In vitro pharmacological activity of the tetrahydroisoquinoline salsolinol present in products from Theobroma cacao L. like cocoa and chocolate.

Cocoa and chocolate contain the tetrahydroisoquinoline alkaloid salsolinol up to a concentration of 25 microg/g. Salsolinol is a dopaminergic active compound which binds to the D(2) receptor family, especially to the D(3) receptor with a K(i) of 0.48+/-0.021 micromol/l. It inhibits the formation of cyclic AMP and the release of beta-endorphin and ACTH in a pituitary cell system. Taking the detected concentration and the pharmacological properties into account, salsolinol seems to be one of the main psychoactive compounds present in cocoa and chocolate and might be included in chocolate addiction.

Inhibition of corticotropin releasing factor (CRF)-induced adrenocorticotropin (ACTH) secretion in pituitary corticotropic cells by substance P.

Substance P (SP) is one of the three distinct peptides of tachykinin system which possess a common spectrum of biological activities including a modulation of stress. It is assumed that the anterior pituitary is one possible target of SP in attenuation the stress response. Therefore the interaction between the hypothalamic stress hormone corticotropin releasing factor (CRF) and SP was investigated in AtT20/D16v-cells, a cellular model derived from a pituitary tumor. CRF stimulates the release of ACTH from AtT20/D16v cells in a concentration dependent manner. SP (1 microM) was able to abolish the CRF (100 nM)-induced ACTH release. In the same way SP inhibited the CRF-induced accumulation of cyclic adenosine monophosphate (cAMP), indicating that SP influenced the signal transduction pathway of CRF receptor activation. Thus, a direct inhibition of the CRF-mediated stress response by SP at the level of anterior pituitary seems to be likely.

Plasma and urine salsolinol in humans: effect of acute ethanol intake on the enantiomeric composition of salsolinol.

The tetrahydroisoquinoline (TIQ) salsolinol (SAL), a condensation product of dopamine and pyruvate or acetaldehyde, is one of the neuropharmacologically active alkaloids in mammals. Previous HPLC studies have shown that the R-enantiomer of SAL is largely predominant, or is the only enantiomer in the urine of healthy subjects, whereas the S-enantiomer was found predominant in the urine of alcoholics. An enzymatic pathway for SAL formation that is influenced by chronic alcohol intake was proposed. However, our analyses showed that the SAL detectable in human urine and plasma is racemic, at least in healthy subjects. No change of the enantiomeric distribution was observed after an acute alcohol ingestion (1 g alcohol/kg body weight). Using a new method for the resolution of the SAL enantiomers and gas chromatography mass spectrometry analysis, the SAL enantiomers were quantified in the urine and plasma of 24 subjects before and after the intake of alcohol. Special dietary conditions were observed to avoid interferences by the SAL of the foodstuff. Although the distribution of SAL enantiomers was not changed after alcohol intake, the total urinary SAL output and the plasma concentration of SAL were significantly influenced in different ways. Only five subjects showed a significant increase both in plasma SAL concentration and in the total urinary SAL output, whereas 19 subjects showed decreased or unchanged SAL levels after alcohol administration. Data also show that only the subjects with low baseline levels (mean of 0.148 ng SAL/ml plasma) tend to increase SAL levels after ethanol ingestion, which may imply some genetic basis for the response.

Effect of S(-)- and R(+)-salsolinol on the POMC gene expression and ACTH release of an anterior pituitary cell line.

Tetrahydroisoquinolines (TIQs) are thought to play an important role in the process of development of alcohol dependence. Being a condensation product between the alcohol metabolite acetaldehyde and dopamine they might be involved in the balance of the opioid system as well as the reward system. Therefore, the influence of the TIQ salsolinol (SAL) on the pro-opiomelanocortin (POMC) gene expression was investigated using the ArT-20 mouse anterior pituitary tumor cell line. Our results show a significant decrease in the POMC gene expression by the S(-)-enantiomer of SAL. The basal secretion of adrenocorticotropin (ACTH) as well as the corticotropin-releasing factor (CRF)-stimulated ACTH released remained unchanged after R(+)- and S(-)-SAL treatment. Interestingly, it was clearly shown that a reduction of intracellular cAMP level occurred after the treatment of the cells with S(-)-SAL whereas R(+)-SAL did not affect the cAMP production. The obtained results suggest that S(-)-SAL is possibly involved in the establishment of the opioid deficiency in alcoholics.

Influence of ethanol on the salsolinol excretion in healthy subjects.

This report describes the change of salsolinol (SAL) levels in the urine of healthy subjects after ethanol ingestion. A new rapid method for SAL extraction from urine sample and a GC-MS assay were used to study the urinary SAL excretion in a group of adult males (n = 14) and females (n = 13) with and without ingestion of ethanol. The results of this study show that the urinary SAL output of all subjects is significantly influenced by the intake of ethanol. A decrease in the SAL level was found in the urine of most of the volunteers (n = 17), whereas only eight subjects showed an increase in the SAL level after administration of ethanol.