either the parenteral administra tion of insulin or its release following the consumption of carbohydrates increases the uptake of tryptophan (TRP) and p-tyrosine into the brain [8, 10].…”

Changes in Brain Monoaminergic Neurotransmitter Concentrations in Rat after Intracerebroventricular Injection of Streptozotocin

“…The relationship between (pancreas) insulin effi cacy and brain neurotransmitters has been investi gated after the induction of experimental diabetes mellitus in rats in various studies. Th� most fre quent result reported has been a reduction in the cerebral tissue concentration of the 5-HT precursor tryptophan by 30--50% observed 1-4 weeks after intraperitoneal injection of STZ (Curzon and Fernando, 1977;Mackenzie and Trulson, 1978a;Trulson et aI., 1986). In contrast to these reports, according to which there were no alterations in the brain tissue levels of 5-HT or 5-HIAA, concentra tions of these were also reduced 2 weeks after in traperitoneal STZ treatment in the study of Kwok and Juorio (1987).…”

Effects of precursors on brain neurotransmitter synthesis and brain functions

“…In diabetes, blood levels of the branchedchain amino acids are very high [12]. Such abnormal elevations in the blood levels of these amino acids should and do diminish tryptophan uptake into brain, and brain tryptophan levels [13,14]. In addition, because of the absence of insulin secretion, blood LNAA levels, and therefore brain indoles, do not change normally after carbohydrate ingestion.…”