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 11,717 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent pharmacologic studies suggest that nefazodone may possess antidepressant activity. Nefazodone is active in behavioral models predictive of antidepressant potential. It is active in reversing learned helplessness, prevents reserpine-induced ptosis, and enhances response efficiency in the differential reinforcement for low rates of response paradigm. In in vitro studies, nefazodone inhibits the binding of [3H]ketanserin to cortical serotonin2 (5-HT2) binding sites, whereas in vivo, it antagonizes the 5-HT2-mediated quipazine-induced head shake in rats. In ex vivo studies, acute oral administration of nefazodone inhibits cortical serotonin uptake and occupies frontal cortical 5-HT2 receptor binding sites. Chronic administration of nefazodone produces a reduction in 5-HT2-mediated behavior and decreases cortical 5-HT2 receptor binding site density. Further, a chronic high-dose nefazodone regimen significantly potentiates 5-HT1A-mediated behavioral responses in rats. Nefazodone exhibits decreased anticholinergic, alpha-adrenolytic, and sedative activity relative to other antidepressants.
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PMID:Nefazodone: preclinical pharmacology of a new antidepressant. 227 30

In view of the involvement of central alpha 1-adrenoceptors in the expression of 5-HT1A receptor-mediated spontaneous tail-flicks (STFs) in the rat, this study examined whether the putative alpha 1-adrenoceptor antagonist (alpha 1-antagonist) properties of certain 5-HT1A receptor agonists, (+)-flesinoxan and LY 165,163, might modify their behavior in the STF paradigm. Whereas the 5-HT1A receptor agonists 8-OH-DPAT and WY 48,723 dose-dependently elicited STFs, (+)-flesinoxan was only weakly active and LY 165,163 was ineffective. Further, (+)-flesinoxan and LY 165,163 antagonized the induction of STFs by 8-OH-DPAT and WY 48,723. Nevertheless, (+)-flesinoxan and LY 165,163 mimicked 8-OH-DPAT and WY 48,723 in eliciting a pronounced rise in plasma corticosterone and a marked hypothermia: these actions were blocked by the 5-HT1A receptor antagonist, (-)-alprenolol, but they were not affected by the alpha 1-antagonist prazosin. Reflecting its antagonist actions at alpha 1-adrenoceptors, prazosin evoked a pronounced ptosis, an action mimicked by the preferential alpha 1A-antagonists WB 4101, methylurapidil and benoxathian, whereas chlorethylclonidine, which irreversibly inactivates alpha 1B- but not alpha 1A-adrenoceptors, was inactive. Although 8-OH-DPAT and WY 48,723 failed to modify palpebral aperture, (+)-flesinoxan and LY 165,163 provoked a ptosis, suggesting that they possess alpha 1A-antagonist properties. The alpha 1-agonists cirazoline and ST 587 did not elicit STFs alone and failed to modify the induction of STFs by 8-OH-DPAT and WY 48,723. By contrast, they greatly facilitated the ability of both (+)-flesinoxan and LY 165,163 to induce STFs. STFs elicited by (+)-flesinoxan and LY 165,163 in the presence of cirazoline or ST 587 were blocked not only by prazosin but also by (-)-alprenolol, BMY 7378 and S 15535, all of which are antagonists of postsynaptic 5-HT1A receptors. The facilitatory actions of cirazoline and ST 587 were selective in that they did not permit the induction of STFs by agonists at other 5-HT receptor subtypes (5-HT1B, 5-HT1C, 5-HT2 or 5-HT3). In conclusion, in the STF paradigm, the high-efficacy agonist actions of (+)-flesinoxan and LY 165,163 at 5-HT1A receptors are "masked" by their "intrinsic" alpha 1A-antagonist properties, the neutralization of which by alpha 1-agonists reveals the activation of 5-HT1A receptors.
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PMID:5-HT1A receptors and the tail-flick response. VI. Intrinsic alpha 1A-adrenoceptor antagonist properties can mask the actions of 5-HT1A receptor agonists in the spontaneous tail-flick paradigm. 790 55

The novel benzodioxopiperazine, S 15535 (4-(benzodioxan-5-yl)1-(indan-2- yl)piperazine), displayed high affinity for 5-HT1A binding sites (1.8 nM) whereas its affinity was 100-fold lower at other 5-HT receptor types, at alpha 1, alpha 2- and beta-adrenoceptors and at dopamine D1 and D2 receptors. In vivo, S 15535 (0.16-10 mg/kg s.c.) acted as an antagonist at postsynaptic 5-HT1A receptors in completely blocking the flat-body posture and hypothermia elicited by the 5-HT1A receptor agonist, 8-OH-DPAT. It had no effect when applied alone. At presynaptic 5-HT1A receptors, S 15535 acted as an agonist in inhibiting striatal accumulation of 5-hydroxytryptophan (0.04-0.63 mg/kg s.c.) and in spiperone reversibly reducing electrical activity of the dorsal raphe nucleus (0.004-0.031 mg/kg i.v.). At doses up to 40.0 mg/kg s.c., S 15535 neither inhibited methylphenidate-induced gnawing nor elicited ptosis suggesting a lack of antagonist properties at, respectively, dopamine D2 receptors and alpha 1-adrenoceptors. In conclusion, S 15535 is a potent 5-HT1A ligand which acts, in vivo, as a highly selective agonist and antagonist at presynaptic and postsynaptic 5-HT1A receptors, respectively.
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PMID:S 15535: a highly selective benzodioxopiperazine 5-HT1A receptor ligand which acts as an agonist and an antagonist at presynaptic and postsynaptic sites respectively. 838 59

The antipsychotic efficacy of aripiprazole is not generally associated with extrapyramidal symptoms, cardiovascular effects, sedation or elevations in serum prolactin that characterize typical or atypical antipsychotics. The aim of this study was to clarify the mechanism of action of aripiprazole that underlies its favourable clinical profiles. The preclinical efficacy and side-effect profiles of aripiprazole were evaluated using several pharmaco-behavioural test systems in mice and rats, both in vivo and ex vivo, and compared with those of other conventional and atypical antipsychotics. Each of the antipsychotics induced catalepsy and inhibited apomorphine-induced stereotypy. The catalepsy liability ratios for these drugs were 6.5 for aripiprazole, 4.7 for both olanzapine and risperidone. The ptosis liability ratios for aripiprazole, olanzapine and risperidone were 14, 7.2 and 3.3, respectively. Aripiprazole slightly increased DOPA accumulation in the forebrain of reserpinised mice, reduced 5-HTP accumulation at the highest dose and exhibited a weaker inhibition of 5-methoxy-N,N-dimethyl-tryptamine-induced head twitches. Aripiprazole did not inhibit physostigmine- or norepinephrine-induced lethality in rats. In conclusion, aripiprazole shows a favourable preclinical efficacy and side-effect profile compared to a typical antipsychotics. This profile may result from its high affinity partial agonist activity at D2 and 5-HT1A receptors and its antagonism of 5-HT2A receptors.
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PMID:Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile. 1535 81