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Serotonin autoreceptor subsensitivity and antidepressant activity.

Moret C, Briley M.

Centre de Recherche Pierre Fabre, Castres, France.

Release of [3H]serotonin elicited by electrical stimulation from rat hypothalamus and its modulation through autoreceptors has been studied after chronic administration of two antidepressants, citalopram, specific inhibitor of serotonin uptake, and milnacipran (previously called midalcipran, F 2207) which blocks the uptake of serotonin and noradrenaline to the same extent. The amount of [3H]serotonin released by electrical stimulation was enhanced and the inhibitory effect of the agonist, LSD (lysergic acid diethylamide), reduced in rats treated with citalopram at 10 and 50 mg/kg per day for 21 days. These effects existed at both doses but were accentuated at the higher dose. Thus a chronic treatment with citalopram provokes a down-regulation of the serotonergic autoreceptor, allowing an increase of serotonin neurotransmission. After 21 days treatment with milnacipran, at 50 mg/kg per day, none of the parameters studied were modified. These data suggest that down-regulation of the serotonin autoreceptor is not a universally applicable hypothesis to explain the action of all antidepressants acting on the uptake of serotonin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2365009&dopt=Abstract citalopram escitalopram Lexapro



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Indoleamine stores in maturing mouse brain reexposed to citalopram following extended uptake inhibition.

Baker PC, Hoff KM.

Department of Biology, Cleveland State University, OH 44115.

1. Mice of various ages between birth and adulthood were injected daily for 5 days with the serotonin specific uptake inhibitor citalopram (LU 10-171). 2 days later they were reinjected with citalopram 2. 2 hr, 1 day and 3 days following the last injection animals were killed and their brains assayed for 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA). 3. Brains were found to still respond to citalopram's acute action despite the fact younger brains had undergone long term alteration of 5-HIAA stores. 4. The possibility that indoleamines are subject to different regulatory mechanisms in young brain is discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2465935&dopt=Abstract citalopram escitalopram Lexapro



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Antinociceptive effects of serotonergic reuptake inhibitors in mice.

Fasmer OB, Hunskaar S, Hole K.

Department of Physiology, University of Bergen, Norway.

The antinociceptive effects of three predominantly serotonergic reuptake inhibitors, alaproclate, citalopram and clomipramine, were examined in mice using the hot-plate, formalin and substance P tests. The effects were compared with those of the noradrenergic reuptake inhibitor, desipramine. Different profiles in the three nociceptive tests were found for all four drugs, using doses of 10 and 40 mg/kg. The selective serotonergic reuptake inhibitor, alaproclate, seemed to have the least antinociceptive effects, and was the only drug that was ineffective in the hot-plate test. The other selective drug, citalopram, had a stronger effect than alaproclate in the substance P test, but in the formalin test, both drugs were approximately equally effective. Clomipramine differed from citalopram by being more effective in the formalin test. These findings thus indicate that selective inhibitors of the uptake of 5-HT have weaker antinociceptive effects than less selective drugs. Desipramine seemed to be no less effective than the serotonergic drugs and was the most potent drug in the hot-plate test.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2482459&dopt=Abstract citalopram escitalopram Lexapro



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Long-term effect of antidepressant drugs and electroconvulsive shock (ECS) on cortical alpha 1-adrenoceptors following destruction of dopaminergic nerve terminals.

Nowak G.

Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

The effect of repeated treatment with imipramine, citalopram and ECS on the density of alpha 1-adrenoceptors in the cerebral cortex of rats with a dopaminergic lesion was studied. Imipramine and citalopram produced alph 1-upregulation in normal animals but not in animals with a dopaminergic lesion. On the other hand, ECS, produced such an effect in both normal and lesioned rats. Our results indicate that the investigated drugs (imipramine, citalopram) and ECS induce alpha 1-up-regulation via different mechanisms, and that the effect of these drugs depends on intact dopaminergic nerve terminals.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2549530&dopt=Abstract citalopram escitalopram Lexapro



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The effect of repeated administration of imipramine, citalopram and mianserin on responsiveness of central serotonergic, alpha 2-adrenergic and cholinergic system in mice.

Maj J, Rogoz Z, Skuza G, Sowinska H.

Institute of Pharmacology, Polish Academy of Sciences, Krakow.

The effect of antidepressant drugs: imipramine, citalopram and mianserin given either in a single dose or twice a day for 14 days in a dose of 10 mg/kg was investigated in mice in tests for the responsiveness of central serotonergic (L-5 hydroxytryptophan-induced head twitches), alpha 2-adrenergic (donidine hypoactivity) and cholinergic (oxotremorine syndrome) systems. The effect of L-5 hydroxytryptophan was inhibited by repeated administration of citalopram and mianserin but unchanged by administration of imipramine. After a single administration only mianserin inhibited the L-5 hydroxytryptophan effect. Given repeatedly, the investigated antidepressant drugs did not affect the effect of clonidine; only mianserin potentiated the hypoactivity when given in a single dose. Repeatedly administered antidepressant drugs did not affect the action of oxotremorine, although imipramine (but not citalopram or mianserin) antagonized it after a single administration. The results indicate that under the present conditions repeatedly given mianserin and citalopram, but not imipramine, antagonize behavioral effects of L-5 hydroxytryptophan. No one of the investigated antidepressant drugs given repeatedly changed the responsiveness of alpha 2 -adrenergic and cholinergic systems to their agonists. It might be concluded that the changes in alpha 1-adrenergic and dopaminergic systems, observed previously after repeated administration of antidepressant drugs, are selective.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2561380&dopt=Abstract citalopram escitalopram Lexapro



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Increase in endogenous 5-hydroxytryptamine levels modulates the central network underlying locomotion in the lamprey spinal cord.

Christenson J, Franck J, Grillner S.

Nobel Institute for Neurophysiology, Karolinska institutet, Stockholm, Sweden.

To investigate the effects of an endogenous release of serotonin (5-HT) in the lamprey spinal cord, in vitro, the 5-HT uptake-blocker citalopram (1-10 microM) was added to the bathing solution. Samples taken from the physiological solution through high-performance liquid chromatography (HPLC) showed that 5-HT was released from the spinal cord. To study the effect of this endogenous release of 5-HT on the spinal network generating locomotion, 'fictive locomotion' was induced by bath application of N-methyl-D-aspartate (NMDA, 100 microM). It elicited a steady locomotor rhythm between 0.2 and 2.5 Hz. The effects of citalopram were the following: (1) the locomotor frequency slowed down, (2) the intensity of the ventral root bursts was increased and (3) the intersegmental phase lag was prolonged. The effects of citalopram and thus presumably of an endogenous release of 5-HT were similar to what has previously been observed during bath application of 5-HT. In the latter case the conditions are different, since all 5-HT receptors regardless of their location in relation to the 5-HT-containing boutons will be affected in a similar way.

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Long-term effect of antidepressant drugs and electroconvulsive shock on brain alpha 1-adrenoceptors following destruction of noradrenergic or serotonergic nerve terminals.

Nowak G, Przegalinski E.

Institute of Pharmacology, Polish Academy of Sciences, Krakow.

Antidepressant drugs and electroconvulsive shock (ECS) given repeatedly increase the density of brain alpha 1-adrenoceptors. However, the mechanism involved in this effect is unknown. To study the role of presynaptic noradrenaline (NA) and 5-hydroxytryptamine (5-HT) nerve terminals in the above phenomenon we examined the density of [3H]prazosin binding sites in the rat cerebral cortex following a prolonged treatment with imipramine and citalopram (10 mg/kg po, twice daily for 14 days) or ECS (once daily for 8 days) in animals pretreated with DSP-4 (62.5 mg/kg ip) and p-chloroamphetamine (PCA, 2 x 10 mg/kg ip). In normal rats imipramine, citalopram and ECS increased the density (Bmax) of [3H]prazosin binding sites by 30, 25 and 19%, respectively. DSP-4 pretreatment abolished the effect of imipramine and citalopram but not that of ECS. Pretreatment with PCA influenced the effect of neither antidepressant drugs nor ECS. Our results indicate that the "up-regulation" of alpha 1-adrenoceptors induced by imipramine and citalopram, but not by ECS, depends on intact NA nerve terminals. They also show that the 5-HT system is not involved in the above phenomenon.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2851781&dopt=Abstract citalopram escitalopram Lexapro