Metergoline - 5-ht1a antagonist

[Kinncrimson]

Has anyone ever heard of Metergoline?

It is a strong prolactin inhibator, which is achieved through serotonin antagonism.
It differs from all other prolactin disinhibators, because it is not a direct dopamine agonist, it is a serotonin anatagonist and only a indirect d2 agonist.

Here we have the binding profile at page 22:
https://books.google.at/books?id=7v0kBQ ... le&f=false

Metergolin is much more potent on the 5-ht1a receptor than for example Cyproheptadine and Mianserin. The ki is 20 nm.
It is used for women to stop the lactate production and in men for low libido and reproduction problems.
For men the dosage is 4mg, 3 times per day for at least 3 months, if necessary the dosage can be increased to 24 mg.

I couldn't find this information on an english internet site, but in german:
https://imedikament.de/liserdol
"Senkung erhöhter Prolaktinspiegel beim Mann:
Die übliche Dosierung beträgt 3 Filmtabletten täglich. Falls erforderlich kann die Dosis bis auf 6 Filmtabletten täglich erhöht werden.
Die Behandlung des erhöhten Prolaktinspiegels beim Mann sollte bis zum Abklingen der Symptomatik durchgeführt werden, bei Fruchtbarkeitsstörungen mindestens über 3 Monate."

Metergolin is distributed in Germany and Italy under the name Liserdol.
I was able to get a prescripton for it and bought a 6 month cycle.

Can anybody say something or find more information to this medication? Could Metergolin be useful for PSSD?

[Kinncrimson]

Here are 4 studies, Metergoline antagonises 5-ht1a autoreceptors:

http://www.ncbi.nlm.nih.gov/pubmed/7690117
Are 5-HT1A autoreceptors involved in the inhibitory effect of ipsapirone on cold-elicited thyrotropin secretion?
Abstract
Administration of the serotonin (5-HT)1A receptor agonist ipsapirone has been shown to decrease cold-elicited thyrotropin (TSH) secretion. We have analyzed (1) the influence of 5-HT1A receptors and ipsapirone metabolism into 1-(2-pyrimidinyl)-piperazine (1-PP, an alpha 2-adrenoceptor antagonist) on the effect of ipsapirone on TSH release, and (2) the interaction between the corticosterone-releasing effect of ipsapirone and its inhibitory influence on TSH release. Pretreatment with proadifen (50 mg/kg, 5 h before ipsapirone), i.e. an inhibitor of ipsapirone metabolism into 1-PP, did not affect ipsapirone-induced inhibition of cold-elicited TSH secretion. Pretreatment (15 min before ipsapirone) with the 5-HT1/5-HT2 receptor antagonist metergoline 2 mg/kg) or with the 5-HT1A receptor blocker (-)-pindolol (5 mg/kg) increased baseline and cold-elicited TSH release but the inhibitory influence of ipsapirone on cold-elicited TSH release was alleviated by (-)-pindolol pretreatment only. Cold exposure increased corticosterone release, an effect which was insensitive to (-)-pindolol pretreatment. Lastly, pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine prevented the immediate inhibitory effect of the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) upon cold-induced TSH release, but it amplified the late release of TSH in cold-exposed 8-OH-DPAT-injected rats. These results suggest that presynaptic 5-HT1A receptors mediate ipsapirone-induced inhibition of cold-elicited TSH release, an effect which may be partially opposed by postsynaptic 5-HT1A receptor stimulation.

http://www.ncbi.nlm.nih.gov/pubmed/2958718
The serotonin (5-HT) autoreceptor in the hippocampus of the rabbit: role of 5-HT biophase concentration.
Abstract
Slices of hippocampus from the rabbit were preincubated with [3H]5-HT), then superfused continuously and twice stimulated electrically. The stimulation-evoked overflow of tritium was inhibited by the 5-HT autoreceptor ligands 5-carboxamido-tryptamine (5-COHT), 5-HT, 5-methoxy-N,N-dimethyl-tryptamine (5-MeOMT), (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), methysergide and (+/-)-cyanopindolol in a concentration-dependent manner. These effects were competitively inhibited by the 5-HT autoreceptor antagonists, metitepin and metergoline. (+/-)-Cyanopindolol also reduced the evoked release of 5-HT from slices of cortex from the rat. The inhibitor of the uptake of 5-HT, 6-nitroquipazine diminished the autoreceptor-mediated depression of release of 5-HT. In cortex tissue from the rat, 6-nitroquipazine reversed the decreased release of 5-HT, due to (+/-)-cyanopindolol, to a facilitation. The disinhibition of the release of 5-HT by autoreceptor antagonists was further enhanced by 6-nitroquipazine. Non-linear regression analysis of concentration-response curves for 5-COHT yielded the following pKd of endogenous 5-HT at the autoreceptor: 7.753 +/- 0.116. This value corresponds to the pKd of 5-HT at the 5-HT1B binding site. The 5-HT biophase concentration at the autoreceptor of 10(-8.220 +/- 0.132)M was markedly enhanced by 6-nitroquipazine (10(-6)M) to 10(-7.476 +/- 0.132)M. It is concluded that the 5-HT autoreceptor belongs to the 5-HT1B subtype of receptor; the corresponding 5-HT biophase concentration can be estimated quantitatively; 8-OH-DPAT decreased the evoked release of 5-HT through both 5-HT autoreceptors and alpha 2-heteroreceptors and (+/-)-cyanopindolol acts as partial agonist at the 5-HT autoreceptor.

http://www.ncbi.nlm.nih.gov/pubmed/6694097
ifferential actions of serotonin antagonists on two behavioral models of serotonin receptor activation in the rat.
Abstract
Ligand binding studies have identified certain serotonin (5-HT) antagonists with selective affinity for 5-HT2 receptors and other serotonin antagonists with affinity for both 5-HT1 and 5-HT2 receptors. This study compared the actions of ketanserin and pipamperone, selective 5-HT2 receptor antagonists, with metergoline and methysergide, nonselective 5-HT antagonists, on two behavioral responses in rats that are produced by the activation of 5-HT receptors: 1) the head shake response and 2) the 5-HT syndrome. Both the selective and the nonselective 5-HT antagonists blocked the head shake response produced by 5-hydroxy-L-tryptophan. The order of relative potency was: metergoline greater than ketanserin greater than pipamperone greater than methysergide. All four antagonists also blocked the head shake response produced by the 5-HT agonist quipazine. In contrast, the symptoms of the 5-HT syndrome produced by 5-methoxy-N,N-dimethyltryptamine were blocked by pretreatment with the nonselective 5-HT receptor antagonists but not by the 5-HT2 receptor antagonists. The differential actions of 5-HT antagonists on these behavioral responses suggest that different 5-HT receptors are involved in the head shake response and the 5-HT syndrome. That the order of relative potency for these drugs to block the head shake response was the same as their reported affinity for the 5-HT2 receptor suggests that the 5-HT2 receptor is involved in the head shake response. In contrast, the ability of 5-HT antagonists with affinity for the 5-HT1 receptor to block the 5-HT syndrome and the inability of 5-HT2 receptor antagonists to block the syndrome suggests that this behavioral response probably involves the activation of 5-HT1 receptors.

http://www.ncbi.nlm.nih.gov/pubmed/22290996
The unique effect of methiothepin on the terminal serotonin autoreceptor in the rat hypothalamus could be an example of inverse agonism.
Abstract
Slices of rat hypothalamus were pre-incubated with [(3)H] 5-hydroxytryptamine ([(3)H ] 5-HT), then superfused continuously and twice stimulated electrically. The effects of methiothepin, metergoline and alprenolol, all considered to be terminal 5-HT autoreceptor antagonists (although they also act at a number of other receptors), were studied. The stimulation-evoked overflow of tritium was increased by methiothepin in a concentration- dependent manner. The slight enhancing effect of alprenolol was not concentration dependent and metergoline, at concentrations which did not modify spontaneous outflow, was devoid of effect on evoked tritium overflow. The concentration-dependent inhibition by the terminal 5-HT autoreceptor agonist, lysergic acid diethylamide (LSD), of the electrically induced release of [(3)H] 5-HT was antagonized by methiothepin, alprenolol and metergoline. The stimulatory effect of methiothepin on tritium release was diminished by metergoline and by alprenolol at a concentration which slightly enhanced the evoked overflow of [(3)H ] 5-HT when given alone. Thus methiothepin induced an effect opposite to that of an agonist, in contrast to alprenolol and metergoline which under our conditions had no effect by themselves but reduced the effect of an agonist. In addition, the stimulating effect of methiothepin on release was reversed by two terminal 5-HT autoreceptor antagonists, alprenolol and metergoline. These results are consistent with methiothepin being an inverse agonist at the terminal 5-HT autoreceptor.

[Kinncrimson]

Here is some more information about Metergoline:

This book says Metergoline targets the 5-ht1a autoreceptor in the raphe:
https://books.google.at/books?id=GZ4ACA ... or&f=false

and this book says Metergoline is a 5-HT1A,1B,1C,1D antagonist:
https://books.google.at/books?id=kj3Jgr ... 1a&f=false

http://onlinelibrary.wiley.com/doi/10.1 ... x/abstract
Abstract
5-hydroxytryptamine (5-HT) (3 × 10−9 to 10−6 M) produced a concentration-related inhibition of potassium-evoked tritium release from slices of rat hypothalamus preloaded with [3H]-5-HT. The response to 5-HT was unaffected by the presence of yohimbine (10−6 M), pimozide (10−7 M), domperidone (10−7 M) or tetrodotoxin (10−7 M), indicating that the response was not mediated via α1- or α2-adrenoceptors or dopamine receptors and that the receptors that were involved were located directly on the 5-HT nerve terminal. The 5-HT antagonist metergoline (10−8 to 3 × 10−7 M) produced a parallel rightward shift in the concentration-effect curve to 5-HT with no reduction in the size of the maximum response. The pA10 value for metergoline was 6.82 and the slope of the Arunlakshana-Schild plot was not significantly different from 1.0 indicating that it was a competitive antagonist. Methiothepin produced a similar effect to metergoline whilst cyproheptadine and methysergide were less potent as antagonists of 5-HT and were not competitive. Cinanserin was inactive. Thus we have characterized the 5-HT autoreceptor in the rat hypothalamus using a classical pharmacological approach and found that it has more in common with the autoreceptor which we have previously identified in the raphe nuclei of the rat than it has with the 5-HT receptor located on dopamine neuroterminals in the striatum.

https://books.google.at/books?id=JkIfAw ... or&f=false

http://onlinelibrary.wiley.com/doi/10.1 ... 4630.x/pdf
"the classical 5-HT receptor antagonists, metergoline (5mgkg-1s.c.), methysergide (10mgkg-'s.c.) and methiothepin (10mgkg-1s.c.) each reduced dialysate levels of 5-HT which complicated their use as antagonists in these experiments. Nevertheless, pretreatment with metergoline but not methiothepin and methysergide partially
reduced the 5-HT response to a maximally effective dose of 8-OH-DPAT (0.25 mg kg'-s.c.)."


https://www.researchgate.net/publicatio ... tic_nerves
Abstract
The affinities of 16 5-hydroxytryptamine (5-HT) receptor agonists (indole derivatives) and 7 5-HT receptor antagonists for [3H]5-hydroxytryptamine [( 3H]5-HT) binding sites in rat cerebral cortex membranes were determined. In addition, the potencies of the agonists for inhibiting the electrically induced tritium overflow from rat brain cortex slices preincubated with [3H]5-HT and from canine saphenous veins preincubated with [3H]noradrenaline were measured. Furthermore, the potencies of the indole derivatives for inducing contractile responses of canine saphenous veins were recorded. In addition, the interaction of the antagonists with unlabelled 5-HT at the 5-HT autoreceptor was studied in rat brain cortex slices. There was a good correlation between the binding affinities of the indole derivatives for the [3H]5-HT sites of rat brain cortex membranes and their potencies for inhibiting the evoked tritium overflow from both rat brain cortex slices and strips of canine saphenous vein. Comparison of the inhibition constants derived from the overflow experiments in both tissues again revealed a high correlation coefficient while there was only weak correlation between the binding affinities in rat brain cortex and the contractile potencies of the drugs in canine saphenous vein strips. When 5-HT receptor antagonists were investigated, metitepin and metergoline showed moderate affinities for the 5-HT autoreceptors in rat brain cortex slices, whereas quipazine had only weak affinity, and ketanserin, metoclopramide, cinanserin and cyproheptadine exhibited no antagonistic property. In binding experiments, the competition curves of most 5-HT receptor antagonists were biphasic, suggesting that the [3H]5-HT binding sites are heterogeneous.

these are about prolactin:

https://www.ncbi.nlm.nih.gov/pubmed/1745704
Does metergoline selectively attenuate 5-HT mediated prolactin release?
Administration of the non-selective 5-HT receptor antagonist metergoline (0.5 mg/kg) to male rats attenuated the prolactin response to the 5-HT releasing agent d-fenfluramine (7.5 mg/kg) but not to the dopamine receptor antagonist haloperidol (1.5 mg/kg). In contrast, in healthy male volunteers, pretreatment with metergoline (4 mg orally) abolished the prolactin response to intravenous haloperidol (5 micrograms/kg). The findings suggest that in humans blockade of a prolactin response by a conventional oral dose of metergoline cannot be taken as evidence of involvement of 5-HT-mediated mechanisms.

https://www.ncbi.nlm.nih.gov/pubmed/7426830
Metergoline and cyproheptadine suppress prolactin release by a non-5-hydroxytryptaminergic, non-dopaminergic mechanism.
Abstract
A dispersed rat anterior pituitary cell system has been used to investigate the effects of cyproheptadine and metergoline on prolactin secretion. Both drugs were potent inhibitors of prolactin secretion. However, the inhibition was not antagonized by either 5-hydroxytryptamine or a variety of dopamine antagonists. We conclude that both drugs act through mechanisms that are neither 5-hydroxytryptaminergic nor dopaminergic.


https://www.ncbi.nlm.nih.gov/pubmed/2305017
Metergoline abolishes the prolactin response to buspirone.
Abstract
Pretreatment of nine healthy subjects with the non-selective 5-HT receptor antagonist, metergoline (4 mg), abolished the increase in plasma prolactin produced by the anxiolytic drug, buspirone (15 mg). While these findings are consistent with a role for 5-HT receptors in the stimulatory effect of buspirone on plasma prolactin, a dopaminergic mechanism cannot be excluded by the present data.

https://www.ncbi.nlm.nih.gov/pubmed/7472261
It is assumed that in these experimental conditions Metergoline inhibited Prolactin release by blockade of the central serotonin receptors in addition to its dopaminergic effect and that at low doses (0.1 mg/kg or less) the entire inhibiting effect of ME was probably due to its antiserotonergic activity.

Metergolin also seems to have mood lifting effects:

https://www.ncbi.nlm.nih.gov/pubmed/11910270
ouble-blind, placebo-controlled study of single-dose metergoline in depressed patients with seasonal affective disorder.
Abstract
A role for serotonin in season affective disorder (SAD) has been explored with a variety of serotonergic pharmacologic agents. The authors initially hypothesized that metergoline, a nonspecific serotonin antagonist, would exacerbate depressive symptoms. In a small, open-label pilot study, the authors observed the opposite effect. They decided to follow up on this finding with this formal study. The study followed a double-blind, randomized cross-over design. Sixteen untreated, depressed patients with SAD received single oral doses of metergoline 8 mg and of placebo, spaced 1 week apart. Fourteen patients were restudied after 2 weeks of light treatment. Depression ratings using the Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version were performed at baseline and at 3 and 6 days after each intervention. These data were analyzed by baseline-corrected repeated measures with analysis of variance. In the off-lights condition, severity of depression was diminished after metergoline compared with placebo administration (p = 0.001). Patient daily self-ratings suggested that the peak effect occurred 2 to 4 days after study drug administration. In contrast, after 2 weeks of treatment with bright artificial light, metergoline did not demonstrate a significant effect on mood. These data suggest that single doses of metergoline may have antidepressant effects that last several days. Possible mechanisms include 5-hydroxytryptamine(2) receptor downregulation and dopamine agonism.

[Kinncrimson]

Does really no one have some thoughts on this?

[Sonny]

I think this sounds good. One of the most promising things I've seen in a while.

[Kinncrimson]

I also think this sounds good, i am currently tapering off mianserin, so I can not start metergoline yet, but when I'm off the mianserin, I will start the treatment and report.... But I have one concern, when metergoline really is able to reverse some of the desensitisation of the 5-ht1a autoreceptor, what about the downregulation through antagonism of the 5-ht2a receptors? Let's say the 5-ht1-receptors are re-sensitised and now the 5-ht2-receptors are desensitized, what then?

[fablecloth]

I also think this sounds good, i am currently tapering off mianserin, so I can not start metergoline yet, but when I'm off the mianserin, I will start the treatment and report.... But I have one concern, when metergoline really is able to reverse some of the desensitisation of the 5-ht1a autoreceptor, what about the downregulation through antagonism of the 5-ht2a receptors? Let's say the 5-ht1-receptors are re-sensitised and now the 5-ht2-receptors are desensitized, what then?

5HT-2A antagonism may not be so bad. See this article on Trazodone, by Stahl: http://citeseerx.ist.psu.edu/viewdoc/do ... 1&type=pdf

On pages 3 and 4, you'll see comment on how antagonism of 5HT-2A and 2C receptors can prevent sexual dysfunction.

[Kinncrimson]

Thank you for this information.
I also looked around for this topic and it seems that 5-ht2a/2 is nothing to worry, I feel relieved. Mianserin is also a 5-ht2 and 5-ht1a antagonist, but unfortunatly only post-synaptic.
I can't wait to start the Metergoline, and I hope I can give you some hope then with the results....I hope it so much.

[ssinus]

Kinncrimson, isnt there any German PSSD site to ask people whether someone has tried it yet ?
Have you had some relief with mianserin ? I tried it twice, both times discontinued after short time, felt bad + it caused huge eye bags.
I have checked Liserdol, not available in Slovakia unfortunately - I would definitely give it a shot.

[Kinncrimson]

No, unfortunately there is nothing, I think no one has tried Metergoline for PSSD.

Mianserin was also bad for me, I totally understand what you mean, I didn't feel good, I felt sick, I was tired and even more depressed than before, but I told myself to persevere, it had to get better.
And I was right, pretty exact at the 3 month mark it felt better, far from great, but better. From now on the antidepressant-action was there and I sometimes could laugh and smile again, before it I NEVER could laugh or smile, because I was always thinking about PSSD. Also this went away a little, this self-destructive constant thinking about PSSD.
I think I can somewhat understand, what Louis Syfer meant with "he doesn't feel damaged by Antidepressants anymore".
Mianserin has also helped with anhedonia, before I often wasn't able to cook for myself or go to the grocery store, that got a lot better.
Also I am now dreaming more often.
This is about the psychological effects.
The two physical effects what I got from Mianserin are my Testosterone must be higher because I gained muscles and got mild acne on my back and my permanent diarrhea got less, before I had diarrhea EVERY day , now "only" every second day.

But I have to say Mianserin still doesn't feel "right" for me, I still feel tired sometimes, exhausted, also depressed sometimes and I feel drugged most of the time but the MOST important: it hasn't helped with libido by now.
And I am still unable to feel when I have to urinate.
This are the 2 main reasons that I'm tapering off now, I should be off the Mianserin in 2-3 months, then I would have taken it for 7 months overall.

And then I think I should give my body a little rest but after that I will start the Metergoline and I will report!

Here are two studies regarding Mianserin and anhedonia:

https://www.ncbi.nlm.nih.gov/pubmed/8148366
Curative effects of the atypical antidepressant mianserin in the chronic mild stress-induced anhedonia model of depression.
Abstract
This study was designed to validate a novel animal model of depression by testing the curative effects of the atypical antidepressant mianserin. In this paradigm, the hedonic state of rats was assessed using an intracranial self-stimulation (ICSS) procedure. The ICSS threshold was determined before, during and after a 38-day period of exposure to a variety of intermittent, unpredictable, mild stressors. After 11 days of this regimen, the ICSS threshold was significantly higher in the stressed rats, suggesting a gradual decrease of sensitivity to reward. This "anhedonia" lasted throughout the stress regimen and progressively diminished over a 20-day period after stress was terminated. When stressed animals exhibiting anhedonia were treated with mianserin, the stress-induced increase in the ICSS threshold was gradually reversed over ten days of treatment. These results provide further support for the value of this anhedonia paradigm in modelling an important aspect of human depressive disorders.

https://www.ncbi.nlm.nih.gov/pubmed/7701058
Stereospecific reversal of stress-induced anhedonia by mianserin and its (+)-enantiomer.
Abstract
Chronic sequential exposure to a variety of mild unpredictable stressors has previously been found to depress the consumption of a dilute (1%) sucrose solution and to inhibit food-induced place preference conditioning. In the present study, using a simplified version of the mild stress procedure, the decreased sucrose intake was reversed by chronic (4 weeks) treatment with the atypical antidepressant mianserin. The racemic compound (+/-)-mianserin (5 mg/kg per day) and one of its enantiomers, (+)-mianserin (2.5 mg/kg) were effective in this model; a lower dose of (+/-)-mianserin (2.5 mg/kg), and the other enantiomer. (-)-mianserin (2.5 mg/kg), were ineffective. Vehicle-treated stressed animals were also subsensitive to food reward in the place conditioning procedure: normal place preference conditioning was reinstated by chronic treatment with (+/-)-mianserin (5 mg/kg) or (+)-mianserin, but not by the lower dose of (+/-)-mianserin (2.5 mg/kg) or by (-)-mianserin. Raclopride (100 micrograms/kg) reinstated the decrease in sucrose intake in stressed animals successfully treated with (+/-)- or (+)-mianserin. The results suggest that (+)-mianserin is the active enantiomer in reversing chronic mild stress-induced anhedonia, and further support the hypothesis of a dopaminergic mechanism of antidepressant action in this paradigm.

And here are two very interesting studies, about Mianserin and serotonin levels, unlike Mirtazapine it doesn't increase brain serotonin levels, it decreases it:

https://www.ncbi.nlm.nih.gov/pubmed/8627567
Differences in modulation of noradrenergic and serotonergic transmission by the alpha-2 adrenoceptor antagonists, mirtazapine, mianserin and idazoxan.
Abstract
The effects of three compounds with alpha-2 adrenoceptor antagonistic properties, mirtazapine (Org 3770; Remeron), mianserin and idazoxan, were measured on hippocampal noradrenergic and serotonergic transmission in freely moving rats by using microdialysis. Dihydroxyphenylacetic acid (DOPAC) was measured as a correlate of noradrenergic presynaptic activity. Infusing 1 microM tetrodotoxin decreased extracellular serotonin (5-HT) and DOPAC by 65 and 40%, respectively. 5-Hydroxytryptophan (25 mg/kg s.c.) increased extracellular 5-HT by 500%, whereas 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (0.5 mg/kg s.c.) decreased 5-HT release by 60%. Prazosin decreased 5-HT release to 60% of base-line in agreement with an alpha-1-mediated control of 5-HT transmission, whereas it increased DOPAC release with 80%. Both mirtazapine (2 and 5 mg/kg s.c.) and idazoxan (1 mg/kg s.c.) caused a rapid increase in DOPAC by up to 80%. Mianserin slowly increased DOPAC, reaching a maximal increase of 30 and 60% at 2 and 5 mg/kg s.c., respectively. Only mirtazapine caused a concurrent increase in 5-HT, reaching up to 80% above base-line within 60 min, whereas mianserin and idazoxan failed to change 5-HT levels significantly. Mirtazapine (5 mg/kg s.c.) only slightly affected DOPAC and homovanillic acid levels in the striatum, hardly affected 5-HT release, but clearly increased 5-hydroxyindole acetic acid. Thus, the antidepressants mirtazapine and mianserin markedly differ in their effects on noradrenergic and serotonergic transmission in vivo as measured with microdialysis in freely moving rats. These differences are explained by their different modulatory effects on noradrenergic transmission.

https://www.ncbi.nlm.nih.gov/pubmed/15193954
Effect of treatment at weaning with the serotonin antagonist mianserin on the brain serotonin and cerebrospinal fluid nocistatin level of adult female rats: a case of late imprinting.
Abstract
Four weeks old (weanling) female rats were treated with the tricyclic antidepressant and histamine/serotonin receptor blocker mianserin for studying its faulty hormonal imprinting effect. Measurements were done four months later. Brain serotonin levels significantly decreased in four regions (hippocampus, hypothalamus, striatum and brainstem), without any change in the cortex. Sexual activity of the treated and control rats was similar. Cerebrospinal fluid nocistatin level was one magnitude higher in the treated rats, than in the controls. The density of uterine estrogen receptors was significantly reduced, while binding capacity of glucocorticoid receptors of liver and thymus remained at control level. The results call attention to the possibility of 1. a broad spectrum imprinting at the time of weaning by a receptor level acting non-hormone molecule 2. imprinting of the brain in a non-neonatal period of life and 3. a very durable (lifelong?) effect of the late imprinting with an antidepressant.