PubMed · 11638728
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L J Vanderwiele. 1993. [Not Available].. https://pubmed.ncbi.nlm.nih.gov/11638728/
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Addiction is a relapsing brain disease with a tendency towards chronicity. Biological, psychological and socio-cultural factors play a role in the onset and course of this disease. The Health Council of the Netherlands has issued a report on pharmacotherapeutic interventions. The treatment of addiction should be regarded as a medical intervention. A growing number of effective pharmacotherapies are becoming available for the treatment of heroin addiction, although not all of those are available in the Netherlands. Currently, no effective pharmacotherapies are available for the treatment of cocaine addiction. In polydrug addicts, pharmacotherapeutic interventions should be directed at the various separate addictions. In the majority of cases pharmacotherapy is part of an integrated treatment approach in which supportive psychosocial interventions are also important. The long-term continuation of treatment is usually indicated. The Health Council recommends that addiction physicians be put in charge of the multidisciplinary treatment. Medical schools should pay attention to the practical aspects of the treatment and management of addicts. The organisation and workforce of addiction treatment services should comply with the demands that are placed upon healthcare services. Public information campaigns about addiction and the treatment options for addicts can contribute to the destigmatisation of this patient category.
To explore aqueous accessibility and functional contributions of transmembrane domain (TM) 1 in human serotonin transporter (hSERT) proteins, we utilized the largely methanethiosulfonate (MTS) insensitive hSERT C109A mutant and mutated individual residues of hSERT TM1 to Cys followed by tests of MTS inactivation of 5-hydroxytryptamine (5-HT) transport. Residues in TM1 cytoplasmic to Gly-94 were largely unaffected by Cys substitution, whereas the mutation of residues extracellular to Ile-93 variably diminished transport activity. TM1 Cys substitutions displayed differential sensitivity to MTS reagents, with residues more cytoplasmic to Asp-98 being largely insensitive to MTS inactivation. Aminoethylmethanethiosulfonate (MTSEA), [2-(trimethylammonium) ethyl]methanethiosulfonate bromide (MTSET), and sodium (2-sulfonatoethyl)-methanethiosulfonate (MTSES) similarly and profoundly inactivated 5-HT transport by SERT mutants D98C, G100C, W103C, and Y107C. MTSEA uniquely inactivated transport activity of S91C, G94C, Y95C but increased activity at I108C. MTSEA and MTSET, but not MTSES, inactivated transport function at N101C. Notably, 5-HT provided partial to complete protection from MTSET inactivation for D98C, G100C, N101C, and Y107C. Equivalent blockade of MTSET inactivation at N101C was observed with 5-HT at both room temperature and at 4 degrees C, inconsistent with major conformational changes leading to protection. Notably, cocaine also protected MTSET inactivation of G100C and N101C, although MTS incubations with N101C that eliminate 5-HT transport do not preclude cocaine analog binding nor its inhibition by 5-HT. 5-HT modestly enhanced the inactivation by MTSET at I93C and Y95C, whereas cocaine significantly enhanced MTSET sensitivity at Y107C and I108C. In summary, our studies reveal physical differences in TM1 accessibility to externally applied MTS reagents and reveal sites supporting substrate and antagonist modulation of MTS inactivation. Moreover, we identify a limit to accessibility for membrane-impermeant MTS reagents that may reflect aspects of an occluded permeation pathway.
A capillary electrophoretic method for the separation of cocaine and its stereoisomers was developed. In this study, the effect of organic modifier was also investigated. The separation was achieved using 1% sulfated cyclodextrin, 10 mmol L(-1) phosphate buffer, 10% methanol at pH 3. The method provides good reproducibility and easy application.