Effect of chronic infusion of olanzapine and clozapine on food intake and body weight gain in male and female rats

Many antipsychotics cause weight gain in humans, but usually not in rats, when injected once or twice daily. Since blood antipsychotic half-lives are short in rats, compared to humans, chronic administration by constant infusion may be necessary to see consistent weight gain in rats. Male and female rats were implanted with mini-pumps for constant infusion of olanzapine (5 mg/kg/day), clozapine (10 mg/kg/day) or vehicle for 11 days. Food intake and body weight were measured; blood drug levels were measured by HPLC. Olanzapine increased food intake and body weight in female, but not male rats. Serum olanzapine concentrations were 30-35 ng/ml. Clozapine had no effect on food intake or body weight in female or male rats. Serum clozapine concentrations were about 75 ng/ml. Single-dose pharmacokinetic analysis revealed a serum terminal half-life of 1.2-1.5 h for each drug, with no sex differences. Despite the fact that olanzapine and clozapine promote weight gain in humans, these drugs appear to have minimal effects on body weight and food intake in rats, except for a modest effect of olanzapine in female rats, even though therapeutic levels of olanzapine are achieved in serum during chronic infusion. Hence, the rapid clearance of drug following single administration in previous studies cannot explain the weak or absent effects of antipsychotics on weight gain in this species. The rat thus appears to be an inadequate model of weight gain produced by some antipsychotics in humans.     

The chronic ingestion of diets containing different proteins produces marked variations in brain tryptophan levels and serotonin synthesis in the rat

Serotonin (5HT) synthesis in brain is influenced by precursor (tryptophan (TRP)) concentrations, which are modified by food ingestion. Hence, in rats, a carbohydrate meal raises brain TRP and 5HT; a protein-containing meal does not, but little attention has focused on differences among dietary proteins. Recently, single meals containing different proteins have been shown to produce marked changes in TRP and 5HT. The present studies evaluate if such differences persist when rats ingest such diets chronically. Male rats were studied that ingested diets for 9 days containing zein, wheat gluten, soy protein, casein, or α-lactalbumin (17% dry weight). Brain TRP varied up to eightfold, and 5HT synthesis fivefold among the different protein groups. TYR and LEU concentrations, and catecholamine synthesis rate in brain varied much less. The effects of dietary protein on brain TRP and 5HT previously noted after single meals thus continue undiminished when such diets are consumed chronically.     

Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines

Exercise raises brain serotonin release and is postulated to cause fatigue in athletes; ingestion of branched-chain amino acids (BCAA), by competitively inhibiting tryptophan transport into brain, lowers brain tryptophan uptake and serotonin synthesis and release in rats, and reputedly in humans prevents exercise-induced increases in serotonin and fatigue. This latter effect in humans is disputed. But BCAA also competitively inhibit tyrosine uptake into brain, and thus catecholamine synthesis and release. Since increasing brain catecholamines enhances physical performance, BCAA ingestion could lower catecholamines, reduce performance and thus negate any serotonin-linked benefit. We therefore examined in rats whether BCAA would reduce both brain tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis. Sedentary and exercising rats received BCAA or vehicle orally; tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis rates were measured 1 h later in brain. BCAA reduced brain tryptophan and tyrosine concentrations, and serotonin and catecholamine synthesis. These reductions in tyrosine concentrations and catecholamine synthesis, but not tryptophan or serotonin synthesis, could be prevented by co-administering tyrosine with BCAA. Complete essential amino acid mixtures, used to maintain or build muscle mass, were also studied, and produced different effects on brain tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis. Since pharmacologically increasing brain catecholamine function improves physical performance, the finding that BCAA reduce catecholamine synthesis may explain why this treatment does not enhance physical performance in humans, despite reducing serotonin synthesis. If so, adding tyrosine to BCAA supplements might allow a positive action on performance to emerge.     

5,7-Dihydroxytryptamine: Regional Brain Concentrations Following Intraventricular Administration to Rats

The concentrations of 5,7-dihydroxytryptamine (5,7-DHT) and serotonin (5-HT) were measured in brainstem, hypothalamus and cerebral cortex 0, 2, 6, 12, and 24 hours following the bilateral, lateral ventricular injection of 5,7-DHT (100 g/each ventricle) into adult male rats. At 6 hours, 5,7-DHT levels had decreased 99% from 0 hr values in all brain regions. Thereafter, 5,7-DHT levels continued to decline in cortex, but not in hypothalamus or brainstem; at 24 hr, but not 48 hr, 5,7-DHT peaks were still measurable in each brain region examined. Serotonin levels in all three regions also fell markedly by 2-6 hours after 5,7-DHT administration. At 24 hours, hypothalamus and brainstem 5HT levels had declined >70% and cerebral cortex 50% below control values. The relevance of these findings to the protective action of monoamine reuptake blockers is discussed.