Library

Notes: The serotonin transporter (SERT), which belongs to a family of sodium/chloride-dependent transporters, is the major pharmacological target in the treatment of several clinical disorders, including depression and anxiety. In the present study we show that the dissociation rate, of [3H]S-citalopram from human SERT, is retarded by the presence of serotonin, as well as by several antidepressants, when present in the dissociation buffer. Dissociation of [3H]S-citalopram from SERT is most potently inhibited by S-citalopram followed by R-citalopram, sertraline, serotonin and paroxetine. EC50 values for S- and R-citalopram are 3.6 ± 0.4 µm and 19.4 ± 2.3 µm, respectively. Fluoxetine, venlafaxine and duloxetine have no significant effect on the dissociation of [3H]S-citalopram. Allosteric modulation of dissociation is independent of temperature, or the presence of Na+ in the dissociation buffer. Dissociation of [3H]S-citalopram from a complex with the SERT double-mutant, N208Q/N217Q, which has been suggested to be unable to self-assemble into oligomeric complexes, is retarded to an extent similar to that found with the wild-type, raising the possibility that the allosteric mechanism is mediated within a single subunit. A species-scanning mutagenesis study comparing human and bovine SERT revealed that Met180, Tyr495 and Ser513 are important residues in mediating the allosteric effect, as well as contributing to high-affinity binding at the primary site.

Notes: Abstract The role of serotonergic (5-HT) receptor subtypes in mediation of aggressive behaviour in isolated male mice has been studied. Increase of attack latency was used as a simple measure of antiaggressive behaviour. 5-HT1A agonists (BAY R 1531, 8-OHDPAT, flesinoxan, gepirone, 5MeO DMT, buspirone, ipsapirone, BMY 14802) completely inhibit the aggressive behaviour irrespective of their intrinsic activities. Also the putative antagonists spiroxatrine and NAN 190 as well as the non-selective 5-HT1 agonists RU 24969, TFMPP, mCPP and eltoprazine have an antiaggressive effect. The mixed 5-HT1A andβ-adrenoceptor antagonists (−)-alprenolol and pindolol are ineffective and do not inhibit the effect of 8-OHDPAT. Neither does the non-selective 5-HT antagonist metergoline. The antiaggressive effect correlates with 5-HT1A receptor affinity in vitro and with generalization to the 8-OHDPAT-induced discriminative stimulus. The selective 5-HT uptake inhibitor citalopram does not inhibit aggressive behaviour. The 5-HT2 agonist DOI has an antiaggressive effect only at high doses, whereas the 5-HT2 antagonist ritanserin and the 5-HT3 antagonist ondansetron are ineffective. Prazosin (α 1-adrenoceptor antagonist), clonidine (α 2-adrenoceptor agonist), clenbuterol (β-adrenoceptor agonist), ketanserin (5-HT2 receptor andα 1-adrenoceptor antagonist), clozapine and (−)-octoclothepin (dopamine (DA), 5-HT2 receptor andα 1-adrenoceptor antagonist) all show an antiaggressive effect. SCH 23390 (DA D1 receptor antagonist) and emonapride (DA D2 receptor antagonist) are ineffective. In conclusion, 5-HT1A receptors are involved in mediation of isolation-induced aggressive behaviour in mice. The involvement of other 5-HT receptor subtypes needs further clarification. The adrenergic system may also be involved. DA antagonists are ineffective.

Notes: Abstract 1. The present survey compares the effects of antidepressants and their principal metabolites on reuptake of biogenic amines and on receptor binding. The following antidepressants were included in the study: the tricyclic antidepressants amitriptyline, dothiepin, and lofepramine and the atypical antidepressant bupropion, which all have considerable market shares in the UK and/or US markets; the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; and the recently approved antidepressants venlafaxine and nefazodone. 2. Amitriptyline has similar in vitro reuptake inhibitory potencies for 5-HT and NA, whereas the metabolite nortriptyline is preferentially a NA reuptake inhibitor. Both amitriptyline and nortriptyline are also 5-HT2 receptor antagonists. 3. Dothiepin has equipotent 5-HT and NA reuptake inhibitory activity, whereas northiaden shows a slight selectivity for NA reuptake inhibition. Dothiepin and northiaden are also 5-HT2 receptor antagonists. The slow elimination rate of northiaden (36–46 hr) compared to dothiepin (14–24 hr) suggests that northiaden contributes significantly to the therapeutic effect of dothiepin. 4. Lofepramine is extensively metabolized to desipramine. Desipramine plays an important role in the antidepressant activity of lofepramine, as the plasma elimination half-life of lofepramine (4–6 hr) is much shorter than that of desipramine (24 hr). Both compounds are potent and selective inhibitors of NA reuptake. 5. The five approved SSRIs, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, are potent 5-HT reuptake inhibitors, and the demethyl metabolites, norfluoxetine, demethylsertraline, and demethylcitalopram, also show selectivity. Paroxetine and sertraline are the most potent inhibitors of 5-HT reuptake, whereas citalopram is the most selective. Fluoxetine is the least selective and the metabolite of fluoxetine, norfluoxetine, is a more selective and more potent 5-HT reuptake inhibitor than the parent compound and has an extremely long half-life (7–15 compared to 1–3 days). Thus the metabolite plays an important role for the therapeutic effect of fluoxetine. Fluoxetine is also a 5-HT2C receptor antagonist. Demethylsertraline is a weaker and less selective 5-HT reuptake inhibitor in vitro than sertraline, but demethylsertraline has a very long half-life (62–104 hr) compared to the parent compound (24 hr) and it might play a role in the therapeutic effects of sertraline. Demethylcitalopram has about a 10 times lower 5-HT reuptake inhibitory potency in vitro than citalopram, and the elimination half-lives are approximately 1.5 and 2 days, respectively. 6. Bupropion and hydroxybupropion are weak inhibitors of biogenic amine reuptake. The mechanisms of action responsible for the clinical effects of bupropion are not fully understood, but it has been suggested that both dopaminergic and noradrenergic components play a role and that the hydroxybupropion metabolite contributes significantly to the antidepressant activity. 7. Venlafaxine and O-demethylvenlafaxine are weak inhibitors of 5-HT and NA reuptake, and the selectivity ratios are close to one. O-Demethylvenlafaxine is eliminated more slowly than venlafaxine (plasma half-lives of 5 and 11 hr, respectively), and it is likely that it contributes to the overall therapeutic effect of venlafaxin. 8. Nefazodone and α-hydroxynefazodone are equipotent 5-HT and NA reuptake inhibitors. Both compounds are also 5-HT2 receptor antagonists. Both parent compound and metabolite have short elimination half-lives.