On 7 Feb 2002 13:51:41 GMT, dag.stenberg at nospam.helsinki.fi wrote:
>et_al at my-deja.com wrote:
>> SSRIs don't actually increase serotonin levels.
>>Yes, they do, provided that inhibitory autoreceptors are downregulated
>(e.g. through long-term use of SSRIs, through 5-HT1A-antagonist drugs
>or sleep deprivation).
>Hmmm. These, among others, seem not to agree:
:: The selective serotonin re-uptake inhibitor (SSRI) citalopram decreases
:: the synthesis of 5-hydroxytryptamine (5-HT) in the mouse brain in vivo
and
:: It is concluded that the citalopram-induced decrease in 5-HT synthesis
:: differs in sensitivity from that mediated by 5-HT1A or 5-HT1B receptor
:: agonists and citalopram also seems to require endogenous 5-HT for its
:: full effect.
Stenfors C, Yu H, Ross SB. (2001)
"Pharmacological characterisation of the decrease in 5-HT synthesis in
the mouse brain evoked by the selective serotonin re-uptake inhibitor
citalopram."
Naunyn Schmiedebergs Arch Pharmacol, vol 363(2):p 222-32
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11218075&dopt=Abstract
:: It is concluded that, although chronic treatment with citalopram does
:: induce desensitisation of 5-HT(1A) receptors, the absence of augmented
:: effects of citalopram on 5-HT levels indicates that other mechanisms
:: compensate for the loss of autoreceptor control.
Cremers TI, Spoelstra EN, de Boer P, et al. (2000)
"Desensitisation of 5-HT autoreceptors upon pharmacokinetically
monitored chronic treatment with citalopram."
Eur J Pharmacol, vol 397(2-3):p 351-7
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10844134&dopt=Abstract
:: Our results show significantly different effects between central and
:: peripheral indices of 5-HT metabolism according to time and to the
:: antidepressant assessed:
:: (i) an enhancement of total tissue 5-HT levels in the three brain areas
:: studied after steady-state achievement of the 3 antidepressants,
:: (ii) the return to initial values of brain 5-HT levels after repeated
:: administration of the two 5-HT re-uptake inhibitors, consistent with
:: the presence of brain adaptative mechanisms,
Alvarez JC, Sanceaume M, Advenier C, et al. (1999)
"Differential changes in brain and platelet 5-HT concentrations after
steady-state achievement and repeated administration of antidepressant
drugs in mice."
Eur Neuropsychopharmacol, vol 10(1):p 31-6
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10647094&dopt=Abstract
:: Acute administration of venlafaxine to rats by i.p. injection
:: resulted in dose-dependent increases in cortical and hippocampal
:: 5-HT levels, as measured by in vivo microdialysis, over the range
:: 5-20 mg/kg. The effect of venlafaxine (10 mg/kg i.p.) was potentiated
:: by prior administration of pindolol (10 mg/kg s.c.) in hippocampus but
:: not in frontal cortex. Daily administration of venlafaxine (5 mg/kg i.p.)
:: for 4 weeks did not change basal 5-HT levels in either brain area.
Gur E, Dremencov E, Lerer B, Newman ME. (1999)
"Venlafaxine: acute and chronic effects on 5-hydroxytryptamine levels in
rat brain in vivo."
Eur J Pharmacol, vol 372(1):p 17-24
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10374710&dopt=Abstract
::Suggest you read full extract or paper:
Moret C, Briley M. (1997)
"Ex vivo inhibitory effect of the 5-HT uptake blocker citalopram on 5-HT
synthesis."
J Neural Transm 1997;104(2-3):147-60
::Suggest you read full extract or paper:
Zangen A, Overstreet DH, Yadid G. (1997)
"High serotonin and 5-hydroxyindoleacetic acid levels in limbic brain
regions in a rat model of depression: normalization by chronic
antidepressant treatment."
J Neurochem, vol 69(6):p 2477-83
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9375680&dopt=Abstract
:: The effects of repeated fluoxetine (Flx) administration
:: (5, 10, or 15 mg/kg i.p., twice daily for 21 days) on serotonin
:: and 5-HIAA metabolism were examined in the hypothalamus,
:: hippocampus, pons medulla and cerebral cortex of rats killed
:: 1-28 days after the last dose. Dose-dependent weight loss was
:: observed during treatment, followed by gradual and complete
:: recovery of body weight over the following two weeks. Chronic
:: Flx treatment caused a dose-dependent decrease in brain 5-HT
:: levels (by between 10 and 50% depending on the region examined),
:: lasting for 3-7 days after cessation of treatment with the lowest
:: and intermediate doses, and for 7-14 days after cessation of the highest dose.
Trouvin JH, Gardier AM, Chanut E, et al. (1993)
"Time course of brain serotonin metabolism after cessation of long-term
fluoxetine treatment in the rat."
Life Sci, vol 52(18):p PL187-92
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7683363&dopt=Abstract
:: Continued injections of fluoxetine, however, significantly reduced 5-HT
:: in the brain of the rat, the depletion being significant on days 7 and 21
:: in the hippocampus and cortex, respectively. The content of indoles
:: remained significantly decreased for at least a week after the last dose
:: of fluoxetine in the 21-day regimen,
Caccia S, Fracasso C, Garattini S, et al (1992)
"Effects of short- and long-term administration of fluoxetine on the
monoamine content of rat brain."
Neuropharmacology Apr; vol 31(4):p 343-7
This next paper doesn't adress the question of total brain serotonin
levels, but does make the point that the inhibitory effects of SSRIs on
serotonin turnover is a short lived effect.
:: Evidence suggests that the initial reduction in serotonin turnover after
:: acute administration of serotonin reuptake inhibitors is followed by a
:: return to control values after the drug has been administered for at least 2 weeks.
Leonard BE. (1988)
"Pharmacological effects of serotonin reuptake inhibitors."
J Clin Psychiatry, vol 49 Suppl:p 12-7
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3045106&dopt=Abstract
And, as per my original post, the best guide that antidepressants
generally, and SSRIs in particular, aren't effective because they
increase serotonin in the synapses, as is often claimed, is the
effectiveness of the French antidepressants which is a Selective
Serotonin Re-uptake Enhancer, that is it facilitates the withdrawal of
serotonin from synapses.
Ian
>5HT1A autoreceptors:
>Hervas et al. Br J Pharmacol. 2000 May;130(1):160-6.
>Perez et al. J Clin Psychopharmacol. 2001 Feb;21(1):36-45.
>Raurich et al. Synapse. 1999 Oct;34(1):68-76.
>Artigas et al. Trends Pharmacol Sci. 2001 May;22(5):224-8. Review.
>>Sleep deprivation:
>Benedetti et al. Eur Arch Psychiatry Clin Neurosci. 1997;247(2):100-3.
>Prévot et al. J Sleep Res. 1996 Dec;5(4):238-45.
>>Dag Stenberg