On the mechanism of imipramine's influence in lowering p-hydroxyphenylglycol concentrations in the brain. The role of tyrosine.

Administration of imipramine (IMI) to rats was shown to lower after 4.5 hr the brain concentration of the octopamine metabolite p-hydroxyphenylglycol (pHPG) in a dose-dependent manner over the range of 10-40 mg/kg of IMI. Assay of plasma and brain levels of tyrosine revealed that IMI produced a reduction in both but with a shorter time-course than for the depletion in pHPG, with the maximal decreases occurring at 1.5 hr, before there was any loss of pHPG. The reductions in tyrosine and pHPG levels could not be explained by an effect of IMI on food intake, since the levels were diminished even in 24-hr fasted animals. When rats were injected with IMI 4.5 hr before 200 mg/kg of tyrosine and 5.5 hr before being killed, the elevation in brain pHPG levels were attenuated by about 50%, as compared to the animals that received tyrosine alone. These data suggest that the ability of IMI to lower brain pHPG probably involves two distinct mechanisms: (1) a lowering of brain and plasma tyrosine concentrations, and (2) an inhibition of the conversion of tyrosine to pHPG. It is unclear whether these effects are due to IMI itself or to one of its metabolites, such as desmethylimipramine or didesmethylimipramine, which were found in the plasma in amounts equal to or greater than IMI.

Decreases in tyrosine and p-hydroxyphenylglycol caused by various antidepressants.

The effects of eleven different antidepressant drugs on brain p-hydroxyphenylglycol (pHPG) and on brain and plasma tyrosine concentrations were investigated in rats. Imipramine, amitriptyline, amoxapine, desmethylimipramine and iprindole (20 mg/kg each) and bupropion (50 mg/kg) decreased brain pHPG levels 4.5 or 6 hr after injection. Each of these drugs also significantly reduced plasma tyrosine levels 1.5 hr after injection. In contrast, zimelidine, amitriptylinoxide, trimipramine and trazodone had no significant effect on either brain pHPG or plasma tyrosine. Mianserin significantly lowered plasma tyrosine but produced a nonsignificant decrease in brain pHPG. The decreases in brain pHPG caused by the various drugs were significantly correlated with 3,4-dihydroxyphenylethyleneglycol. Moreover, decreases in brain pHPG and brain and plasma tyrosine concentrations were correlated with the potencies of these drugs to inhibit in vitro norepinephrine uptake. These results suggest the possibility that noradrenergic (or similar) mechanisms regulate both pHPG and tyrosine levels. However, the decreases in pHPG cannot be explained entirely by a deficiency in tyrosine, since the depletions in pHPG were much larger and longer lasting than those of tyrosine.

The effect of dietary precursors on the excretion of amines and their metabolites in the rat.

The influence of diet on the excretion of catecholamines, some of their metabolites, and pHPG, an octopamine metabolite, was examined. Two groups of rats were fed either a cereal-containing standard laboratory Purina rat chow or a cereal-free casein diet. Use of the standard chow resulted in significant increases in the urinary values for total MHPG, pHPG, DHPE, MHPE, and free and total DOPAC by the seventh day in comparison to the casein diet. No changes were noted in the excretion of free and total NE, DA, and HVA. The data indicate that it is necessary to place the animals on the casein diet several days before determining the excretion of the aforementioned metabolites.

The effects of imipramine and iprindole on the metabolism of octopamine in the rat.

Acute injections of imipramine and iprindole in rats produced significant decreases in the concentration of p-hydroxyphenylglycol (pHPG), a neutral metabolite of octopamine in brain at 6 and 24 hr after the administration of drugs. The 24-hr urinary levels of both free and total pHPG were reduced to 25-29% of control with acute administration of imipramine, while iprindole produced a 30% decrease in free pHPG. With chronic administration of imipramine, concentrations of pHPG in brain returned to normal, while the 24-hr urinary levels were still decreased (to 24%). Octopamine in brain was unaltered after both single and repeated injections of imipramine. Thus, these data suggest that the turnover of octopamine in brain is reduced after acute administration of imipramine and iprindole, while after chronic treatment with imipramine, turnover of octopamine in brain has returned to control levels.

Opposite effects of chronic imipramine treatment on brain and urine MHPG levels in the rat.

Acute imipramine (IMI; 20 mg/kg, ip) in rats decreased the brain concentration of 3-methoxy-4-hydroxyphenethylene glycol (MHPG), a metabolite of norepinephrine (NE), to 85% of control 24 hr after injection. In contrast, chronic IMI (20 mg/kg, ip, daily for 14 days) significantly raised brain MHPG levels to 123% of control, while reducing brain NE levels. Urinary MHPG levels were reduced by both acute and chronic IMI treatments, to 52% and 51%, respectively. These data suggest that the brain turnover of NE is reduced after acute IMI, but is elevated after chronic treatment. Although urinary levels of MHPG changed in parallel with brain levels following an acute administration of IMI, such was not the case after chronic administration. We conclude that caution must be used in extrapolating drug-induced changes in urinary metabolite levels to brain amine function.

Effects of intraventricular injections of 6-hydroxydopamine on amine metabolites in rat brain and urine.

The effects in rats of intraventricular injections of 6-hydroxydopamine (6-OHDA) on the urinary excretion 1-3 weeks later of 3-methoxy-4-hydroxyphenethylene glycol (MHPG), 3,4-dihydroxyphenethanol (DHPE), 3-methoxy-4-hydroxyphenethanol (MHPE), p-hydroxyphenylglycol (pHPG), homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were examined. The excretion of MHPG was decreased to 63 and 71% of control on days 7 and 14, respectively, but had returned to control levels by day 23, even though the brain levels were decreased by 87%. Free and total HVA excretion was reduced on both days 7 and 23, but free and total DOPAC was reduced only on day 7. Based on these data, it can be estimated that about 39% of the free and 46% of the total HVA in urine originates in the CNS. The excretion of conjugated HVA was decreased by 70-80%, but this decrease does not support the notion that the conjugated form of HVA is derived principally from the brain and thus serves as a better marker of brain dopamine metabolism, since the level of this metabolite in the brain was not correspondingly decreased but was instead increased. Urinary DOPAC levels were generally more variable and derived to a greater extent from the periphery; therefore, DOPAC appears to be less suitable than HVA as a marker of brain dopamine. The results also indicate that as much as 35% of the urinary MHPG may originate in the CNS, although compensatory changes in catecholamine metabolism in either the brain or in the periphery may have somewhat influenced this estimate. The results also suggest that at least as much pHPG as MHPG in urine derives from the CNS. The data are consistent with the idea that the neutral dopamine metabolites largely derive from the brain, but the relatively small depletion in their brain levels produced by 6-OHDA prevented the exact proportion being determined accurately.